Skin whitening: Difference between revisions

Content deleted Content added

Inline

Revision as of 22:56, 7 August 2016

Skin whitening^{[notes 1]} is the practice of using substances, mixtures, or physical treatments to lighten skin color. Skin whitening treatments work by reducing the content of melanin of the skin. Many agents have been shown to be effective in skin whitening; some have beneficial side effects (e.g: are antioxidants,^[1] nutrients, or decrease the risk of some types of cancer); some are a significant risk to health (for example, those containing mercury).

Uses

Specific zones of abnormally high pigmentation such as lentigo spots, moles and birthmarks may be depigmented to match to the surrounding skin. In cases of vitiligo, unaffected skin may be lightened to achieve a more uniform appearance.

In India, the sales of skin lightening creams in 2012 totaled 258 tons^[2] and the global market for skin lighteners is projected to reach US $19.8 billion by 2018 based on sales growth primarily in Asia, Africa and the Middle East.^[3]

Discovery and design

Melanogenesis inhibitors have been discovered and developed through several methods, including: screening of synthetic chemical libraries (high throughput screening is occasionally used), screening of plant extracts,^[4] computational (in silico) search,^[5]^[6] found as a side effect of previously known drugs^[7]^[8]^[9]^[10] and exploration of structural analogues of previously known tyrosinase inhibitors^[11]^[12] based on knowledge (in varying degrees) of their structure-activity relationship. Thus, the development and discovery of melanogenesis inhibitors illustrates many of the methods used in drug design. Some of the most potent competitive reversible tyrosinase inhibitors are synthetic compounds with a potency hundreds of times that of kojic acid.

Mechanisms of action

For a review of mechanism of action of skin whitening agents, see Chang (2012)^[13] or Ebanks, Wickett, Boissy (2009).^[14]

Melanin is the main substance responsible for the color of the skin. Melanin is class of dark polymers generated by the body through the process of melanogenesis. Among the melanin pigmenting the skin and hair, 2 types can be distinguished based on its chemical composition and biological route of synthesis: the black/brown eumelanin and the red/yellow pheomelanin. The variation of skin color among individuals is mostly because of variation of the content of melanin in the skin. Skin with little or no melanin is almost white. Other factors influence skin color in a lesser degree, including the amount of blood in blood vessels (because of the color of blood), skin thickness and content of carotenoids in skin.^[15]^[16]

Melanin in synthesized in melanosomes which are organelles produced in melanocytes. Melanocytes are cells dedicated to this function that are present in the skin, hair follicles, and other structures of the body. The synthesis of melanin (also called "melanogenesis" and "melanization") involves a chain of enzyme-catalyzed chemical reactions and non-enzyme-catalyzed reactions.^{[notes 2]} The main precursor to melanin is L-tyrosine. The first step of melanogenesis is the conversion of L-tyrosine to L-DOPA; this is the first and rate-limiting step and is catalized by the enzyme tyrosinase (TYR).^[18]^: 1163 Other enzymes involved in the synthesis include tyrosinase-related protein 1 (TRP1) and tyrosinase-related protein 2 (TRP2); TRP2 is also known as "dopachorome tautomerase" (DCT). L-tyrosine is taken by the melanocytes from the intercellular medium, then transported to the melanosomes. L-tyrosine is also synthesized within the melanocytes from L-phenylalanine by the enzyme phenylalanine hydroxylase (PAH).^[18]^: 1164

Melanosomes are transferred to keratinocytes (the most abundant cell type in the skin). Most of the melanin of skin is found in keratinocytes. Additionally, melanocytes interact with keratinocytes through chemical signaling. See § Preventing the transfer of melanosomes to keratinocytes.

Skin whitening agents work by reducing the presence of melanin in the skin. To accomplish this, there are several possible mechanism of actions:^{[notes 3]}^[14]

Inhibition of the activity of tyrosinase: The catalytic action of tyrosinase is inhibited (slowed or nearly stopped) by the skin whitening agent.
Inhibition of the expression or activation of tyrosinase: The antimelanogenic agent causes that less tyrosinase is generated or that tyrosinase is not activated to its functional form.
Scavenging of the intermediate products of melanin synthesis.
Preventing the transfer of melanosomes to keratinocytes.
Directly destroying existing melanin.
Destroying melanocytes.

Inhibition of the activity of tyrosinase

Many tyrosinase inhibitors have been discovered or developed. Very many inhibitors of tyrosinase are known; most are of the reversible type.^{[notes 4]} For a review of tyrosinase inhibitors see Chang (2009).^[4] Reviews of patents on tyrosinase inhibitors have been published.^[19]^[20]

Evaluation of effectivity:^{[notes 5]} The potency (how little of a substance is needed to achieve an effect) of reversible inhibitors is usually given in terms of its IC₅₀. The IC₅₀ is highly dependent on the assay conditions, making it incomparable among different assays (unless designed to be comparable). It is customary practice in studies of tyrosinase inhibitors to assay one or several well known inhibitors as a positive control and point of comparison. The relative activity (RA) of a compound under investigation is its activity divided by the activity of the positive control; in turn the activity of a compound is usually defined as 1/IC₅₀. The RA is less dependent on assay conditions that the IC₅₀ and is suitable to compare the results of different assays provided the same positive control was used. The positive control is commonly kojic acid.

Upregulation of tyrosinase caused by tyrosinase inhibitors: Several skin whitening agents including some which are tyrosinase inhibitors have been found to cause an increase in the expression of tyrosinase (which by itself would increase melanin synthesis).^[21]^[13]

Irreversible inhibitors of tyrosinase include: nonyl trans-caffeate,^[22] α-Na₈SiW₁₁CoO₄₀ (a polyoxometalate),^[23] a structural analog of aloe emodin,^[24] structural analogues of barbituric acid,^[25]^[26]^[27] structural analogues of chalcone,^[28] sodium hydrogen sulfite,^[29] structural analogues of coumarin,^[30] structural analogues of the following 2 compounds: benzene-1,2-diamine and 2-aminophenol, and 2,3-dihydroxybenzoic acid itself,^[31] tetrahydrofolic acid,^[32] analogues of pyrimidine and rhodanine,^[33] tetrahydropterines,^[34] cardol triene (a triene analogue of cardol extracted from cashew),^[35] N-(3,5-dihydroxybenzoyl)-6-hydroxytryptamine,^[36] aminoethylisothiourea,^[37] 8-hydroxynaringenin,^[38] NADH,^[39] 8-hydroxydaidzein^[40] and captopril.^[10]

Inhibition of the expression or activation of tyrosinase

Microphthalmia-associated transcription factor (MITF) is the master transcription factor that controls the expression of TYR, TRP1 and TRP2, MART1, PMEL17 and many other important proteins involved in the function of melanocytes.^{[notes 6]} Downregulation of MITF decreases melanogenesis^{[notes 6]} and is a mechanism of action of some skin whitening agents.^[13]^[41] As an heuristic rule, agents acting through downregulation of MITF are more likely to have side effects that selective tyrosinase inhibitors.^{[notes 7]} Various signaling pathways and genetic mutations mutations influence the expression of MITF.^{[notes 8]}^[44]^[45]

Inhibitors of melanogenesis whose mechanism of action includes reducing the genetic expression of melanogenic enzymes include caffeoylserotonin,^[46] AP736,^[47] pomegranate extract,^[48] betulinic acid (extracted from Vitis amurensis root),^[49] and

The MC1R receptor and cAMP

The melanocortin 1 receptor (MC1R) is a transmembrane and G-protein coupled receptor expressed in melanocytes. MC1R is an important target for the regulation of melanogenesis.^[50]^[51]^[42] Agonism (i.e: activation) of MC1R increases the ratio of eumelanin to pheomelanin and increases the generation of melanin overall.

MC1R/cAMP signaling pathway:^{[notes 8]}^{[notes 9]}^[50]^[51]^[52] Activation of MC1R causes activation of adenylyl cyclase (AC), which produces cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA), which activates (by protein phosphorylation) cAMP response element-binding protein (CREB), which upregulates MITF (CREB is a transcription factor of MITF). Whitening agents that interfere with the MC1R/cAMP signaling pathway have been reviewed by Chang (2012).^[13]

cAMP is degraded by phosphodiesterases (PDE). The PDE5 inhibitors sildenafil and vardenafil, the cAMP-promoter IBMX and 8-CPT-cGMP (a cyclic guanosine monophosphate (cGMP) analogue) increase melanin synthesis.^[53]

MC1R ligands: alpha-melanocyte stimulating hormone (α-MSH),^{[notes 9]} beta-melanocyte stimulating hormone (β-MSH) and adrenocorticotropic hormone are endogenous agonists of MC1R.^[18]^: 1175 Agouti signaling protein (ASIP) appears to be the only endogenous antagonist of MC1R.^{[notes 10]} Synthetic MC1R agonists have been designed; examples include the peptides afamelanotide and melanotan II.^[50]

Mutations of the MC1R gene correlate, and in some individuals are at least partially responsible for red hair, white skin and an increased risk for skin cancer.^{[notes 11]}^[50]^[55]^[51]^[56]^[57]^[58]^[59]^[60]^[18]^: 1175

Serotonin signaling

Melanocytes express serotonin receptors and are capable of producing serotonin. Pharmacological interference with the serotonin system of melanocytes can result in either increased or decreased melanin synthesis. Serotonin itself is a weak inhibitor of tyrosinase^[61] with 0.11 times the potency of kojic acid.^{[notes 12]} Nonetheless, serotonin increases synthesis of melanin when its overall effect on melanocytes (as opposed to isolated tyrosinase) is evaluated.^[62] Activation of 5-HT_2B receptors with BW-723C86 inhibits melanogenesis^[63] while activation of 5-HT_2A receptors with the amphetamine structural analog DOI promotes melanogenesis.^[64] The serotonin reuptake inhibitor (SRI) 6-nitroquipazine inhibits melanogenesis in-vitro.^[65]

Preventing the transfer of melanosomes to keratinocytes

For an overview of the interaction between keratinocytes and melanocytes see Yamaguchi, Hearing (2009).^[42]

Keratinocytes in the skin: Within the skin, melanocytes are present in the basal layer of the epidermis; from these melanocytes originate dendrites that reach keratinocytes.^{[notes 13]} Keratinocytes are the most abundant cell type in the epidermis.^{[notes 14]} In the skin, there are approximately 36 keratinocytes per melanocyte.^{[notes 13]} Keratinocytes are continuously generated in the basal layer of the epidermis and displace older keratinocytes of the skin towards the surface.

Melanosome transfer: Melanosomes along with the melanin they contain is transferred from melanocytes to keratinocytes when keratinocytes are low in the epidermis.^{[notes 15]} Keratinocytes carry the melanosomes with them as they move towards the surface. Keratinocytes contribute to skin pigmentation holding the melanin originated in melanocytes and induce melanogenesis through chemical signals directed at melanocytes.^{[notes 8]} The transfer of melanosomes to keratinocytes is a necessary condition for the visible pigmentation of the skin.^[66] Blocking this transfer is a mechanism of action of some skin whitening agents.^[41]^[14] Skin whitening agents that block melanocyte transfer include niacinamide, heparin,^[67] madecassoside,^[68] soybean^[69] and Saccharomyces cerevisiae (a species of yeast).^[70]

The protease-activated receptor 2 (PAR2) is a transmembrane and G-protein coupled receptor expressed in keratinocytes and involved in melanocyte transfer.^{[notes 16]}^{[notes 17]} Antagonists of PAR2 inhibit the transfer of melanosomes and have a skin whitening affects while agonists of PAR2 have the opposite effect, as expected.^{[notes 17]} The common endogenous agonists of PAR2 are serine proteases which irreversibly activate PAR2 by cleaving a part of the extracellular terminal of this receptor thereby exposing a part of it that subsequently works as a ligand tethered to the reset of the receptor at the molecular scale. Some synthetic agonists of PAR2 are short peptides that imitate the aforesaid tethered ligand but do not cleave the extracellular terminal.

Directly destroying existing melanin

Several species of fungi produce enzymes that reduce pigmentation by degrading melanin.^[75] These enzymes often require the presence of hydrogen peroxide and sometimes the presence of Mg⁺² ions to work.^[75] They have been proposed as a safer alternative to hydrogen peroxide for cosmetic hair depigmentation.^[75]

The enzyme lignin peroxidase produced by the fungus phanerochaete chrysosporium has been studied as an ingredient suitable for skin-whitening: A double-blind placebo-controlled split-face randomized study found this enzyme to be effective and superior to hydroquinone in skin whitening.^[76] In a non-controlled study, this enzyme was applied to volunteers with facial melasma during 8 weeks; the treatment was found effective in reducing pigmentation in both skin affected by melasma and skin unaffected by melasma.^[77]

Destroying melanocytes

Some compounds are known to destroy melanocytes; this mechanism of action is often used to remove the remaining pigmentation in cases of vitiligo.^[78]^[79]

Non-pharmacological treatments

Most skin-lightening treatments, which can reduce or block some amount of melanin production, are aimed at inhibiting tyrosinase. Many treatments use a combination of topical lotions or gels containing melanin-inhibiting ingredients along with a sunscreen, and a prescription retinoid. Depending on how the skin responds to these treatments, exfoliants ‒either in the form of topical cosmetic or chemical peels‒ and lasers may be used. New development using LED systems are also showing good results.^[80]^[81]^[82]^[83]^[84]

Whitening agents

Pre-melanin synthesis

Tretinoin

Research has shown that the use of tretinoin (also known as all-trans retinoic acid) can only be somewhat effective in treating skin discolorations.^[81]^[85]^[86]^[87] Users of tretinoin have to avoid sunlight, as the skin can tan. Using tretinoin always makes the skin more sensitive to UVA and UVB rays.

During melanin synthesis

Hydroquinone

In medical literature, hydroquinone is considered the primary topical ingredient for inhibiting melanin production.^[88]^[89]^[90]^[91] Its components have potent antioxidant abilities.^[92] Topical hydroquinone comes in 2% (available in cosmetics) to 4% (or more) concentrations (available from a physician or by prescription), alone or in combination with tretinoin 0.05% to 0.1%. Research has shown hydroquinone and tretinoin to prevent sun- or hormone-induced melasma.^[81]

Hydroquinone is a strong inhibitor of melanin production, meaning that it prevents dark skin from making the substance responsible for skin color.^[93] Hydroquinone does not bleach the skin but lightens it, and can only disrupt the synthesis and production of melanin hyperpigmentation. It has been banned in all European countries (e.g. France) because of fears of a cancer risk.

Some concerns about hydroquinone's safety on skin have been expressed, but the research when it comes to topical application indicates negative reactions are minor or a result of using extremely high concentrations or from other skin-lightening agents such as glucocorticoids or mercury iodine. Any perceived risk is most likely applicable for African women.^[94] Hydroquinone has been shown to cause leukemia in mice and other animals. The European Union banned it from cosmetics in 2001, but it shows up in bootleg creams in the developing world. It is sold in the United States as an over-the-counter drug, but with a concentration of hydroquinone not exceeding 2 percent.^[95]

Because of hydroquinone's action on the skin, it can be an irritant, particularly in higher concentrations of 4% or greater and predictably when combined with tretinoin. Some medications have been created that combine 4% hydroquinone with tretinoin and a form of cortisone. The cortisone is included as an anti-inflammatory. The negative side effect of repeated application of cortisone is countered by the positive effect of the tretinoin so that it does not cause thinning of skin and damage to collagen.^[96]

Arbutin

Some of alternative lighteners are derived from natural sources of hydroquinone. These include Mitracarpus scaber extract, Uva ursi (bearberry) extract, Morus bombycis (mulberry), Morus alba (white mulberry), and Broussonetia papyrifera (paper mulberry). All of these contain arbutin (technically known as hydroquinone-β-D-glucoside), which can inhibit melanin production. Pure forms of arbutin are considered more potent for affecting skin lightening.

Arbutin is derived from the leaves of bearberry, cranberry, mulberry or blueberry shrubs, and also is present in most types of pears. It can have melanin-inhibiting properties.^[97] Arbutin and other plant extracts are considered safe alternatives to commonly used depigmenting agents to make the skin fairer. Medical studies have shown the efficiency of arbutin for skin lightening.^[98]^{[failed verification]} There are patents controlling its use for skin lightening. Arbutin actually exists in two isomers, alpha and beta. The alpha isomer offers higher stability over the beta isomer and is the preferred form for skin lightening indications.

Kojic acid

Kojic acid is a by-product in the fermentation process of malting rice for use in the manufacturing of sake, the Japanese rice wine. Some research shows kojic acid to be effective for inhibiting melanin production.^[99] However, kojic acid is an unstable ingredient in cosmetic formulations. Upon exposure to air or sunlight it can turn brown and lose its efficancy. Many cosmetic companies use kojic dipalmitate as an alternative because it is more stable in formulations. However, there is no research showing kojic dipalmitate to be as effective as kojic acid, although it is a good antioxidant. Further, some controversial research has suggested that kojic acid may have carcinogenic properties in large doses.^[100] Other further studies show that kojic acid is not carcinogenic, but can cause allergic contact dermatitis^[101] and skin irritation.^[102]^[103]

Azelaic acid

Azelaic acid is a component of grains, such as wheat, rye, and barley. It is applied topically in a cream formulation at a 10-20% concentration. Azelaic acid is used to treat acne, but there also is research showing it to be effective for skin discolorations.^[104] Other research also indicates azelaic acid may be an option for inhibiting melanin production.^[80]

Vitamin C

Vitamin C and its various forms (ascorbic acid, magnesium ascorbyl phosphate, etc.) are considered an effective antioxidant for the skin and help to lighten skin.^{[medical citation needed]} One study^[105] found it raises glutathione levels in the body. Another study found that brownish guinea pigs given vitamin C, vitamin E and L-cysteine, simultaneously, led to lighter skin.^[106]

Glutathione

Glutathione is a tripeptide molecule found in mammalian bodies. It is an antioxidant that plays an important role in preventing oxidative damage to the skin. In addition to its many recognized biological functions, glutathione has also been associated with skin lightening ability.

A double-blind placebo-controlled study found glutathione to be effective as a skin whitening agent and in reducing dark spots; the dose regime was 500 mg per day (split in 2 equal doses per day) for 4 weeks.^[107] In contrast, a study that examined the effect of glutathione and related compounds in-vitro found that glutathione monoethyl ester but not glutathione had a depigmenting effect.^[108] A review of the use of glutathione for skin whitening was published in 2016.^[109]

Glutathione is an ingredient in some cosmetics preparations. Glutathione for skin whitening is available in cream, soap, lotion, nasal spray and injectable form. Glutathione that is applied on the skin in the form of lotion is not efficiently absorbed by the skin cells as the thiol group undergoes rapid formation of disulfide. When taken orally, glutathione is hydrolyzed by enzymes in the gastrointestinal tract resulting in reduced bioavailability. The level of glutathione increased in smalls amounts temporarily when large oral doses were administered.^[110] As a result, the effectiveness of externally administered glutathione is slowed down by its inability to cross cell membranes efficiently and its rapid degradation by enzymes in the gastrointestinal tract. On the contrary, intravenous glutathione delivers very high doses directly into the systemic circulation and is the preferred mode of administering glutathione. However, this method of administrating the antioxidant might flood the cells with glutathione that may cause reductive stress. This might expose people to potential health risks associated with long-term use of high dose of glutathione.

Glutathione can be combined with many other agents like vitamin C to increase its absorption, N-acetyl cysteine to boost its level, and other antioxidants like vitamin E. Some oral intake of glutathione could have dangerous effect when combined with other skin whitening agents such as hydroquinone which is a carcinogenic element and monobenzone which causes irreversible depigmentation.

Post-melanin synthesis

Alpha hydroxy acids

Alpha hydroxy acids (AHAs) — primarily in the form of lactic acid and glycolic acid — are the most researched forms of AHAs because they have a molecular size that allows effective penetration into the top layers of skin. It is generally assumed that in and of themselves AHAs in concentrations of 4% to 15% are not effective for inhibiting melanin production and will not lighten skin discolorations in that manner. It is believed that their benefit is in helping cell turnover rates and removing unhealthy or abnormal layers of superficial skin cells (exfoliation) where hyperpigmented cells can accumulate. However, other research has shown that lactic and glycolic acids can indeed inhibit melanin production separate from their actions as an exfoliant on skin.^[111]

Alpha hydroxy acid peels (using 50% concentrations or greater) may remove skin discolorations. Only a qualified physician should perform these types of facial peels.^[112]

Niacinamide

Niacinamide is claimed to be a much safer alternative when applied topically for skin or genitalia whitening. According to research by Procter & Gamble, a cosmetics company, niacinamide has no adverse side-effects. It also promotes acne reduction, increases skin moisture, and reduces fine wrinkles.^[113]

Other/ungrouped

Depigmenting agents

Most commonly, depigmentation of the skin is linked to people born with vitiligo, which produces differing areas of light and dark skin. These individuals, if they so decided to use a lightening process to even out their skin tone, could apply a topical cream containing the organic compound monobenzone to lessen the remaining pigment. Monobenzone may cause destruction of melanocytes and permanent depigmentation. An alternate method of lightening is to use the chemical mequinol over an extended period of time. Increasingly, people who are not afflicted with the vitiligo experiment with lower concentrations of monobenzone creams in the hope of lightening their skin tone evenly. However, monobenzone is not recommended for skin conditions other than vitiligo.

Mercury

Many skin whiteners contain toxic mercury, such as mercury(II) chloride or ammoniated mercury as the active ingredient. However, mercury has been banned in most countries for use in skin whitening (1976 in Europe, 1990 in the USA) because it accumulates on skin and it can have the opposite results in the long term. As late as January 2016, the FDA published a warning not to use a particular brand of whitener - Viansilk’s "Crema Piel De Seda" ("Silky Skin Cream"), sold in the United States due to its mercury content.^[114]

Other

Other options with some amount of research regarding their potential skin lightening abilities are licorice extract (specifically glabridin).

There is also a small amount of research showing oral supplements of pomegranate extract, ellagic acid, vitamin E, and ferulic acid can inhibit melanin production.^[115]

Laser treatments

Both ablative and nonablative lasers can have a profound effect on melasma^{[citation needed]}. However, the results are not always consistent, and problems have been reported (such as hypo- or hyperpigmentation). Laser treatments of this kind are more likely to result in problems for those with darker skin tones.^[116]

Cryosurgery

Another alternative to laser treatment is cryosurgery using liquid nitrogen. Controlled destruction of skin cells causes the skin to naturally regenerate itself. Excess melanin comes to the surface and peels off in a few days. This is particularly useful in sensitive areas like the genitals where laser treatment could leave a scar. Efficacy of the treatment depends on the depth of the pigment. Freckles in any part of the body can be treated the same way.^{[citation needed]}

Controversy and negative health effects

There is evidence to suggest that some types of skin-whitening products use active ingredients (such as mercurous chloride) and hydroquinone which can be harmful.^[117] Hydroquinone had been banned in Europe. However, it is now available again but only when prescribed by a medical doctor. This is also the case in many other countries, where hydroquinone can only be prescribed by a doctor for certain skin conditions.

A test of common skin lightening creams available in Nigeria showed that they caused mutations in bacteria and were possibly carcinogenic.^[118] A study that examined skin whitening creams in Mexico found an high concentration of mercury in several of them.^[119]

Notes

Italics have been preserved whenever they appear in quotations. Text between square brackets are additional notes not present in the source.

^ Instead of "whitening", the terms "lightening", "brightening", "depigmentation" and "bleaching" are also used.
^ The chemical pathways of the synthesis of melanin has been described by many papers; however, it is often oversimplified. The following references are suggested: Kondo, Hearing (2011),^[17] Chang (2009)^[4] and Slominski et. al. (2004).^[18]
^ "In addition to inhibition of tyrosinase catalytic activity, other approaches to treat hyperpigmentation include inhibition of tyrosinase mRNA transcription, aberration of tyrosinase glycosylation and maturation, acceleration of tyrosinase degradation, interference with melanosome maturation and transfer, inhibition of inflammation-induced melanogenic response, and acceleration of skin turnover. Accordingly, a huge number of depigmenting agents or whitening agents developed by those alternative approaches have been successfully identified and deeply reviewed in many articles [references omitted]."^[4]
^ "In contrast to the huge number of reversible inhibitors has been identified, rarely irreversible inhibitors of tyrosinase were found until now. These irreversible inhibitors, which are also called specific inactivators, can form irreversibly covalent bond with the target enzyme and then inactivate it."^[4]
^ "Inhibitor strength is usually expressed as the inhibitory IC₅₀ value, which is the concentration of an inhibitor needed to inhibit half of the enzyme activity in the tested condition. However, for the tyrosinase inhibitors in the literature, the IC₅₀ values are incomparable due to the varied assay conditions, including different substrate concentrations, varied incubation time, and different batches of commercial tyrosinase. Fortunately, in most studies conducted to discover new tyrosinase inhibitors, a well-known tyrosinase inhibitor such as kojic acid is often used as a positive standard at the same time. Hence, in order to compare the inhibitors described in different literature in a more practical manner, a relative inhibitory activity (RA), which is calculated by dividing the IC₅₀ value of kojic acid with that of a newly found inhibitor in the same report, is used to express and compare the inhibitory strength of an inhibitor with others in this review."^[4]
^ ^a ^b "The transcriptional level is the first stage by which the expression of tyrosinase and related melanogenic enzymes may be modulated. Influential in this process, the microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor that regulates melanocyte cellular differentiation as well as the transcription of melanogenic enzymes (tyrosinase, TYRP1 and TYRP2) and melanosome structural proteins (MART-1 and PMEL17) [references omitted]."^[14]

"In addition to being involved in the survival, proliferation, and differentiation of melanocytes, MITF is the master regulator of melanogenesis in melanocytes via binding to the M box of a promoter region and regulating the gene expression of tyrosinase, TRP-1, and TRP-2 [references omitted]. The up-regulation of MITF activity activates the expression of the melanogenesis-related enzymes, thus stimulating melanogenesis. In contrast, the down-regulation of MITF activity depresses the expression of the related enzymes, thereby inhibiting melanogenesis."^[13]
^ "Because tyrosinase is produced only by melanocytic cells, tyrosinase inhibitors have highly specific targeting to melanogenesis in the cells without other side effects. In contrast, those melanogenesis inhibitors targeting to the tyrosinase gene expressions or protein degradations are rarely used as clinical hypopigmenting agents, due to their non-specific and global effects via intracellular signaling pathways."^[13]
^ ^a ^b ^c Many papers have described the signaling pathways affecting melanogenesis and other functions of melanocytes. The following reviews are suggested reading (all of which are available online at no cost):

For a description with emphasis on the relation with skin whitening, see Chang (2012)^[13] or Smit, Vicanova, Pavel (2009).^[41] For a description with emphasis on physiology, see Yamaguchi, Hearing (2009)^[42] or Kondo (2011).^[17] For a description of intra-melanocyte signaling pathways, see Imokawa, Ishida (2014).^[43] An extensive and detailed review was written by Slominski et. al. (2004).^[18]
^ ^a ^b "Alpha melanocyte-stimulating hormone (α-MSH), a peptide derived from proopiomelanocortin (POMC), regulates melanogenesis via a cyclic adenosine monophosphate (cAMP)-dependent pathway [references omitted]. When binding to its receptor, melanocortin receptor 1 (MC1R), on the membrane of melanocytes, the hormone activates adenylate cyclase (AC) to produce cAMP as an intracellular second message via a G-protein-coupled receptor (GPCR)-type activation. cAMP activates protein kinase A (PKA), which then activates the gene expression of MITF via phosphorylation of the cAMP response element-binding protein (CREB). Finally, MITF efficiently activates the melanogenesis-related enzymes and stimulates melanogenesis. Once α-MSH binds to MC1R, up to a 100-fold increase in melanogenesis attends. In addition to α-MSH, other POMC-derived peptides, such as β-MSH and adrenocorticotropic hormone (ACTH), also stimulate melanogenesis via the same pathway."^[13]

"α-MSH binding to melanocortin 1 receptor (MC1R) on melanocytes in the basal epidermis generates the second messenger cAMP via interactions between MC1R and adenylyl cyclase, and leads to activation of protein kinase A and the cAMP responsive binding element (CREB) and microphthalmia (Mitf) transcription factors. CREB and Mitf directly enhance melanin production by raising levels of tyrosinase and other melanin biosynthetic enzymes. Thus, MSH-MC1R signaling leads to enhanced pigment synthesis by melanocytes and accumulation of melanin by epidermal keratinocytes.
[etcetera]
The MC1R is found on the surface of melanocytes where it binds to α-melanocyte stimulating hormone (MSH) and transmits differentiation signals into the cell through activation of adenylyl cyclase and generation of cAMP [references omitted]. cAMP signaling leads to activation of the protein kinase A (PKA) cascade which, in turn, leads to increased levels and/or activity of many melanogenic enzymes to enhance production and export of melanin by melanocytes [references and figure omitted]."^[54]
^ The assertion that ASIP is the only endogenous antagonist is found in Yamaguchi, Hearing (2009).^[42]
^ "Loss-of-signaling MC1R polymorphisms are commonly found among fair-skinned, sun-sensitive and skin cancer-prone populations (e.g., Northern Europeans). The most prevalent MC1R mutations (D84E, R151C, R160W and D294H) are commonly referred to as “RHC” (red hair color) alleles because of their association with red hair color, freckling and tendency to burn after UV exposure [references omitted]."^[54]
^ Computed from the data reported by Yamazaki et. al. (2009):^[61] IC₅₀(serotonin)=550 µmol/l. IC₅₀(kojic acid)=68 µmol/l.
^ ^a ^b "In the skin, melanocytes are situated on the basal layer which separates dermis and epidermis. One melanocyte is surrounded by approximately 36 keratinocytes. Together, they form the so-called epidermal melanin unit. The melanin produced and stored inside the melanocyte in the melanosomal compartment is transported via dendrites to the overlaying keratinocytes."^[41]

"Each melanocyte resides in the basal epithelial layer and, by virtue of its dendrites, interacts with approximately 36 keratinocytes to transfer melanosomes and protect the skin from photo-induced carcinogenesis. Furthermore, the amount and type of melanin produced and transferred to the keratinocytes with subsequent incorporation, aggregation and degradation influences skin complexion coloration [reference omitted]."^[14]

Wu, Hammer (2014) describe the number of keratinocytes per melanocyte as above 40.^[66]
^ "Keratinocytes are the most abundant cells in the epidermis and are characterized by their expression of cytokeratins and formation of desmosomes and tight junctions with each other to form an effective physicochemical barrier."^[54]
^ Research about the mechanism of melanosome transfer has been reviewed by Wu, Hammer (2014).^[66]
^ "Protease-activated receptor (PAR)-2 is a member of a novel G-protein-coupled seven-transmembrane receptor family. In epidermis, PAR-2 is expressed in keratinocytes [references omitted], but not melanocytes [references omitted]. A central role for PAR-2 in keratinocyte uptake of melanosomes has been established [references omitted]. PAR-2 has been linked to the upregulation of COX-2 and the release of arachidonic acid and secretion of PGE2 and PGF2α [references omitted]. Several reports have suggested that PAR-2 mediates cutaneous pigmentation through increased uptake of melanosomes by keratinocytes and by the release of PGE2 and PGF2α that stimulate melanocyte dendricity [references omitted]."^[68]
^ ^a ^b References about PAR2 and its role in skin pigmentation: Kim (2016),^[71] Choi (2014),^[72] Makino-Okamura (2014),^[67] Wu, Hammer (2014),^[66] Ando (2012),^[73] Ando (2010).^[74]

References

^ Lee, Heun Joo; Lee, Woo Jin; Chang, Sung Eun; Lee, Ga-Young (2015). "Hesperidin, A Popular Antioxidant Inhibits Melanogenesis via Erk1/2 Mediated MITF Degradation". Int. J. Mol. Sci. 16 (8). doi:10.3390/ijms160818384. PMC 4581251. PMID 26262610.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref
^ Narayan, A. Bloomberg Business Week, A Lucrative Promise for India's men: Whiter skin, Dec 5, 2013
^ McDougall, A. Cosmeticsdesign-Asia.com, Skin lightening trend in Asia boosts global market.
^ ^a ^b ^c ^d ^e ^f Chang, Te-Sheng (2009). "An Updated Review of Tyrosinase Inhibitors". Int. J. Mol. Sci. 10 (6). doi:10.3390/ijms10062440. PMC 2705500. PMID 19582213.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref
^ Choi, Joonhyeok; Choi, Kwang-Eun; Park, Sung Jean; Kim, Sun Yeou; Jee, Jun-Goo (2016). "Ensemble-Based Virtual Screening Led to the Discovery of New Classes of Potent Tyrosinase Inhibitors". J. Chem. Inf. Model. 56 (2). doi:10.1021/acs.jcim.5b00484. PMID 26750991. Restricted access.
^ Ai, Ni; Welsh, William J.; Santhanam, Uma; Hu, Hong; Lyga, John (2014). "Novel Virtual Screening Approach for the Discovery of Human Tyrosinase Inhibitors". PLoS ONE. 9 (11). doi:10.1371/journal.pone.0112788. PMC 4245091. PMID 25426625.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref
^ Baek, Seung-Hwa; Lee, Sang-Han (2015). "Proton pump inhibitors decrease melanogenesis in melanocytes". Biomed. Rep. 3 (5). doi:10.3892/br.2015.492. PMC 4535079. PMID 26405553. Template:Lref
^ Choi, Joonhyeok; Jee, Jun-Goo (2015). "Repositioning of Thiourea-Containing Drugs as Tyrosinase Inhibitors". Int. J. Mol. Sci. 16 (12). doi:10.3390/ijms161226114. PMC 4691061. PMID 26633377.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref
^ "Inhibitory effects of imatinib mesylate on human epidermal melanocytes". Clin. Exp. Dermatol. 39 (2). 2014. doi:10.1111/ced.12261. PMID 24479586. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.
^ ^a ^b Espín, Juan Carlos; Wichers, Harry J. (2001). "Effect of captopril on mushroom tyrosinase activity in vitro". Biochim. Biophys. Acta. 1544 (1–2). doi:10.1016/s0167-4838(00)00230-2. PMID 11341938. Restricted access.
^ Liu, Qing; Kim, Cheong Taek; Jo, Yang Hee; Kim, Seon Beom; Hwang, Bang Yeon; Lee, Mi Kyeong (2015). "Synthesis and Biological Evaluation of Resveratrol Derivatives as Melanogenesis Inhibitors". Molecules. 20 (9). doi:10.3390/molecules200916933. PMID 26393543.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref
^ "Synthesis and Biological Evaluation of Unsymmetrical Curcumin Analogues as Tyrosinase Inhibitors". Molecules. 18 (4). 2013. doi:10.3390/molecules18043948. PMID 23552906. {{cite journal}}: Cite uses deprecated parameter |authors= (help)CS1 maint: unflagged free DOI (link) Template:Lref
^ ^a ^b ^c ^d ^e ^f ^g ^h Chang, Te-Sheng (2012). "Natural Melanogenesis Inhibitors Acting Through the Down-Regulation of Tyrosinase Activity". Materials. 5 (9). doi:10.3390/ma5091661.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref
^ ^a ^b ^c ^d ^e Ebanks, Jody P.; Wickett, R. Randall; Boissy, Raymond E. (2009). "Mechanisms Regulating Skin Pigmentation: The Rise and Fall of Complexion Coloration". Int. J. Mol. Sci. 10 (9). doi:10.3390/ijms10094066. PMC 2769151. PMID 19865532.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref
^ Whitehead, Ross D.; Re, Daniel; Xiao, Dengke; Ozakinci, Gozde; Perrett, David I. (2012). "You Are What You Eat: Within-Subject Increases in Fruit and Vegetable Consumption Confer Beneficial Skin-Color Changes". PLoS ONE. 7 (3). doi:10.1371/journal.pone.0032988. PMC 3296758. PMID 22412966.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref
^ Pezdirc, Kristine; Hutchesson, Melinda J.; Whitehead, Ross; Ozakinci, Gozde; Perrett, David; Collins, Clare E. (2015). "Fruit, Vegetable and Dietary Carotenoid Intakes Explain Variation in Skin-Color in Young Caucasian Women: a Cross-Sectional Study". Nutrients. 7 (7). doi:10.3390/nu7075251. PMC 4517028. PMID 26184306.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref
^ ^a ^b Kondo, Taisuke; Hearing, Vincent J. (2011). "Update on the regulation of mammalian melanocyte function and skin pigmentation". Expert. Rev. Dermatol. 6 (1). doi:10.1586/edm.10.70. PMC 3093193. PMID 21572549. Template:Lref
^ ^a ^b ^c ^d ^e ^f Slominski, Andrzej; Tobin, Desmond J.; Shibahara, Shigeki; Wortsman, Jacobo (2004). "Melanin Pigmentation in Mammalian Skin and its Hormonal Regulation". Physiol. Rev. 84 (4). doi:10.1152/physrev.00044.2003. PMID 15383650. Template:Lref
^ "Tyrosinase inhibitors: a patent review (2011-2015)" (PDF). Expert. Opin. Ther. Pat. 26 (3). 2016. doi:10.1517/13543776.2016.1146253. PMID 26815044. {{cite journal}}: Cite uses deprecated parameter |authors= (help)
^ Pillaiyar, Thanigaimalai; Manickam, Manoj; Jung, Sang-Hun. "Inhibitors of melanogenesis: a patent review (2009-2014)" (PDF). Expert. Opin. Ther. Pat. 25 (7). doi:10.1517/13543776.2015.1039985. PMID 25939410.
^ Gruber, James V.; Holtz, Robert (2013). "Examining the Impact of Skin Lighteners In Vitro". Oxidative Medicine and Cellular Longevity. doi:10.1155/2013/702120. PMC 3655678. PMID 23738040.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref
^ "Anti-tyrosinase kinetics and antibacterial process of caffeic acid N-nonyl ester in Chinese Olive (Canarium album) postharvest". Int. J. Biol. Macromol. 91. 2016. doi:10.1016/j.ijbiomac.2016.05.098. PMID 27246378. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.
^ Chen, Bing-Nian; Xing, Rui; Wang, Fang; Zheng, A-Ping; Wang, Li (2015). "Inhibitory effects of α-Na8SiW11CoO40 on tyrosinase and its application in controlling browning of fresh-cut apples". Food Chem. 188. doi:10.1016/j.foodchem.2015.05.003. PMID 26041180. Restricted access.
^ Liu, Jinbing; Wu, Fengyan; Chen, Changhong (2015). "Design and synthesis of aloe-emodin derivatives as potent anti-tyrosinase, antibacterial and anti-inflammatory agents". Bioorg. Med. Chem. Lett. 25 (22). doi:10.1016/j.bmcl.2015.10.004. PMID 26471089. Restricted access.
^ "Design, synthesis and biological evaluation of hydroxy- or methoxy-substituted 5-benzylidene(thio) barbiturates as novel tyrosinase inhibitors" (PDF). Bioorg. Med. Chem. 22 (13). 2014. doi:10.1016/j.bmc.2014.04.060. PMID 24857777. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref
^ "Inhibitory effects of 5-benzylidene barbiturate derivatives on mushroom tyrosinase and their antibacterial activities" (PDF). Eur. J. Med. Chem. 44 (10). 2009. doi:10.1016/j.ejmech.2009.05.023. PMID 19552984. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref
^ "Synthesis and evaluation of 5-benzylidene(thio)barbiturate-β-D-glycosides as mushroom tyrosinase inhibitors" (PDF). Bioorg. Med. Chem. Lett. 19 (15). 2009. doi:10.1016/j.bmcl.2009.06.018. PMID 19564107. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref
^ Liu, Jinbing; Chen, Changhong; Wu, Fengyan; Zhao, Liangzhong (2013). "Microwave-assisted synthesis and tyrosinase inhibitory activity of chalcone derivatives". Chem. Biol. Drug. Des. 82 (1). doi:10.1111/cbdd.12126. PMID 23461881. Template:Lref
^ Kuijpers, Tomas F. M.; Gruppen, Harry; Sforza, Stefano; van Berkel, Willem J. H.; Vincken, Jean-Paul (2013). "The antibrowning agent sulfite inactivates Agaricus bisporus tyrosinase through covalent modification of the copper-B site". FEBS J. 280 (23). doi:10.1111/febs.12539. PMID 24112416. Template:Lref
^ "Biological evaluation of coumarin derivatives as mushroom tyrosinase inhibitors". Food Chem. 135 (4). 2012. doi:10.1016/j.foodchem.2012.07.055. PMID 22980884. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.
^ "Kinetic characterisation of o-aminophenols and aromatic o-diamines as suicide substrates of tyrosinase". Biochim. Biophys. Acta. 1824 (4). 2012. doi:10.1016/j.bbapap.2012.02.001. PMID 22342555. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.
^ "Tetrahydrofolic Acid is a potent suicide substrate of mushroom tyrosinase". J. Agric. Food Chem. 59 (4). 2011. doi:10.1021/jf1035433. PMID 21265541. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.
^ "Evaluation of dihydropyrimidin-(2H)-one analogues and rhodanine derivatives as tyrosinase inhibitors". Bioorg. Med. Chem. Lett. 21 (8). 2011. doi:10.1016/j.bmcl.2011.02.076. PMID 21411319. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.
^ "Suicide inactivation of tyrosinase in its action on tetrahydropterines". J. Enzyme Inhib. Med. Chem. 26 (5). 2010. doi:10.3109/14756366.2010.548811. PMID 21299451. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.
^ "Irreversible competitive inhibitory kinetics of cardol triene on mushroom tyrosinase". J. Agric. Food Chem. 58 (24). 2010. doi:10.1021/jf103723k. PMID 21121650. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.
^ Yamazaki, Yoshimitsu; Kawano, Yasuhiro (2010). "N-(3,5-dihydroxybenzoyl)-6-hydroxytryptamine as a novel human tyrosinase inhibitor that inactivates the enzyme in cooperation with l-3,4-dihydroxyphenylalanine". Chem. Pharm. Bull. 58 (11). doi:10.1248/cpb.58.1536. PMID 21048351. Template:Lref
^ Li, Shu-Bai; Nie, Hua-Li; Zhang, Hai-Tao; Xue, Yong; Zhu, Li-Min (2010). "Kinetic Evaluation of Aminoethylisothiourea on Mushroom Tyrosinase Activity". Appl. Biochem. Biotechnol. 162 (3). doi:10.1007/s12010-009-8760-3. PMID 19763898. Template:Lref
^ Chang, Te-Sheng; Lin, Meng-Yi; Lin, Hsuan-Jung (2010). "Identifying 8-hydroxynaringenin as a suicide substrate of mushroom tyrosinase" (PDF). J. Cosmet. Sci. 61 (3). doi:10.1111/j.1468-2494.2010.00619_1.x. PMID 20587349. Template:Lref
^ "Melanogenesis Inhibition Due to NADH". Biosci. Biotechnol. Biochem. 74 (9). 2010. doi:10.1271/bbb.90965. PMID 20834177. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref
^ Tai, Sorgan Shou-Ku; Lin, Ching-Gong; Wu, Mon-Han; Chang, Te-Sheng (2009). "Evaluation of Depigmenting Activity by 8-Hydroxydaidzein in Mouse B16 Melanoma Cells and Human Volunteers". Int. J. Mol. Sci. 10 (10). doi:10.3390/ijms10104257. PMC 2790106. PMID 20057943.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref
^ ^a ^b ^c ^d Smit, Nico; Vicanova, Jana; Pavel, Stan (2009). "The Hunt for Natural Skin Whitening Agents". Int. J. Mol. Sci. 10 (12). doi:10.3390/ijms10125326. PMC 2801997. PMID 20054473.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref
^ ^a ^b ^c ^d Yamaguchi, Yuji; Hearing, Vincent J. (2009). "Physiological factors that regulate skin pigmentation". Biofactors. 35 (2). doi:10.1002/biof.29. PMC 2793097. PMID 19449448. Template:Lref
^ Imokawa, Genji; Ishida, Koichi (2014). "Inhibitors of Intracellular Signaling Pathways that Lead to Stimulated Epidermal Pigmentation: Perspective of Anti-Pigmenting Agents". Int. J. Mol. Sci. 15 (5). doi:10.3390/ijms15058293. PMC 4057732. PMID 24823877.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref
^ "A systems-biological study on the identification of safe and effective molecular targets for the reduction of ultraviolet B-induced skin pigmentation". Sci. Rep. 5. 2015. doi:10.1038/srep10305. PMC 4434836. PMID 25980672. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref
^ "UVB Stimulates the Expression of Endothelin B Receptor in Human Melanocytes via a Sequential Activation of the p38/MSK1/CREB/MITF Pathway Which Can Be Interrupted by a French Maritime Pine Bark Extract through a Direct Inactivation of MSK1". PLOS ONE. 10 (6). 2015. doi:10.1371/journal.pone.0128678. PMC 4452497. PMID 26030901. {{cite journal}}: Cite uses deprecated parameter |authors= (help)CS1 maint: unflagged free DOI (link) Template:Lref
^ Kim, Hye-Eun; Ishihara, Atsushi; Lee, Seong-Gene (2012). "The effects of Caffeoylserotonin on inhibition of melanogenesis through the downregulation of MITF via the reduction of intracellular cAMP and acceleration of ERK activation in B16 murine melanoma cells". BMB Rep. 45 (12). doi:10.5483/BMBRep.2012.45.12.039. PMC 4133815. PMID 23261059. Template:Lref
^ "A novel adamantyl benzylbenzamide derivative, AP736, inhibits melanogenesis in B16F10 mouse melanoma cells via glycogen synthase kinase 3β phosphorylation". Int. J. Mol. Med. 2015. doi:10.3892/ijmm.2015.2348. PMID 26398893. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref
^ "Inhibitory Effect of Dried Pomegranate Concentration Powder on Melanogenesis in B16F10 Melanoma Cells; Involvement of p38 and PKA Signaling Pathways". Int. J. Mol. Sci. 16 (10). 2015. doi:10.3390/ijms161024219. PMC 4632747. PMID 26473849. {{cite journal}}: Cite uses deprecated parameter |authors= (help)CS1 maint: unflagged free DOI (link) Template:Lref
^ Jin, Kyong-Suk; Oh, You Na; Hyun, Sook Kyung; Kwon, Hyun Ju; Kim, Byung Woo (2014). "Betulinic acid isolated from Vitis amurensis root inhibits 3-isobutyl-1-methylxanthine induced melanogenesis via the regulation of MEK/ERK and PI3K/Akt pathways in B16F10 cells". Food Chem. Toxicol. 68. doi:10.1016/j.fct.2014.03.001. PMID 24632067.
^ ^a ^b ^c ^d Chen, Hongxiang; Weng, Qing Y.; Fisher, David E. (2014). "UV Signaling Pathways within the Skin". J. Invest. Dermatol. 134 (4). doi:10.1038/jid.2014.161. PMC 4102648. PMID 24759085. Template:Lref
^ ^a ^b ^c Rodríguez, Carlos Iván; Setaluri, Vijayasaradhi (2014). "Cyclic AMP (cAMP) signaling in melanocytes and melanoma". Arch. Biochem. Biophys. 563. doi:10.1016/j.abb.2014.07.003. PMID 25017568. Restricted access.
^ Lee, Ai-Young; Noh, Minsoo (2013). "The regulation of epidermal melanogenesis via cAMP and/or PKC signaling pathways: insights for the development of hypopigmenting agents". Arch. Pharm. Res. 36 (7). doi:10.1007/s12272-013-0130-6. PMID 23604723. Restricted access.
^ "PDE5 inhibitor promotes melanin synthesis through the PKG pathway in B16 melanoma cells". J. Cell Biochem. 113 (8). 2012. doi:10.1002/jcb.24147. PMID 22441938. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref
^ ^a ^b ^c D’Orazio, John; Jarrett, Stuart; Amaro-Ortiz, Alexandra; Scott, Timothy (2013). "UV Radiation and the Skin". Int. J. Mol. Sci. 14 (6). doi:10.3390/ijms140612222. PMC 3709783. PMID 23749111.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref
^ Marzuka-Alcalá, Alexander; Gabree, Michele Jacobs; Tsao, Hensin (2014). "Melanoma susceptibility genes and risk assessment". Methods Mol. Biol. doi:10.1007/978-1-62703-727-3_20. PMID 24258989. Restricted access.
^ Law, Matthew H.; MacGregor, Stuart; Hayward, Nicholas K. (2012). "Melanoma Genetics: Recent Findings Take Us Beyond Well-Traveled Pathways". J. Invest. Dermatol. 132 (7). doi:10.1038/jid.2012.75. PMID 22475760. Template:Lref
^ Nelson, Andrew A.; Tsao, Hensin (2009). "Melanoma and genetics". Clin. Dermatol. 27 (1). doi:10.1016/j.clindermatol.2008.09.005. PMID 19095153. Restricted access.
^ Sturm, Richard A. (2009). "Molecular genetics of human pigmentation diversity". Hum. Mol. Genet. 19 (R1). doi:10.1093/hmg/ddp003. PMID 19297406. Template:Lref
^ "Genetic determinants of hair, eye and skin pigmentation in Europeans" (PDF). Nat. Genet. 39 (12). 2007. doi:10.1038/ng.2007.13. PMID 17952075. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref
^ Barsh, Gregory S. (2003). "What Controls Variation in Human Skin Color?". PLoS Biology. doi:10.1371/journal.pbio.0000027. PMC 212702. PMID 14551921.{{cite journal}}: CS1 maint: unflagged free DOI (link) No-cost access, unknown license.
^ ^a ^b Yamazaki, Yoshimitsu; Kawano, Yasuhiro; Yamanaka, Akiko; Maruyama, Susumu (2009). "N-[(Dihydroxyphenyl)acyl]serotonins as potent inhibitors of tyrosinase from mouse and human melanoma cells". Bioorg. Med. Chem. Lett. 19 (15). doi:10.1016/j.bmcl.2009.05.115. PMID 19524439. Restricted access.
^ Zhou, Jia; Geng, Kun-kun; Ping, Feng-feng; Gao, Yue-ying; Liu, Lei; Feng, Bai-nian (2016). "Cross-talk between 5-hydroxytryptamine and substance P in the melanogensis and apoptosis of B16F10 melanoma cells". Eur. J. Pharmacol. doi:10.1016/j.ejphar.2016.02.026. PMID 26872989. Restricted access.
^ "A Novel Role of Serotonin Receptor 2B Agonist as an Anti-Melanogenesis Agent". Int. J. Mol. Sci. 17 (4). 2016. doi:10.3390/ijms17040546. PMC 4849002. PMID 27077852. {{cite journal}}: Cite uses deprecated parameter |authors= (help)CS1 maint: unflagged free DOI (link) Template:Lref
^ Lee, H. J.; Park, M. K.; Kim, S. Y.; Park Choo, H. Y.; Lee, A. Y.; Lee, C. H. (2011). "Serotonin induces melanogenesis via serotonin receptor 2A". Br. J. Dermatol. 165 (6). doi:10.1111/j.1365-2133.2011.10490.x. PMID 21711335. Template:Lref
^ Max, McEwan; Persons, Peter G. (1987). "Inhibition of melanization in human melanoma cells by a serotonin uptake inhibitor" (PDF). J. Invest. Dermatol. 89 (1). doi:10.1111/1523-1747.ep12580425. PMID 3110297. Template:Lref
^ ^a ^b ^c ^d Wu, Wufeng; Hammer, John A. (2014). "Melanosome transfer: It is best to give and receive". Curr. Opin. Cell Biol. 29. doi:10.1016/j.ceb.2014.02.003. PMC 4130791. PMID 24662021. Manuscript in PMC.
^ ^a ^b "Heparin inhibits melanosome uptake and inflammatory response coupled with phagocytosis through blocking PI3k/Akt and MEK/ERK signaling pathways in human epidermal keratinocytes" (PDF). Pigment Cell Melanoma Res. 27 (6). 2014. doi:10.1111/pcmr.12287. PMID 24961476. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref
^ ^a ^b Jung, Eunsun; Lee, Jung-A; Shin, Seoungwoo; Roh, Kyung-Baeg; Kim, Jang-Hyun; Park, Deokhoon (2013). "Madecassoside Inhibits Melanin Synthesis by Blocking Ultraviolet-Induced Inflammation". Molecules. 18 (12). doi:10.3390/molecules181215724. PMID 24352025.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref
^ Leyden, James; Wallo, Warren (2011). "The mechanism of action and clinical benefits of soy for the treatment of hyperpigmentation". Int. J. Dermatol. 50 (4). doi:10.1111/j.1365-4632.2010.04765.x. PMID 21332714. Restricted access.
^ "The natural yeast extract isolated by ethanol precipitation inhibits melanin synthesis by modulating tyrosinase activity and downregulating melanosome transfer". Biosci. Biotechnol. Biochem. 79 (9). 2015. doi:10.1080/09168451.2015.1032880. PMID 25943301. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.
^ Kim, Ji Young; Kim, Dae Suk; Sohn, Hyojung; Lee, Eun Jung; Oh, Sang Ho (2016). "PAR-2 is involved in melanogenesis by mediating stem cell factor production in keratinocytes". Exp. Dermatol. 25 (6). doi:10.1111/exd.12982. PMID 26909822. Template:Lref
^ "Melanosome uptake is associated with the proliferation and differentiation of keratinocytes" (PDF). Arch. Dermatol. Res. 306. 2014. doi:10.1007/s00403-013-1422-x. PMID 24173125. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref
^ "Melanosomes are transferred from melanocytes to keratinocytes through the processes of packaging, release, uptake, and dispersion" (PDF). J. Invest. Dermatol. 132 (4). 2012. doi:10.1038/jid.2011.413. PMID 22189785. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref
^ "Keratinocytes in culture accumulate phagocytosed melanosomes in the perinuclear area" (PDF). Pigment Cell Melanoma Res. 23 (1). 2010. doi:10.1111/j.1755-148X.2009.00640.x. PMID 19761520. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref
^ ^a ^b ^c Nagasaki, Kenji; Kumazawa, Masaro; Murakami, Shuichiro; Takenaka, Shinji; Koike, Kenzo; Aoki, Kenji (2008). "Purification, characterization, and gene cloning of Ceriporiopsis sp. strain MD-1 peroxidases that decolorize human hair melanin". Appl. Environ. Microbiol. 74 (16). doi:10.1128/AEM.00253-08. PMC 2519264. PMID 18586974. Template:Lref
^ Mauricio, Tess; Karmon, Yoram; Khaiat, Alain (2011). "A randomized and placebo-controlled study to compare the skin-lightening efficacy and safety of lignin peroxidase cream vs. 2% hydroquinone cream". J. Cosmet. Dermatol. 10 (4). doi:10.1111/j.1473-2165.2011.00581.x. PMID 22151932. Restricted access.
^ Zhong, Shao-Min; Sun, Nan; Liu, Hui-Xian; Niu, Yue-Qing; Wu, Yan (2015). "Reduction of facial pigmentation of melasma by topical lignin peroxidase: A novel fast-acting skin-lightening agent". Exp. Ther. Med. 9 (2). doi:10.3892/etm.2014.2118. PMC 4280934. PMID 25574195. Template:Lref
^ van den Boorn, Jasper G.; Melief, Cornelis J.; Luiten, Rosalie M. "The Monobenzone-induced depigmentation: from enzymatic blockade to autoimmunity" (PDF). Pigment Cell Melanoma Res. 24 (4). doi:10.1111/j.1755-148X.2011.00878.x. PMID 21689385. Template:Lref
^ Ito, Shosuke; Wakamatsu, Kazumasa (2015). "A convenient screening method to differentiate phenolic skin whitening tyrosinase inhibitors from leukoderma-inducing phenols" (PDF). J. Dermatol. Sci. 80 (1). doi:10.1016/j.jdermsci.2015.07.007. PMID 26228294. Template:Lref
^ ^a ^b Rendon, Marta; Berneburg, Mark; Arellano, Ivonne; Picardo, Mauro (May 2006). "Treatment of melasma". Journal of the American Academy of Dermatology. Supplement 2. 54 (5): S272–S281. doi:10.1016/j.jaad.2005.12.039.
^ ^a ^b ^c "Repeated Treatment Protocols for Melasma and Acquired Dermal Melanocytosis". Dermatologic Surgery. 32: 365–371. March 2006. doi:10.1097/00042728-200603000-00005.
^ Journal of Drugs in Dermatology: 27–34. 2004. {{cite journal}}: Missing or empty |title= (help)
^ "Safety and efficacy of 4% hydroquinone combined with 10% glycolic acid, antioxidants, and sunscreen in the treatment of melasma". International Journal of Dermatology. 42: 966–972. 2003. doi:10.1111/j.1365-4632.2003.02017.x.
^ "Efficacy of Glycolic Acid Peels in the Treatment of Melasma". Archives of Dermatology. 138: 1578–1582. December 2002. doi:10.1001/archderm.138.12.1578.
^ "Hypopigmented Macules of Photodamaged Skin and Their Treatment with Topical Tretinoin". Acta Dermato-Venereologica. 79: 305–310. July 1999. doi:10.1080/000155599750010724.
^ "Short- and long-term histologic effects of topical tretinoin on photodamaged skin". International Journal of Dermatology. 37: 286–292. April 1998. doi:10.1046/j.1365-4362.1998.00433.x.
^ "Treatment of photodamage with topical tretinoin: An overview". Journal of the American Academy of Dermatology. 36: S27–S36. March 1997. doi:10.1016/s0190-9622(97)70058-6.
^ Cutis: 177–184. March 2006. {{cite journal}}: Missing or empty |title= (help)
^ Journal of Drugs in Dermatology: 592–597. September–October 2005. {{cite journal}}: Missing or empty |title= (help)
^ Journal of Cosmetic Science: 208–290. May–June 1998. {{cite journal}}: Missing or empty |title= (help)
^ Dermatological Surgery. 22: 443–447. May 1996. doi:10.1016/1076-0512(96)00065-9. {{cite journal}}: Missing or empty |title= (help)
^ "New Antioxidant Hydroquinone Derivatives from the Algicolous Marine Fungus Acremonium sp". Journal of Natural Products. 65: 1605–1611. November 2002. doi:10.1021/np020128p.
^ Journal of Dermatological Science: 68–75. August 2001. {{cite journal}}: Missing or empty |title= (help)
^ "Skin diseases associated with the cosmetic use of bleaching products in women from Dakar, Senegal". British Journal of Dermatology. 148: 493–500. March 2003. doi:10.1046/j.1365-2133.2003.05161.x.
^ Fuller, Thomas (2006-05-14). "A Vision of Pale Beauty Carries Risks for Asia's Women". The New York Times. Retrieved 2010-05-23.
^ Drugs in Dermatology: 377–381. July–August 2004. {{cite journal}}: Missing or empty |title= (help)
^ Maeda, K; Fukuda, M (1996). "Arbutin: mechanism of its depigmenting action in human melanocyte culture". Journal of Pharmacology and Experimental Therapeutics. 276 (2): 765–769. PMID 8632348.
^ Jun, So-Young; Park, Kyung-Min; Choi, Ki-Won; Jang, Min Kyung; Kang, Hwan Yul; Lee, Sang-Hyeon; Park, Kwan-Hwa; Cha, Jaeho (2007). "Inhibitory effects of arbutin-β-glycosides synthesized from enzymatic transglycosylation for melanogenesis". Biotechnology Letters. 30 (4): 743–8. doi:10.1007/s10529-007-9605-1. PMID 18040603.
^ Archives of Pharmacal Research, August 2001, pages 307-311.
^ Mutation Research, Genetic Toxicology and Environmental Mutagenesis, June 2005, pages 133-1450 and Toxicological Sciences, September 2004, pages 43–49.
^ Serra-Baldrich, E.; Tribô, M. J.; Camarasa, J. G. (1998). "Allergic contact dermatitis from kojic acid". Contact Dermatitis. 39: 86–87. doi:10.1111/j.1600-0536.1998.tb05843.x.
^ Sarkar, Rashmi; Garg, VijayK; Arya, Latika; Arora, Pooja (2012). "Lasers for treatment of melasma and post-inflammatory hyperpigmentation". Journal of Cutaneous and Aesthetic Surgery. 5 (2): 93. doi:10.4103/0974-2077.99436.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ "Plastic Surgery Articles (Indications, Anatomy, Workup, Surgical Therapy, Treatment, Complications) - Medscape Reference". Retrieved 29 May 2014.
^ Baliña, Luis M.; Graupe, Klaus (December 1991). "The Treatment of Melasma 20% Azelaic Acid versus 4% Hydroquinone Cream". International Journal of Dermatology. 30 (12): 893–895. doi:10.1111/j.1365-4362.1991.tb04362.x.
^ Johnston, CS; Meyer, CG; Srilakshmi, JC (1993). "Vitamin C elevates red blood cell glutathione in healthy adults". The American Journal of Clinical Nutrition. 58 (1): 103–5. PMID 8317379.
^ Fujiwara, Yoko; Sahashi, Yumiko; Aritro, Mitsumi; Hasegawa, Satoko; Akimoto, Koji; Ninomiya, Shinji; Sakaguchi, Yasue; Seyama, Yousuke (2004). "Effect of simultaneous administration of vitamin C, L-cysteine and vitamin E on the melanogenesis". BioFactors. 21 (1–4): 415–8. doi:10.1002/biof.552210182. PMID 15630239.
^ Arjinpathana, Nutthavuth; Asawanonda, Pravit (2012). "Glutathione as an oral whitening agent: a randomized, double-blind, placebo-controlled study". J. Dermatolog. Treat. 23 (2). doi:10.3109/09546631003801619. PMID 20524875.
^ Chung, Bo Young; Choi, So Ra; Moon, Ik Jun; Park, Chun Wook; Kim, Young-Hoon; Chang, Sung Eun (2016). "The Glutathione Derivative, GSH Monoethyl Ester, May Effectively Whiten Skin but GSH Does Not". Int. J. Mol. Sci. 17 (5). doi:10.3390/ijms17050629. PMC 4881455. PMID 27128906.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref
^ Sonthalia, Sidharth; Daulatabad, Deepashree; Sarkar, Rashmi (2016). "Glutathione as a skin whitening agent: Facts, myths, evidence and controversies". Indian J. Dermatol. Venereol. Leprol. 82 (3). doi:10.4103/0378-6323.179088. PMID 27088927.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref
^ Witschi, A.; Reddy, S.; Stofer, B.; Lauterburg, B. H. (1992). "The systemic availability of oral glutathione". European journal of clinical pharmacology. 43 (6). doi:10.1007/BF02284971. PMID 1362956.
^ Experimental Dermatology, January 2003, supplemental. pages 43-50.
^ Dermatologic Surgery, February 2005, pages 149-154; Journal of Cutaneous Medicine and Surgery, April 2004, pages 97-102; Cutis, February 2004, supplemental, pages 18-24; Dermatologic Therapy, June 2004, pages 196-205; and Dermatological Surgery, June 1999, pages 450-454.
^ Hopkins, Michael (24 July 2013). "How is bleaching done?". vaginalbleaching.org. Retrieved 24 October 2015.
^ "Drug Safety and Availability - FDA Warns Consumers Not to Use Viansilk's "Crema Piel De Seda" ("Silky Skin Cream")". Drugs: Drug Safety and Availability. USFDA. January 29, 2016. Retrieved January 30, 2016.
^ Experimental Dermatology, August 2005, pages 601-608; Bioscience, Biotechnology, and Biochemistry, December 2005, pages 2368-2373; International Journal of Dermatology, August 2004, pages 604-607; Journal of Drugs in Dermatology, July–August 2004, pages 377-381; Facial and Plastic Surgery, February 2004, pages 3-9; Dermatologic Surgery, March 2004, pages 385-388; Journal of Bioscience and Bioengineering, March 2005, pages 272-276; Journal of Biological Chemistry, November 7, 2003, pages 44320-44325; Journal of Agriculture and Food Chemistry, February 2003, pages 1201-1207; International Journal of Cosmetic Science, August 2000, pages 291-303; and Anti-Cancer Research, September–October 1999, pages 3769-3774.
^ Journal of the American Academy of Dermatology, May 2006, supplemental, pages 262-271; Dermatologic Therapy, January 2001, page 46; Journal of Cosmetic and Laser Therapy, March 2005, pages 39-43; Journal of Cutaneous Medicine and Surgery, April 2004, pages 97-102; Journal of Drugs in Dermatology, November–December 2005, pages 770-774; Dermatologic Surgery, October 2005, page 1263; and Lasers in Surgery and Medicine, April 2000, pages 376-379.
^ Counter, S. Allen, Whitening skin can be deadly, Boston Globe, 16 Dec 2003
^ Akortha, E.E.; Niemogha, M.T.; Edobor, O. (1 June 2012). "MUTAGENIC AND GENOTOXIC SCREENING OF EIGHT COMMONLY USED SKIN WHITENING CREAMS IN NIGERIA". Bayero Journal of Pure and Applied Sciences. 5 (1): 5–10. doi:10.4314/bajopas.v5i1.2. Retrieved 25 December 2012.
^ Peregrino, C. P.; Moreno, M. V.; Miranda, S. V.; Rubio, A. D.; Leal, L. O. (11 June 2011). "Mercury Levels in Locally Manufactured Mexican Skin-Lightening Creams". Int. J. Environ. Res. Public Health. doi:10.3390/ijerph8062516. PMC 3138038. PMID 21776243.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

Template:Japanese cosmetics

[1] Instead of "whitening", the terms "lightening", "brightening", "depigmentation" and "bleaching" are also used.

[Melanin_synthesis-20] The chemical pathways of the synthesis of melanin has been described by many papers; however, it is often oversimplified. The following references are suggested: Kondo, Hearing (2011),^[17] Chang (2009)^[4] and Slominski et. al. (2004).^[18]

[21] "In addition to inhibition of tyrosinase catalytic activity, other approaches to treat hyperpigmentation include inhibition of tyrosinase mRNA transcription, aberration of tyrosinase glycosylation and maturation, acceleration of tyrosinase degradation, interference with melanosome maturation and transfer, inhibition of inflammation-induced melanogenic response, and acceleration of skin turnover. Accordingly, a huge number of depigmenting agents or whitening agents developed by those alternative approaches have been successfully identified and deeply reviewed in many articles [references omitted]."^[4]

[22] "In contrast to the huge number of reversible inhibitors has been identified, rarely irreversible inhibitors of tyrosinase were found until now. These irreversible inhibitors, which are also called specific inactivators, can form irreversibly covalent bond with the target enzyme and then inactivate it."^[4]

[25] "Inhibitor strength is usually expressed as the inhibitory IC₅₀ value, which is the concentration of an inhibitor needed to inhibit half of the enzyme activity in the tested condition. However, for the tyrosinase inhibitors in the literature, the IC₅₀ values are incomparable due to the varied assay conditions, including different substrate concentrations, varied incubation time, and different batches of commercial tyrosinase. Fortunately, in most studies conducted to discover new tyrosinase inhibitors, a well-known tyrosinase inhibitor such as kojic acid is often used as a positive standard at the same time. Hence, in order to compare the inhibitors described in different literature in a more practical manner, a relative inhibitory activity (RA), which is calculated by dividing the IC₅₀ value of kojic acid with that of a newly found inhibitor in the same report, is used to express and compare the inhibitory strength of an inhibitor with others in this review."^[4]

[MITF-46] "The transcriptional level is the first stage by which the expression of tyrosinase and related melanogenic enzymes may be modulated. Influential in this process, the microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor that regulates melanocyte cellular differentiation as well as the transcription of melanogenic enzymes (tyrosinase, TYRP1 and TYRP2) and melanosome structural proteins (MART-1 and PMEL17) [references omitted]."^[14]

"In addition to being involved in the survival, proliferation, and differentiation of melanocytes, MITF is the master regulator of melanogenesis in melanocytes via binding to the M box of a promoter region and regulating the gene expression of tyrosinase, TRP-1, and TRP-2 [references omitted]. The up-regulation of MITF activity activates the expression of the melanogenesis-related enzymes, thus stimulating melanogenesis. In contrast, the down-regulation of MITF activity depresses the expression of the related enzymes, thereby inhibiting melanogenesis."^[13]

[48] "Because tyrosinase is produced only by melanocytic cells, tyrosinase inhibitors have highly specific targeting to melanogenesis in the cells without other side effects. In contrast, those melanogenesis inhibitors targeting to the tyrosinase gene expressions or protein degradations are rarely used as clinical hypopigmenting agents, due to their non-specific and global effects via intracellular signaling pathways."^[13]

[Signaling_pathways-51] Many papers have described the signaling pathways affecting melanogenesis and other functions of melanocytes. The following reviews are suggested reading (all of which are available online at no cost):

For a description with emphasis on the relation with skin whitening, see Chang (2012)^[13] or Smit, Vicanova, Pavel (2009).^[41] For a description with emphasis on physiology, see Yamaguchi, Hearing (2009)^[42] or Kondo (2011).^[17] For a description of intra-melanocyte signaling pathways, see Imokawa, Ishida (2014).^[43] An extensive and detailed review was written by Slominski et. al. (2004).^[18]

[MC1R-60] "Alpha melanocyte-stimulating hormone (α-MSH), a peptide derived from proopiomelanocortin (POMC), regulates melanogenesis via a cyclic adenosine monophosphate (cAMP)-dependent pathway [references omitted]. When binding to its receptor, melanocortin receptor 1 (MC1R), on the membrane of melanocytes, the hormone activates adenylate cyclase (AC) to produce cAMP as an intracellular second message via a G-protein-coupled receptor (GPCR)-type activation. cAMP activates protein kinase A (PKA), which then activates the gene expression of MITF via phosphorylation of the cAMP response element-binding protein (CREB). Finally, MITF efficiently activates the melanogenesis-related enzymes and stimulates melanogenesis. Once α-MSH binds to MC1R, up to a 100-fold increase in melanogenesis attends. In addition to α-MSH, other POMC-derived peptides, such as β-MSH and adrenocorticotropic hormone (ACTH), also stimulate melanogenesis via the same pathway."^[13]

"α-MSH binding to melanocortin 1 receptor (MC1R) on melanocytes in the basal epidermis generates the second messenger cAMP via interactions between MC1R and adenylyl cyclase, and leads to activation of protein kinase A and the cAMP responsive binding element (CREB) and microphthalmia (Mitf) transcription factors. CREB and Mitf directly enhance melanin production by raising levels of tyrosinase and other melanin biosynthetic enzymes. Thus, MSH-MC1R signaling leads to enhanced pigment synthesis by melanocytes and accumulation of melanin by epidermal keratinocytes.
[etcetera]
The MC1R is found on the surface of melanocytes where it binds to α-melanocyte stimulating hormone (MSH) and transmits differentiation signals into the cell through activation of adenylyl cyclase and generation of cAMP [references omitted]. cAMP signaling leads to activation of the protein kinase A (PKA) cascade which, in turn, leads to increased levels and/or activity of many melanogenic enzymes to enhance production and export of melanin by melanocytes [references and figure omitted]."^[54]

[64] The assertion that ASIP is the only endogenous antagonist is found in Yamaguchi, Hearing (2009).^[42]

[65] "Loss-of-signaling MC1R polymorphisms are commonly found among fair-skinned, sun-sensitive and skin cancer-prone populations (e.g., Northern Europeans). The most prevalent MC1R mutations (D84E, R151C, R160W and D294H) are commonly referred to as “RHC” (red hair color) alleles because of their association with red hair color, freckling and tendency to burn after UV exposure [references omitted]."^[54]

[73] Computed from the data reported by Yamazaki et. al. (2009):^[61] IC₅₀(serotonin)=550 µmol/l. IC₅₀(kojic acid)=68 µmol/l.

[Keratinocytes-79] "In the skin, melanocytes are situated on the basal layer which separates dermis and epidermis. One melanocyte is surrounded by approximately 36 keratinocytes. Together, they form the so-called epidermal melanin unit. The melanin produced and stored inside the melanocyte in the melanosomal compartment is transported via dendrites to the overlaying keratinocytes."^[41]

"Each melanocyte resides in the basal epithelial layer and, by virtue of its dendrites, interacts with approximately 36 keratinocytes to transfer melanosomes and protect the skin from photo-induced carcinogenesis. Furthermore, the amount and type of melanin produced and transferred to the keratinocytes with subsequent incorporation, aggregation and degradation influences skin complexion coloration [reference omitted]."^[14]

Wu, Hammer (2014) describe the number of keratinocytes per melanocyte as above 40.^[66]

[80] "Keratinocytes are the most abundant cells in the epidermis and are characterized by their expression of cytokeratins and formation of desmosomes and tight junctions with each other to form an effective physicochemical barrier."^[54]

[81] Research about the mechanism of melanosome transfer has been reviewed by Wu, Hammer (2014).^[66]

[86] "Protease-activated receptor (PAR)-2 is a member of a novel G-protein-coupled seven-transmembrane receptor family. In epidermis, PAR-2 is expressed in keratinocytes [references omitted], but not melanocytes [references omitted]. A central role for PAR-2 in keratinocyte uptake of melanosomes has been established [references omitted]. PAR-2 has been linked to the upregulation of COX-2 and the release of arachidonic acid and secretion of PGE2 and PGF2α [references omitted]. Several reports have suggested that PAR-2 mediates cutaneous pigmentation through increased uptake of melanosomes by keratinocytes and by the release of PGE2 and PGF2α that stimulate melanocyte dendricity [references omitted]."^[68]

[PAR2-91] References about PAR2 and its role in skin pigmentation: Kim (2016),^[71] Choi (2014),^[72] Makino-Okamura (2014),^[67] Wu, Hammer (2014),^[66] Ando (2012),^[73] Ando (2010).^[74]

[2] Lee, Heun Joo; Lee, Woo Jin; Chang, Sung Eun; Lee, Ga-Young (2015). "Hesperidin, A Popular Antioxidant Inhibits Melanogenesis via Erk1/2 Mediated MITF Degradation". Int. J. Mol. Sci. 16 (8). doi:10.3390/ijms160818384. PMC 4581251. PMID 26262610.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[3] Narayan, A. Bloomberg Business Week, A Lucrative Promise for India's men: Whiter skin, Dec 5, 2013

[4] McDougall, A. Cosmeticsdesign-Asia.com, Skin lightening trend in Asia boosts global market.

[Chang2009-5] ^ ^a ^b ^c ^d ^e ^f Chang, Te-Sheng (2009). "An Updated Review of Tyrosinase Inhibitors". Int. J. Mol. Sci. 10 (6). doi:10.3390/ijms10062440. PMC 2705500. PMID 19582213.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[6] Choi, Joonhyeok; Choi, Kwang-Eun; Park, Sung Jean; Kim, Sun Yeou; Jee, Jun-Goo (2016). "Ensemble-Based Virtual Screening Led to the Discovery of New Classes of Potent Tyrosinase Inhibitors". J. Chem. Inf. Model. 56 (2). doi:10.1021/acs.jcim.5b00484. PMID 26750991. Restricted access.

[7] Ai, Ni; Welsh, William J.; Santhanam, Uma; Hu, Hong; Lyga, John (2014). "Novel Virtual Screening Approach for the Discovery of Human Tyrosinase Inhibitors". PLoS ONE. 9 (11). doi:10.1371/journal.pone.0112788. PMC 4245091. PMID 25426625.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[8] Baek, Seung-Hwa; Lee, Sang-Han (2015). "Proton pump inhibitors decrease melanogenesis in melanocytes". Biomed. Rep. 3 (5). doi:10.3892/br.2015.492. PMC 4535079. PMID 26405553. Template:Lref

[9] Choi, Joonhyeok; Jee, Jun-Goo (2015). "Repositioning of Thiourea-Containing Drugs as Tyrosinase Inhibitors". Int. J. Mol. Sci. 16 (12). doi:10.3390/ijms161226114. PMC 4691061. PMID 26633377.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[10] "Inhibitory effects of imatinib mesylate on human epidermal melanocytes". Clin. Exp. Dermatol. 39 (2). 2014. doi:10.1111/ced.12261. PMID 24479586. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.

[Espín2001-11] Espín, Juan Carlos; Wichers, Harry J. (2001). "Effect of captopril on mushroom tyrosinase activity in vitro". Biochim. Biophys. Acta. 1544 (1–2). doi:10.1016/s0167-4838(00)00230-2. PMID 11341938. Restricted access.

[12] Liu, Qing; Kim, Cheong Taek; Jo, Yang Hee; Kim, Seon Beom; Hwang, Bang Yeon; Lee, Mi Kyeong (2015). "Synthesis and Biological Evaluation of Resveratrol Derivatives as Melanogenesis Inhibitors". Molecules. 20 (9). doi:10.3390/molecules200916933. PMID 26393543.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[13] "Synthesis and Biological Evaluation of Unsymmetrical Curcumin Analogues as Tyrosinase Inhibitors". Molecules. 18 (4). 2013. doi:10.3390/molecules18043948. PMID 23552906. {{cite journal}}: Cite uses deprecated parameter |authors= (help)CS1 maint: unflagged free DOI (link) Template:Lref

[Chang2012-14] ^ ^a ^b ^c ^d ^e ^f ^g ^h Chang, Te-Sheng (2012). "Natural Melanogenesis Inhibitors Acting Through the Down-Regulation of Tyrosinase Activity". Materials. 5 (9). doi:10.3390/ma5091661.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[Ebanks2009-15] Ebanks, Jody P.; Wickett, R. Randall; Boissy, Raymond E. (2009). "Mechanisms Regulating Skin Pigmentation: The Rise and Fall of Complexion Coloration". Int. J. Mol. Sci. 10 (9). doi:10.3390/ijms10094066. PMC 2769151. PMID 19865532.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[16] Whitehead, Ross D.; Re, Daniel; Xiao, Dengke; Ozakinci, Gozde; Perrett, David I. (2012). "You Are What You Eat: Within-Subject Increases in Fruit and Vegetable Consumption Confer Beneficial Skin-Color Changes". PLoS ONE. 7 (3). doi:10.1371/journal.pone.0032988. PMC 3296758. PMID 22412966.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[17] Pezdirc, Kristine; Hutchesson, Melinda J.; Whitehead, Ross; Ozakinci, Gozde; Perrett, David; Collins, Clare E. (2015). "Fruit, Vegetable and Dietary Carotenoid Intakes Explain Variation in Skin-Color in Young Caucasian Women: a Cross-Sectional Study". Nutrients. 7 (7). doi:10.3390/nu7075251. PMC 4517028. PMID 26184306.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[Kondo2011-18] Kondo, Taisuke; Hearing, Vincent J. (2011). "Update on the regulation of mammalian melanocyte function and skin pigmentation". Expert. Rev. Dermatol. 6 (1). doi:10.1586/edm.10.70. PMC 3093193. PMID 21572549. Template:Lref

[Slominski2004-19] ^ ^a ^b ^c ^d ^e ^f Slominski, Andrzej; Tobin, Desmond J.; Shibahara, Shigeki; Wortsman, Jacobo (2004). "Melanin Pigmentation in Mammalian Skin and its Hormonal Regulation". Physiol. Rev. 84 (4). doi:10.1152/physrev.00044.2003. PMID 15383650. Template:Lref

[23] "Tyrosinase inhibitors: a patent review (2011-2015)" (PDF). Expert. Opin. Ther. Pat. 26 (3). 2016. doi:10.1517/13543776.2016.1146253. PMID 26815044. {{cite journal}}: Cite uses deprecated parameter |authors= (help)

[24] Pillaiyar, Thanigaimalai; Manickam, Manoj; Jung, Sang-Hun. "Inhibitors of melanogenesis: a patent review (2009-2014)" (PDF). Expert. Opin. Ther. Pat. 25 (7). doi:10.1517/13543776.2015.1039985. PMID 25939410.

[26] Gruber, James V.; Holtz, Robert (2013). "Examining the Impact of Skin Lighteners In Vitro". Oxidative Medicine and Cellular Longevity. doi:10.1155/2013/702120. PMC 3655678. PMID 23738040.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[27] "Anti-tyrosinase kinetics and antibacterial process of caffeic acid N-nonyl ester in Chinese Olive (Canarium album) postharvest". Int. J. Biol. Macromol. 91. 2016. doi:10.1016/j.ijbiomac.2016.05.098. PMID 27246378. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.

[28] Chen, Bing-Nian; Xing, Rui; Wang, Fang; Zheng, A-Ping; Wang, Li (2015). "Inhibitory effects of α-Na8SiW11CoO40 on tyrosinase and its application in controlling browning of fresh-cut apples". Food Chem. 188. doi:10.1016/j.foodchem.2015.05.003. PMID 26041180. Restricted access.

[29] Liu, Jinbing; Wu, Fengyan; Chen, Changhong (2015). "Design and synthesis of aloe-emodin derivatives as potent anti-tyrosinase, antibacterial and anti-inflammatory agents". Bioorg. Med. Chem. Lett. 25 (22). doi:10.1016/j.bmcl.2015.10.004. PMID 26471089. Restricted access.

[30] "Design, synthesis and biological evaluation of hydroxy- or methoxy-substituted 5-benzylidene(thio) barbiturates as novel tyrosinase inhibitors" (PDF). Bioorg. Med. Chem. 22 (13). 2014. doi:10.1016/j.bmc.2014.04.060. PMID 24857777. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref

[31] "Inhibitory effects of 5-benzylidene barbiturate derivatives on mushroom tyrosinase and their antibacterial activities" (PDF). Eur. J. Med. Chem. 44 (10). 2009. doi:10.1016/j.ejmech.2009.05.023. PMID 19552984. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref

[32] "Synthesis and evaluation of 5-benzylidene(thio)barbiturate-β-D-glycosides as mushroom tyrosinase inhibitors" (PDF). Bioorg. Med. Chem. Lett. 19 (15). 2009. doi:10.1016/j.bmcl.2009.06.018. PMID 19564107. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref

[33] Liu, Jinbing; Chen, Changhong; Wu, Fengyan; Zhao, Liangzhong (2013). "Microwave-assisted synthesis and tyrosinase inhibitory activity of chalcone derivatives". Chem. Biol. Drug. Des. 82 (1). doi:10.1111/cbdd.12126. PMID 23461881. Template:Lref

[34] Kuijpers, Tomas F. M.; Gruppen, Harry; Sforza, Stefano; van Berkel, Willem J. H.; Vincken, Jean-Paul (2013). "The antibrowning agent sulfite inactivates Agaricus bisporus tyrosinase through covalent modification of the copper-B site". FEBS J. 280 (23). doi:10.1111/febs.12539. PMID 24112416. Template:Lref

[35] "Biological evaluation of coumarin derivatives as mushroom tyrosinase inhibitors". Food Chem. 135 (4). 2012. doi:10.1016/j.foodchem.2012.07.055. PMID 22980884. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.

[36] "Kinetic characterisation of o-aminophenols and aromatic o-diamines as suicide substrates of tyrosinase". Biochim. Biophys. Acta. 1824 (4). 2012. doi:10.1016/j.bbapap.2012.02.001. PMID 22342555. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.

[37] "Tetrahydrofolic Acid is a potent suicide substrate of mushroom tyrosinase". J. Agric. Food Chem. 59 (4). 2011. doi:10.1021/jf1035433. PMID 21265541. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.

[38] "Evaluation of dihydropyrimidin-(2H)-one analogues and rhodanine derivatives as tyrosinase inhibitors". Bioorg. Med. Chem. Lett. 21 (8). 2011. doi:10.1016/j.bmcl.2011.02.076. PMID 21411319. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.

[39] "Suicide inactivation of tyrosinase in its action on tetrahydropterines". J. Enzyme Inhib. Med. Chem. 26 (5). 2010. doi:10.3109/14756366.2010.548811. PMID 21299451. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.

[40] "Irreversible competitive inhibitory kinetics of cardol triene on mushroom tyrosinase". J. Agric. Food Chem. 58 (24). 2010. doi:10.1021/jf103723k. PMID 21121650. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.

[41] Yamazaki, Yoshimitsu; Kawano, Yasuhiro (2010). "N-(3,5-dihydroxybenzoyl)-6-hydroxytryptamine as a novel human tyrosinase inhibitor that inactivates the enzyme in cooperation with l-3,4-dihydroxyphenylalanine". Chem. Pharm. Bull. 58 (11). doi:10.1248/cpb.58.1536. PMID 21048351. Template:Lref

[42] Li, Shu-Bai; Nie, Hua-Li; Zhang, Hai-Tao; Xue, Yong; Zhu, Li-Min (2010). "Kinetic Evaluation of Aminoethylisothiourea on Mushroom Tyrosinase Activity". Appl. Biochem. Biotechnol. 162 (3). doi:10.1007/s12010-009-8760-3. PMID 19763898. Template:Lref

[43] Chang, Te-Sheng; Lin, Meng-Yi; Lin, Hsuan-Jung (2010). "Identifying 8-hydroxynaringenin as a suicide substrate of mushroom tyrosinase" (PDF). J. Cosmet. Sci. 61 (3). doi:10.1111/j.1468-2494.2010.00619_1.x. PMID 20587349. Template:Lref

[44] "Melanogenesis Inhibition Due to NADH". Biosci. Biotechnol. Biochem. 74 (9). 2010. doi:10.1271/bbb.90965. PMID 20834177. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref

[45] Tai, Sorgan Shou-Ku; Lin, Ching-Gong; Wu, Mon-Han; Chang, Te-Sheng (2009). "Evaluation of Depigmenting Activity by 8-Hydroxydaidzein in Mouse B16 Melanoma Cells and Human Volunteers". Int. J. Mol. Sci. 10 (10). doi:10.3390/ijms10104257. PMC 2790106. PMID 20057943.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[Smit2009-47] Smit, Nico; Vicanova, Jana; Pavel, Stan (2009). "The Hunt for Natural Skin Whitening Agents". Int. J. Mol. Sci. 10 (12). doi:10.3390/ijms10125326. PMC 2801997. PMID 20054473.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[Yamaguchi2009-49] Yamaguchi, Yuji; Hearing, Vincent J. (2009). "Physiological factors that regulate skin pigmentation". Biofactors. 35 (2). doi:10.1002/biof.29. PMC 2793097. PMID 19449448. Template:Lref

[Imokawa2014-50] Imokawa, Genji; Ishida, Koichi (2014). "Inhibitors of Intracellular Signaling Pathways that Lead to Stimulated Epidermal Pigmentation: Perspective of Anti-Pigmenting Agents". Int. J. Mol. Sci. 15 (5). doi:10.3390/ijms15058293. PMC 4057732. PMID 24823877.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[52] "A systems-biological study on the identification of safe and effective molecular targets for the reduction of ultraviolet B-induced skin pigmentation". Sci. Rep. 5. 2015. doi:10.1038/srep10305. PMC 4434836. PMID 25980672. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref

[53] "UVB Stimulates the Expression of Endothelin B Receptor in Human Melanocytes via a Sequential Activation of the p38/MSK1/CREB/MITF Pathway Which Can Be Interrupted by a French Maritime Pine Bark Extract through a Direct Inactivation of MSK1". PLOS ONE. 10 (6). 2015. doi:10.1371/journal.pone.0128678. PMC 4452497. PMID 26030901. {{cite journal}}: Cite uses deprecated parameter |authors= (help)CS1 maint: unflagged free DOI (link) Template:Lref

[54] Kim, Hye-Eun; Ishihara, Atsushi; Lee, Seong-Gene (2012). "The effects of Caffeoylserotonin on inhibition of melanogenesis through the downregulation of MITF via the reduction of intracellular cAMP and acceleration of ERK activation in B16 murine melanoma cells". BMB Rep. 45 (12). doi:10.5483/BMBRep.2012.45.12.039. PMC 4133815. PMID 23261059. Template:Lref

[55] "A novel adamantyl benzylbenzamide derivative, AP736, inhibits melanogenesis in B16F10 mouse melanoma cells via glycogen synthase kinase 3β phosphorylation". Int. J. Mol. Med. 2015. doi:10.3892/ijmm.2015.2348. PMID 26398893. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref

[56] "Inhibitory Effect of Dried Pomegranate Concentration Powder on Melanogenesis in B16F10 Melanoma Cells; Involvement of p38 and PKA Signaling Pathways". Int. J. Mol. Sci. 16 (10). 2015. doi:10.3390/ijms161024219. PMC 4632747. PMID 26473849. {{cite journal}}: Cite uses deprecated parameter |authors= (help)CS1 maint: unflagged free DOI (link) Template:Lref

[57] Jin, Kyong-Suk; Oh, You Na; Hyun, Sook Kyung; Kwon, Hyun Ju; Kim, Byung Woo (2014). "Betulinic acid isolated from Vitis amurensis root inhibits 3-isobutyl-1-methylxanthine induced melanogenesis via the regulation of MEK/ERK and PI3K/Akt pathways in B16F10 cells". Food Chem. Toxicol. 68. doi:10.1016/j.fct.2014.03.001. PMID 24632067.

[Chen2014-58] Chen, Hongxiang; Weng, Qing Y.; Fisher, David E. (2014). "UV Signaling Pathways within the Skin". J. Invest. Dermatol. 134 (4). doi:10.1038/jid.2014.161. PMC 4102648. PMID 24759085. Template:Lref

[Rodríguez2014-59] Rodríguez, Carlos Iván; Setaluri, Vijayasaradhi (2014). "Cyclic AMP (cAMP) signaling in melanocytes and melanoma". Arch. Biochem. Biophys. 563. doi:10.1016/j.abb.2014.07.003. PMID 25017568. Restricted access.

[Lee2013-61] Lee, Ai-Young; Noh, Minsoo (2013). "The regulation of epidermal melanogenesis via cAMP and/or PKC signaling pathways: insights for the development of hypopigmenting agents". Arch. Pharm. Res. 36 (7). doi:10.1007/s12272-013-0130-6. PMID 23604723. Restricted access.

[62] "PDE5 inhibitor promotes melanin synthesis through the PKG pathway in B16 melanoma cells". J. Cell Biochem. 113 (8). 2012. doi:10.1002/jcb.24147. PMID 22441938. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref

[D'Orazio2013-63] D’Orazio, John; Jarrett, Stuart; Amaro-Ortiz, Alexandra; Scott, Timothy (2013). "UV Radiation and the Skin". Int. J. Mol. Sci. 14 (6). doi:10.3390/ijms140612222. PMC 3709783. PMID 23749111.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[66] Marzuka-Alcalá, Alexander; Gabree, Michele Jacobs; Tsao, Hensin (2014). "Melanoma susceptibility genes and risk assessment". Methods Mol. Biol. doi:10.1007/978-1-62703-727-3_20. PMID 24258989. Restricted access.

[67] Law, Matthew H.; MacGregor, Stuart; Hayward, Nicholas K. (2012). "Melanoma Genetics: Recent Findings Take Us Beyond Well-Traveled Pathways". J. Invest. Dermatol. 132 (7). doi:10.1038/jid.2012.75. PMID 22475760. Template:Lref

[Nelson2009-68] Nelson, Andrew A.; Tsao, Hensin (2009). "Melanoma and genetics". Clin. Dermatol. 27 (1). doi:10.1016/j.clindermatol.2008.09.005. PMID 19095153. Restricted access.

[69] Sturm, Richard A. (2009). "Molecular genetics of human pigmentation diversity". Hum. Mol. Genet. 19 (R1). doi:10.1093/hmg/ddp003. PMID 19297406. Template:Lref

[70] "Genetic determinants of hair, eye and skin pigmentation in Europeans" (PDF). Nat. Genet. 39 (12). 2007. doi:10.1038/ng.2007.13. PMID 17952075. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref

[71] Barsh, Gregory S. (2003). "What Controls Variation in Human Skin Color?". PLoS Biology. doi:10.1371/journal.pbio.0000027. PMC 212702. PMID 14551921.{{cite journal}}: CS1 maint: unflagged free DOI (link) No-cost access, unknown license.

[Yamazaki2009-72] Yamazaki, Yoshimitsu; Kawano, Yasuhiro; Yamanaka, Akiko; Maruyama, Susumu (2009). "N-[(Dihydroxyphenyl)acyl]serotonins as potent inhibitors of tyrosinase from mouse and human melanoma cells". Bioorg. Med. Chem. Lett. 19 (15). doi:10.1016/j.bmcl.2009.05.115. PMID 19524439. Restricted access.

[74] Zhou, Jia; Geng, Kun-kun; Ping, Feng-feng; Gao, Yue-ying; Liu, Lei; Feng, Bai-nian (2016). "Cross-talk between 5-hydroxytryptamine and substance P in the melanogensis and apoptosis of B16F10 melanoma cells". Eur. J. Pharmacol. doi:10.1016/j.ejphar.2016.02.026. PMID 26872989. Restricted access.

[75] "A Novel Role of Serotonin Receptor 2B Agonist as an Anti-Melanogenesis Agent". Int. J. Mol. Sci. 17 (4). 2016. doi:10.3390/ijms17040546. PMC 4849002. PMID 27077852. {{cite journal}}: Cite uses deprecated parameter |authors= (help)CS1 maint: unflagged free DOI (link) Template:Lref

[76] Lee, H. J.; Park, M. K.; Kim, S. Y.; Park Choo, H. Y.; Lee, A. Y.; Lee, C. H. (2011). "Serotonin induces melanogenesis via serotonin receptor 2A". Br. J. Dermatol. 165 (6). doi:10.1111/j.1365-2133.2011.10490.x. PMID 21711335. Template:Lref

[77] Max, McEwan; Persons, Peter G. (1987). "Inhibition of melanization in human melanoma cells by a serotonin uptake inhibitor" (PDF). J. Invest. Dermatol. 89 (1). doi:10.1111/1523-1747.ep12580425. PMID 3110297. Template:Lref

[Wu2014-78] Wu, Wufeng; Hammer, John A. (2014). "Melanosome transfer: It is best to give and receive". Curr. Opin. Cell Biol. 29. doi:10.1016/j.ceb.2014.02.003. PMC 4130791. PMID 24662021. Manuscript in PMC.

[Makino-Okamura2014-82] "Heparin inhibits melanosome uptake and inflammatory response coupled with phagocytosis through blocking PI3k/Akt and MEK/ERK signaling pathways in human epidermal keratinocytes" (PDF). Pigment Cell Melanoma Res. 27 (6). 2014. doi:10.1111/pcmr.12287. PMID 24961476. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref

[Jung2013-83] Jung, Eunsun; Lee, Jung-A; Shin, Seoungwoo; Roh, Kyung-Baeg; Kim, Jang-Hyun; Park, Deokhoon (2013). "Madecassoside Inhibits Melanin Synthesis by Blocking Ultraviolet-Induced Inflammation". Molecules. 18 (12). doi:10.3390/molecules181215724. PMID 24352025.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[84] Leyden, James; Wallo, Warren (2011). "The mechanism of action and clinical benefits of soy for the treatment of hyperpigmentation". Int. J. Dermatol. 50 (4). doi:10.1111/j.1365-4632.2010.04765.x. PMID 21332714. Restricted access.

[85] "The natural yeast extract isolated by ethanol precipitation inhibits melanin synthesis by modulating tyrosinase activity and downregulating melanosome transfer". Biosci. Biotechnol. Biochem. 79 (9). 2015. doi:10.1080/09168451.2015.1032880. PMID 25943301. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Restricted access.

[87] Kim, Ji Young; Kim, Dae Suk; Sohn, Hyojung; Lee, Eun Jung; Oh, Sang Ho (2016). "PAR-2 is involved in melanogenesis by mediating stem cell factor production in keratinocytes". Exp. Dermatol. 25 (6). doi:10.1111/exd.12982. PMID 26909822. Template:Lref

[88] "Melanosome uptake is associated with the proliferation and differentiation of keratinocytes" (PDF). Arch. Dermatol. Res. 306. 2014. doi:10.1007/s00403-013-1422-x. PMID 24173125. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref

[89] "Melanosomes are transferred from melanocytes to keratinocytes through the processes of packaging, release, uptake, and dispersion" (PDF). J. Invest. Dermatol. 132 (4). 2012. doi:10.1038/jid.2011.413. PMID 22189785. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref

[90] "Keratinocytes in culture accumulate phagocytosed melanosomes in the perinuclear area" (PDF). Pigment Cell Melanoma Res. 23 (1). 2010. doi:10.1111/j.1755-148X.2009.00640.x. PMID 19761520. {{cite journal}}: Cite uses deprecated parameter |authors= (help) Template:Lref

[Nagasaki2008-92] Nagasaki, Kenji; Kumazawa, Masaro; Murakami, Shuichiro; Takenaka, Shinji; Koike, Kenzo; Aoki, Kenji (2008). "Purification, characterization, and gene cloning of Ceriporiopsis sp. strain MD-1 peroxidases that decolorize human hair melanin". Appl. Environ. Microbiol. 74 (16). doi:10.1128/AEM.00253-08. PMC 2519264. PMID 18586974. Template:Lref

[93] Mauricio, Tess; Karmon, Yoram; Khaiat, Alain (2011). "A randomized and placebo-controlled study to compare the skin-lightening efficacy and safety of lignin peroxidase cream vs. 2% hydroquinone cream". J. Cosmet. Dermatol. 10 (4). doi:10.1111/j.1473-2165.2011.00581.x. PMID 22151932. Restricted access.

[94] Zhong, Shao-Min; Sun, Nan; Liu, Hui-Xian; Niu, Yue-Qing; Wu, Yan (2015). "Reduction of facial pigmentation of melasma by topical lignin peroxidase: A novel fast-acting skin-lightening agent". Exp. Ther. Med. 9 (2). doi:10.3892/etm.2014.2118. PMC 4280934. PMID 25574195. Template:Lref

[95] van den Boorn, Jasper G.; Melief, Cornelis J.; Luiten, Rosalie M. "The Monobenzone-induced depigmentation: from enzymatic blockade to autoimmunity" (PDF). Pigment Cell Melanoma Res. 24 (4). doi:10.1111/j.1755-148X.2011.00878.x. PMID 21689385. Template:Lref

[96] Ito, Shosuke; Wakamatsu, Kazumasa (2015). "A convenient screening method to differentiate phenolic skin whitening tyrosinase inhibitors from leukoderma-inducing phenols" (PDF). J. Dermatol. Sci. 80 (1). doi:10.1016/j.jdermsci.2015.07.007. PMID 26228294. Template:Lref

[Rendon-97] Rendon, Marta; Berneburg, Mark; Arellano, Ivonne; Picardo, Mauro (May 2006). "Treatment of melasma". Journal of the American Academy of Dermatology. Supplement 2. 54 (5): S272–S281. doi:10.1016/j.jaad.2005.12.039.

[DermatologicSurgery2006-98] "Repeated Treatment Protocols for Melasma and Acquired Dermal Melanocytosis". Dermatologic Surgery. 32: 365–371. March 2006. doi:10.1097/00042728-200603000-00005.

[99] Journal of Drugs in Dermatology: 27–34. 2004. {{cite journal}}: Missing or empty |title= (help)

[100] "Safety and efficacy of 4% hydroquinone combined with 10% glycolic acid, antioxidants, and sunscreen in the treatment of melasma". International Journal of Dermatology. 42: 966–972. 2003. doi:10.1111/j.1365-4632.2003.02017.x.

[101] "Efficacy of Glycolic Acid Peels in the Treatment of Melasma". Archives of Dermatology. 138: 1578–1582. December 2002. doi:10.1001/archderm.138.12.1578.

[102] "Hypopigmented Macules of Photodamaged Skin and Their Treatment with Topical Tretinoin". Acta Dermato-Venereologica. 79: 305–310. July 1999. doi:10.1080/000155599750010724.

[103] "Short- and long-term histologic effects of topical tretinoin on photodamaged skin". International Journal of Dermatology. 37: 286–292. April 1998. doi:10.1046/j.1365-4362.1998.00433.x.

[104] "Treatment of photodamage with topical tretinoin: An overview". Journal of the American Academy of Dermatology. 36: S27–S36. March 1997. doi:10.1016/s0190-9622(97)70058-6.

[105] Cutis: 177–184. March 2006. {{cite journal}}: Missing or empty |title= (help)

[106] Journal of Drugs in Dermatology: 592–597. September–October 2005. {{cite journal}}: Missing or empty |title= (help)

[107] Journal of Cosmetic Science: 208–290. May–June 1998. {{cite journal}}: Missing or empty |title= (help)

[108] Dermatological Surgery. 22: 443–447. May 1996. doi:10.1016/1076-0512(96)00065-9. {{cite journal}}: Missing or empty |title= (help)

[109] "New Antioxidant Hydroquinone Derivatives from the Algicolous Marine Fungus Acremonium sp". Journal of Natural Products. 65: 1605–1611. November 2002. doi:10.1021/np020128p.

[110] Journal of Dermatological Science: 68–75. August 2001. {{cite journal}}: Missing or empty |title= (help)

[111] "Skin diseases associated with the cosmetic use of bleaching products in women from Dakar, Senegal". British Journal of Dermatology. 148: 493–500. March 2003. doi:10.1046/j.1365-2133.2003.05161.x.

[112] Fuller, Thomas (2006-05-14). "A Vision of Pale Beauty Carries Risks for Asia's Women". The New York Times. Retrieved 2010-05-23.

[113] Drugs in Dermatology: 377–381. July–August 2004. {{cite journal}}: Missing or empty |title= (help)

[114] Maeda, K; Fukuda, M (1996). "Arbutin: mechanism of its depigmenting action in human melanocyte culture". Journal of Pharmacology and Experimental Therapeutics. 276 (2): 765–769. PMID 8632348.

[115] Jun, So-Young; Park, Kyung-Min; Choi, Ki-Won; Jang, Min Kyung; Kang, Hwan Yul; Lee, Sang-Hyeon; Park, Kwan-Hwa; Cha, Jaeho (2007). "Inhibitory effects of arbutin-β-glycosides synthesized from enzymatic transglycosylation for melanogenesis". Biotechnology Letters. 30 (4): 743–8. doi:10.1007/s10529-007-9605-1. PMID 18040603.

[116] Archives of Pharmacal Research, August 2001, pages 307-311.

[117] Mutation Research, Genetic Toxicology and Environmental Mutagenesis, June 2005, pages 133-1450 and Toxicological Sciences, September 2004, pages 43–49.

[118] Serra-Baldrich, E.; Tribô, M. J.; Camarasa, J. G. (1998). "Allergic contact dermatitis from kojic acid". Contact Dermatitis. 39: 86–87. doi:10.1111/j.1600-0536.1998.tb05843.x.

[119] Sarkar, Rashmi; Garg, VijayK; Arya, Latika; Arora, Pooja (2012). "Lasers for treatment of melasma and post-inflammatory hyperpigmentation". Journal of Cutaneous and Aesthetic Surgery. 5 (2): 93. doi:10.4103/0974-2077.99436.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[120] "Plastic Surgery Articles (Indications, Anatomy, Workup, Surgical Therapy, Treatment, Complications) - Medscape Reference". Retrieved 29 May 2014.

[121] Baliña, Luis M.; Graupe, Klaus (December 1991). "The Treatment of Melasma 20% Azelaic Acid versus 4% Hydroquinone Cream". International Journal of Dermatology. 30 (12): 893–895. doi:10.1111/j.1365-4362.1991.tb04362.x.

[122] Johnston, CS; Meyer, CG; Srilakshmi, JC (1993). "Vitamin C elevates red blood cell glutathione in healthy adults". The American Journal of Clinical Nutrition. 58 (1): 103–5. PMID 8317379.

[123] Fujiwara, Yoko; Sahashi, Yumiko; Aritro, Mitsumi; Hasegawa, Satoko; Akimoto, Koji; Ninomiya, Shinji; Sakaguchi, Yasue; Seyama, Yousuke (2004). "Effect of simultaneous administration of vitamin C, L-cysteine and vitamin E on the melanogenesis". BioFactors. 21 (1–4): 415–8. doi:10.1002/biof.552210182. PMID 15630239.

[124] Arjinpathana, Nutthavuth; Asawanonda, Pravit (2012). "Glutathione as an oral whitening agent: a randomized, double-blind, placebo-controlled study". J. Dermatolog. Treat. 23 (2). doi:10.3109/09546631003801619. PMID 20524875.

[125] Chung, Bo Young; Choi, So Ra; Moon, Ik Jun; Park, Chun Wook; Kim, Young-Hoon; Chang, Sung Eun (2016). "The Glutathione Derivative, GSH Monoethyl Ester, May Effectively Whiten Skin but GSH Does Not". Int. J. Mol. Sci. 17 (5). doi:10.3390/ijms17050629. PMC 4881455. PMID 27128906.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[126] Sonthalia, Sidharth; Daulatabad, Deepashree; Sarkar, Rashmi (2016). "Glutathione as a skin whitening agent: Facts, myths, evidence and controversies". Indian J. Dermatol. Venereol. Leprol. 82 (3). doi:10.4103/0378-6323.179088. PMID 27088927.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[pmid1362956-127] Witschi, A.; Reddy, S.; Stofer, B.; Lauterburg, B. H. (1992). "The systemic availability of oral glutathione". European journal of clinical pharmacology. 43 (6). doi:10.1007/BF02284971. PMID 1362956.

[128] Experimental Dermatology, January 2003, supplemental. pages 43-50.

[129] Dermatologic Surgery, February 2005, pages 149-154; Journal of Cutaneous Medicine and Surgery, April 2004, pages 97-102; Cutis, February 2004, supplemental, pages 18-24; Dermatologic Therapy, June 2004, pages 196-205; and Dermatological Surgery, June 1999, pages 450-454.

[130] Hopkins, Michael (24 July 2013). "How is bleaching done?". vaginalbleaching.org. Retrieved 24 October 2015.

[131] "Drug Safety and Availability - FDA Warns Consumers Not to Use Viansilk's "Crema Piel De Seda" ("Silky Skin Cream")". Drugs: Drug Safety and Availability. USFDA. January 29, 2016. Retrieved January 30, 2016.

[132] Experimental Dermatology, August 2005, pages 601-608; Bioscience, Biotechnology, and Biochemistry, December 2005, pages 2368-2373; International Journal of Dermatology, August 2004, pages 604-607; Journal of Drugs in Dermatology, July–August 2004, pages 377-381; Facial and Plastic Surgery, February 2004, pages 3-9; Dermatologic Surgery, March 2004, pages 385-388; Journal of Bioscience and Bioengineering, March 2005, pages 272-276; Journal of Biological Chemistry, November 7, 2003, pages 44320-44325; Journal of Agriculture and Food Chemistry, February 2003, pages 1201-1207; International Journal of Cosmetic Science, August 2000, pages 291-303; and Anti-Cancer Research, September–October 1999, pages 3769-3774.

[133] Journal of the American Academy of Dermatology, May 2006, supplemental, pages 262-271; Dermatologic Therapy, January 2001, page 46; Journal of Cosmetic and Laser Therapy, March 2005, pages 39-43; Journal of Cutaneous Medicine and Surgery, April 2004, pages 97-102; Journal of Drugs in Dermatology, November–December 2005, pages 770-774; Dermatologic Surgery, October 2005, page 1263; and Lasers in Surgery and Medicine, April 2000, pages 376-379.

[134] Counter, S. Allen, Whitening skin can be deadly, Boston Globe, 16 Dec 2003

[135] Akortha, E.E.; Niemogha, M.T.; Edobor, O. (1 June 2012). "MUTAGENIC AND GENOTOXIC SCREENING OF EIGHT COMMONLY USED SKIN WHITENING CREAMS IN NIGERIA". Bayero Journal of Pure and Applied Sciences. 5 (1): 5–10. doi:10.4314/bajopas.v5i1.2. Retrieved 25 December 2012.

[136] Peregrino, C. P.; Moreno, M. V.; Miranda, S. V.; Rubio, A. D.; Leal, L. O. (11 June 2011). "Mercury Levels in Locally Manufactured Mexican Skin-Lightening Creams". Int. J. Environ. Res. Public Health. doi:10.3390/ijerph8062516. PMC 3138038. PMID 21776243.{{cite journal}}: CS1 maint: unflagged free DOI (link) Template:Lref

[notes 1]

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[notes 2]

[18]

[notes 3]

[notes 4]

[19]

[20]

[notes 5]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[notes 6]

[41]

[notes 7]

[notes 8]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[42]

[notes 9]

[52]

[53]

[notes 10]

[notes 11]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[notes 12]

[62]

[63]

[64]

[65]

[notes 13]

[notes 14]

[notes 15]

[66]

[67]

[68]

[69]

[70]

[notes 16]

[notes 17]

[75]

[76]

[77]

[78]

[79]

[80]

[81]

[82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

@@ Line 1: / Line 1: @@
+'''Skin whitening'''{{refn|group=notes|Instead of "whitening", the terms "lightening", "brightening", "depigmentation" and "bleaching" are also used.}} is the practice of using substances, mixtures, or physical treatments to lighten skin color. Skin whitening treatments work by reducing the content of [[melanin]] of the skin. Many agents have been shown to be effective in skin whitening; some have beneficial side effects (e.g: are antioxidants,<ref>{{cite journal| title=Hesperidin, A Popular Antioxidant Inhibits Melanogenesis via Erk1/2 Mediated MITF Degradation| last1=Lee| first1=Heun Joo| last2=Lee| first2=Woo Jin| last3=Chang| first3=Sung Eun| last4=Lee| first4=Ga-Young| year=2015| journal=Int. J. Mol. Sci.| volume=16| issue=8| doi=10.3390/ijms160818384| pmc=4581251| pmid=26262610}} {{lref|f|CC BY 4.0}}</ref> nutrients, or decrease the risk of some types of cancer); some are a significant risk to health (for example, those containing mercury).
-{{medref|date=December 2013}}
-'''Skin whitening''', '''skin lightening''', and '''skin bleaching''' refer to the practice of using chemical substances in an attempt to lighten skin tone or provide an even skin complexion by '''reducing''' the [[melanin]] concentration in the skin. Several chemicals have been shown to be effective in skin whitening, while some have proven to be toxic or have questionable safety profiles, adding to the controversy surrounding their use and impacts on certain ethnic groups.
 ==Uses==
-Specific zones of abnormally high pigmentation such as [[Mole (skin marking)|moles]] and [[birthmark]]s may be depigmented to match to the surrounding skin. Conversely, in cases of [[vitiligo]], unaffected skin may be lightened to achieve a more uniform appearance.<ref>{{cite news | author = Rashid, Aliya | title = A rush to cream the fairness fetish | publisher = NDA India | date = Sep 1, 2006 | url = http://www.dnaindia.com/money/report-a-rush-to-cream-the-fairness-fetish-1050554}}</ref>{{medcn|date=December 2013}}  Long term use of skin whiteners can lead to pigmentation increasing to the joints of the fingers, toes, buttocks and ears.{{medcn|date=July 2015}} The skin of the face can become thinned and the area around the eyes can have increased pigmentation causing a 'bleach panda effect'.<ref name="Olumide2010">{{cite journal|last=Olumide|first=Y. M.|year=2010|title=Use of skin lightening creams|journal=BMJ|volume=341|issue=nov23 2|pages=c6102–c6102|issn=0959-8138|doi=10.1136/bmj.c6102}}</ref>
+Specific zones of abnormally high pigmentation such as [[lentigo]] spots, [[mole (skin marking)|moles]] and [[birthmark]]s may be depigmented to match to the surrounding skin. In cases of [[vitiligo]], unaffected skin may be lightened to achieve a more uniform appearance.
-sales of skin lightening creams in India alone totaled 258 tons<ref>Narayan, A.  Bloomberg Business Week, A Lucrative Promise for India's men: Whiter skin, Dec 5, 2013</ref> and the global market for skin lighteners is projected to reach US $19.8 billion by 2018 based on sales growth primarily in Asia, Africa and the Middle East.<ref>McDougall, A.  Cosmeticsdesign-Asia.com, Skin lightening trend in Asia boosts global market.</ref>
+In India, the sales of skin lightening creams in 2012 totaled 258 tons<ref>Narayan, A.  Bloomberg Business Week, A Lucrative Promise for India's men: Whiter skin, Dec 5, 2013</ref> and the global market for skin lighteners is projected to reach US $19.8 billion by 2018 based on sales growth primarily in Asia, Africa and the Middle East.<ref>McDougall, A.  Cosmeticsdesign-Asia.com, Skin lightening trend in Asia boosts global market.</ref>
+==Discovery and design==
-==Combination treatments==
+Melanogenesis inhibitors have been discovered and developed through several methods, including: screening of synthetic [[chemical library|chemical libraries]] ([[high throughput screening]] is occasionally used), screening of plant extracts,{{r|Chang2009}} computational ([[in silico]]) search,<ref>{{cite journal| title=Ensemble-Based Virtual Screening Led to the Discovery of New Classes of Potent Tyrosinase Inhibitors| last1=Choi| first1=Joonhyeok| last2=Choi| first2=Kwang-Eun| last3=Park| first3=Sung Jean| last4=Kim| first4=Sun Yeou| last5=Jee| first5=Jun-Goo| year=2016| journal=J. Chem. Inf. Model.| volume=56| issue=2| doi=10.1021/acs.jcim.5b00484| pmid=26750991}} Restricted access.</ref><ref>{{cite journal| title=Novel Virtual Screening Approach for the Discovery of Human Tyrosinase Inhibitors| last1=Ai| first1=Ni| last2=Welsh| first2=William J.| last3=Santhanam| first3=Uma| last4=Hu| first4=Hong| last5=Lyga| first5=John| year=2014| journal=PLoS ONE| volume=9| issue=11| doi=10.1371/journal.pone.0112788| pmc=4245091| pmid=25426625}} {{lref|f|CC BY 4.0}}</ref> found as a side effect of previously known drugs<ref>{{cite journal| title=Proton pump inhibitors decrease melanogenesis in melanocytes| last1=Baek| first1=Seung-Hwa| last2=Lee| first2=Sang-Han| year=2015| journal=Biomed. Rep.| volume=3| issue=5| doi=10.3892/br.2015.492| pmc=4535079| pmid=26405553}} {{lref|nf}}</ref><ref>{{cite journal| title=Repositioning of Thiourea-Containing Drugs as Tyrosinase Inhibitors| last1=Choi| first1=Joonhyeok| last2=Jee| first2=Jun-Goo| year=2015| journal=Int. J. Mol. Sci| volume=16| issue=12| doi=10.3390/ijms161226114| pmc=4691061| pmid=26633377}} {{lref|f|CC BY 4.0}}</ref><ref>{{cite journal| title=Inhibitory effects of imatinib mesylate on human epidermal melanocytes| authors=Wang, Y. et. al.| year=2014| journal=Clin. Exp. Dermatol.| volume=39| issue=2| doi=10.1111/ced.12261| pmid=24479586}} Restricted access.</ref>{{r|Espín2001}} and exploration of structural analogues of previously known tyrosinase inhibitors<ref>{{cite journal| title=Synthesis and Biological Evaluation of Resveratrol Derivatives as Melanogenesis Inhibitors| last1=Liu| first1=Qing| last2=Kim| first2=Cheong Taek| last3=Jo| first3=Yang Hee| last4=Kim| first4=Seon Beom| last5=Hwang| first5=Bang Yeon| last6=Lee| first6=Mi Kyeong| year=2015| journal=Molecules| volume=20| issue=9| doi=10.3390/molecules200916933| pmid=26393543}} {{lref|f|CC BY 4.0}}</ref><ref>{{cite journal| title=Synthesis and Biological Evaluation of Unsymmetrical Curcumin Analogues as Tyrosinase Inhibitors| authors=Jiang, Yongfu et. al.| year=2013| journal=Molecules| volume=18| issue=4| doi=10.3390/molecules18043948| pmid=23552906}} {{lref|f|CC BY 3.0}}</ref> based on knowledge (in varying degrees) of their [[structure-activity relationship]]. Thus, the development and discovery of melanogenesis inhibitors illustrates many of the methods used in [[drug design]]. Some of the most potent competitive reversible tyrosinase inhibitors are synthetic compounds with a potency hundreds of times that of kojic acid.
-Most skin-lightening treatments, which can reduce or block some amount of melanin production, are aimed at inhibiting [[tyrosinase]]. Many treatments use a combination of topical lotions or gels containing melanin-inhibiting ingredients along with a sunscreen, and a prescription [[retinoid]]. Depending on how the skin responds to these treatments, [[exfoliant]]s — either in the form of topical cosmetic or chemical peels — and [[laser]]s may be used. New development using [[LED]] systems are also showing good results.<ref name="Rendon" /><ref name="DermatologicSurgery2006" /><ref>{{cite journal|journal=Journal of Drugs in Dermatology|year=2004|pages=27–34}}</ref><ref>{{cite journal|journal=International Journal of Dermatology|year=2003|pages=966–972|doi=10.1111/j.1365-4632.2003.02017.x|volume=42|title=Safety and efficacy of 4% hydroquinone combined with 10% glycolic acid, antioxidants, and sunscreen in the treatment of melasma}}</ref><ref>{{cite journal|journal=Archives of Dermatology|date=December 2002|pages=1578–1582|doi=10.1001/archderm.138.12.1578|volume=138|title=Efficacy of Glycolic Acid Peels in the Treatment of Melasma}}</ref>
+==Mechanisms of action==
-There are various mechanisms described for achieving this. Inhibiting tyrosinase activity reduces the synthesis of melanin so that as existing skin cells are naturally exfoliated keratinocytes with less melanin are eventually brought to the surface, giving the skin a lighter, more even toned complexion.<ref name="Skin Lightening mechanisms">{{cite web|last1=Woodruff|first1=John|title=There are various mechanisms described for achieving this. Inhibiting tyrosinase activity reduces the synthesis of melanin so that as existing skin cells are naturally exfoliated keratinocytes with less melanin are eventually brought to the surface, giving the skin a lighter, more even toned complexion.|url=http://www.cosmeticsbusiness.com/technical/article_page/Skin_Lightening__Light_and_smooth_and_even/48676|website=www.cosmeticsbusiness.com|publisher=HPCi Media|accessdate=11 August  2010}}</ref>
+{{see also|melanocyte|melanin|enzyme inhibitor|skin color|hair color}}
+:''For a review of mechanism of action of skin whitening agents, see Chang (2012){{r|Chang2012}} or Ebanks, Wickett, Boissy (2009).{{r|Ebanks2009}}''
+'''[[Melanin]]''' is the main substance responsible for the color of the skin. Melanin is class of dark [[polymer]]s generated by the body through the process of [[melanogenesis]]. Among the melanin pigmenting the skin and hair, 2 types can be distinguished based on its chemical composition and biological route of synthesis: the black/brown '''[[eumelanin]]''' and the red/yellow '''[[pheomelanin]]'''. The variation of [[skin color]] among individuals is mostly because of variation of the content of melanin in the skin. Skin with little or no melanin is [[white skin|almost white]]. Other factors influence skin color in a lesser degree, including the amount of blood in blood vessels (because of the color of blood), skin thickness and content of [[carotenoid]]s in skin.<ref>{{cite journal|title=You Are What You Eat: Within-Subject Increases in Fruit and Vegetable Consumption Confer Beneficial Skin-Color Changes|last1=Whitehead|first1=Ross D.|last2=Re|first2=Daniel|last3=Xiao|first3=Dengke|last4=Ozakinci|first4=Gozde|last5=Perrett|first5=David I.|year=2012|journal=PLoS ONE|volume=7|issue=3|doi=10.1371/journal.pone.0032988|pmc=3296758|pmid=22412966}} {{lref|f|CC BY, version apparently not specified}}</ref><ref>{{cite journal|title=Fruit, Vegetable and Dietary Carotenoid Intakes Explain Variation in Skin-Color in Young Caucasian Women: a Cross-Sectional Study|last1=Pezdirc|first1=Kristine|last2=Hutchesson|first2=Melinda J.|last3=Whitehead
+|first3=Ross|last4=Ozakinci|first4=Gozde|last5=Perrett|first5=David|last6=Collins|first6=Clare E.|year=2015|journal=Nutrients|volume=7|issue=7|doi=10.3390/nu7075251|pmc=4517028|pmid=26184306}} {{lref|f|CC BY 4.0}}</ref>
+Melanin in synthesized in [[melanosomes]] which are organelles produced in [[melanocytes]]. Melanocytes are cells dedicated to this function that are present in the skin, hair follicles, and other structures of the body. The synthesis of melanin (also called "melanogenesis" and "melanization") involves a chain of enzyme-catalyzed chemical reactions and non-enzyme-catalyzed reactions.{{refn| group=notes| name=Melanin synthesis| The chemical pathways of the synthesis of melanin has been described by many papers; however, it is often oversimplified. The following references are suggested: Kondo, Hearing (2011),{{r|Kondo2011}} Chang (2009){{r|Chang2009}} and Slominski et. al. (2004).{{r|Slominski2004}}}} The main precursor to melanin is [[tyrosine|<small>L</small>-tyrosine]]. The first step of melanogenesis is the conversion of <small>L</small>-tyrosine to [[L-DOPA|<small>L</small>-DOPA]]; this is the first and rate-limiting step and is catalized by the enzyme [[tyrosinase]] (TYR).{{r|Slominski2004|p=1163}} Other enzymes involved in the synthesis include [[tyrosinase-related protein 1]] (TRP1) and [[tyrosinase-related protein 2]] (TRP2); TRP2 is also known as "dopachorome tautomerase" (DCT). <small>L</small>-tyrosine is taken by the melanocytes from the intercellular medium, then transported to the melanosomes. <small>L</small>-tyrosine is also synthesized within the melanocytes from [[phenylalanine|<small>L</small>-phenylalanine]] by the enzyme [[phenylalanine hydroxylase]] (PAH).{{r|Slominski2004|p=1164}}
-===Pre-melanin synthesis===
+Melanosomes are transferred to [[keratinocyte]]s (the most abundant cell type in the skin). Most of the melanin of skin is found in keratinocytes. Additionally, melanocytes interact with keratinocytes through chemical signaling. See [[#Preventing the transfer of melanosomes to keratinocytes|§ Preventing the transfer of melanosomes to keratinocytes]].
+Skin whitening agents work by reducing the presence of melanin in the skin. To accomplish this, there are several possible mechanism of actions:{{refn|group=notes|"In addition to inhibition of tyrosinase catalytic activity, other approaches to treat hyperpigmentation include inhibition of tyrosinase mRNA transcription, aberration of tyrosinase glycosylation and maturation, acceleration of tyrosinase degradation, interference with melanosome maturation and transfer, inhibition of inflammation-induced melanogenic response, and acceleration of skin turnover. Accordingly, a huge number of depigmenting agents or whitening agents developed by those alternative approaches have been successfully identified and deeply reviewed in many articles [''references omitted'']."{{r|Chang2009}}}}{{r|Ebanks2009}}
+*[[#Inhibition of the activity of tyrosinase|Inhibition of the activity of tyrosinase]]: The catalytic action of tyrosinase is inhibited (slowed or nearly stopped) by the skin whitening agent.
+*Inhibition of the expression or activation of tyrosinase: The antimelanogenic agent causes that less tyrosinase is generated or that tyrosinase is not activated to its functional form.
+*Scavenging of the intermediate products of melanin synthesis.
+*[[#Preventing the transfer of melanosomes to keratinocytes|Preventing the transfer of melanosomes to keratinocytes]].
+*[[#Directly destroying existing melanin|Directly destroying existing melanin]].
+*Destroying melanocytes.
+===Inhibition of the activity of tyrosinase===
+{{further information|enzyme inhibitor}}
+Many tyrosinase inhibitors have been discovered or developed. Very many inhibitors of tyrosinase are known; most are of the reversible type.{{refn|group=notes|"In contrast to the huge number of reversible inhibitors has been identified, rarely irreversible inhibitors of tyrosinase were found until now. These irreversible inhibitors, which are also called specific inactivators, can form irreversibly covalent bond with the target enzyme and then inactivate it."{{r|Chang2009}}}} For a review of tyrosinase inhibitors see Chang (2009).<ref name=Chang2009 /> Reviews of patents on tyrosinase inhibitors have been published.<ref>{{cite journal| title=Tyrosinase inhibitors: a patent review (2011-2015)| url=https://www.researchgate.net/profile/Sultan_Ullah/publication/292142798_Tyrosinase_inhibitors_A_patent_review_2011-2015/links/56e9030308aea51e7f3b6d39.pdf| year=2016| authors=Ullah, Sultan et. al| journal=Expert. Opin. Ther. Pat.| volume=26| issue=3| doi=10.1517/13543776.2016.1146253| pmid=26815044}}</ref><ref>{{cite journal| title=Inhibitors of melanogenesis: a patent review (2009-2014)| url=https://www.researchgate.net/profile/Manoj_Manickam/publication/275896672_Inhibitors_of_melanogenesis_A_patent_review_2009-2014/links/55e95fd808ae21d099c2ea98.pdf| last1=Pillaiyar| first1=Thanigaimalai| last2=Manickam| first2=Manoj| last3=Jung| first3=Sang-Hun| journal=Expert. Opin. Ther. Pat.| volume=25| issue=7| doi=10.1517/13543776.2015.1039985| pmid=25939410}}</ref>
+'''Evaluation of effectivity:'''{{refn|group=notes|"Inhibitor strength is usually expressed as the inhibitory IC<sub>50</sub> value, which is the concentration of an inhibitor needed to inhibit half of the enzyme activity in the tested condition. However, for the tyrosinase inhibitors in the literature, the IC<sub>50</sub> values are incomparable due to the varied assay conditions, including different substrate concentrations, varied incubation time, and different batches of commercial tyrosinase. Fortunately, in most studies conducted to discover new tyrosinase inhibitors, a well-known tyrosinase inhibitor such as kojic acid is often used as a positive standard at the same time. Hence, in order to compare the inhibitors described in different literature in a more practical manner, a relative inhibitory activity (RA), which is calculated by dividing the IC<sub>50</sub> value of kojic acid with that of a newly found inhibitor in the same report, is used to express and compare the inhibitory strength of an inhibitor with others in this review."{{r|Chang2009}}}} The potency (how little of a substance is needed to achieve an effect) of ''reversible'' inhibitors is usually given in terms of its [[IC50|IC<sub>50</sub>]]. The IC<sub>50</sub> is highly dependent on the assay conditions, making it incomparable among different assays (unless designed to be comparable). It is customary practice in studies of tyrosinase inhibitors to assay one or several well known inhibitors as a positive control and point of comparison. The ''relative activity'' (RA) of a compound under investigation is its activity divided by the activity of the positive control; in turn the ''activity'' of a compound is usually defined as 1/IC<sub>50</sub>. The RA is less dependent on assay conditions that the IC<sub>50</sub> and is suitable to compare the results of different assays provided the same positive control was used. The positive control is commonly [[#Kojic acid|kojic acid]].
+'''Upregulation of tyrosinase caused by tyrosinase inhibitors:''' Several skin whitening agents including some which are tyrosinase inhibitors have been found to cause an ''increase'' in the expression of tyrosinase (which by itself would increase melanin synthesis).<ref>{{cite journal| title=Examining the Impact of Skin Lighteners In Vitro| last1=Gruber| first1=James V.| last2=Holtz| first2=Robert| year=2013| journal=Oxidative Medicine and Cellular Longevity| doi=10.1155/2013/702120| pmc=3655678| pmid=23738040}} {{lref|f|CC BY 3.0}}</ref>{{r|Chang2012}}
+'''Irreversible inhibitors of tyrosinase''' include: nonyl [[caffeic acid|''trans''-caffeate]],<ref>{{cite journal| title=Anti-tyrosinase kinetics and antibacterial process of caffeic acid N-nonyl ester in Chinese Olive (Canarium album) postharvest| authors=Jia, Yu-Long et. al.| year=2016| journal=Int. J. Biol. Macromol.| volume=91| doi=10.1016/j.ijbiomac.2016.05.098| pmid=27246378}} Restricted access.</ref> α-Na<sub>8</sub>SiW<sub>11</sub>CoO<sub>40</sub> (a [[polyoxometalate]]),<ref>{{cite journal| title=Inhibitory effects of α-Na8SiW11CoO40 on tyrosinase and its application in controlling browning of fresh-cut apples| last1=Chen| first1=Bing-Nian| last2=Xing| first2=Rui| last3=Wang| first3=Fang| last4=Zheng| first4=A-Ping| last5=Wang| first5=Li| year=2015| journal=Food Chem.| volume=188| doi=10.1016/j.foodchem.2015.05.003| pmid=26041180}} Restricted access.</ref> a [[structural analog]] of [[aloe emodin]],<ref>{{cite journal| title=Design and synthesis of aloe-emodin derivatives as potent anti-tyrosinase, antibacterial and anti-inflammatory agents| last1=Liu| first1=Jinbing| last2=Wu| first2=Fengyan| last3=Chen| first3=Changhong| year=2015| journal=Bioorg. Med. Chem. Lett.| volume=25| issue=22| doi=10.1016/j.bmcl.2015.10.004| pmid=26471089}} Restricted access.</ref>  structural analogues of [[barbituric acid]],<ref>{{cite journal| title=Design, synthesis and biological evaluation of hydroxy- or methoxy-substituted 5-benzylidene(thio) barbiturates as novel tyrosinase inhibitors| url=https://www.researchgate.net/profile/Wei_Yi7/publication/262609512_Design_synthesis_and_biological_evaluation_of_hydroxy-_or_methoxy-substituted_5-benzylidenethio_barbiturates_as_novel_tyrosinase_inhibitors/links/53e436df0cf25d674e94ba50.pdf| authors=Chen, Zhiyong et. al.| year=2014| journal=Bioorg. Med. Chem.| volume=22| issue=13| doi=10.1016/j.bmc.2014.04.060| pmid=24857777}} {{lref|nf}}</ref><ref>{{cite journal| title=Inhibitory effects of 5-benzylidene barbiturate derivatives on mushroom tyrosinase and their antibacterial activities| url=https://www.researchgate.net/profile/Wei_Yi7/publication/26317383_Inhibitory_effects_of_5-benzylidene_barbiturate_derivatives_on_mushroom_tyrosinase_and_their_antibacterial_activities/links/53e4394b0cf21cc29fc8f2be.pdf| authors=Yan, Qin et. al.| year=2009| journal=Eur. J. Med. Chem.| volume=44| issue=10| doi=10.1016/j.ejmech.2009.05.023| pmid=19552984}} {{lref|nf}}</ref><ref>{{cite journal| title=Synthesis and evaluation of 5-benzylidene(thio)barbiturate-β-D-glycosides as mushroom tyrosinase inhibitors| url=https://www.researchgate.net/profile/Wei_Yi7/publication/26328138_Synthesis_and_evaluation_of_5-benzylidene%28thio%29barbiturate-beta-D-glycosides_as_mushroom_tyrosinase_inhibitors/links/53e4390f0cf2fb748710b518.pdf| authors=Yan, Qin et. al.| year=2009| journal=Bioorg. Med. Chem. Lett.| volume=19| issue=15| doi=10.1016/j.bmcl.2009.06.018| pmid=19564107}} {{lref|nf}}</ref> structural analogues of [[chalcone]],<ref>{{cite journal| title=Microwave-assisted synthesis and tyrosinase inhibitory activity of chalcone derivatives| last1=Liu| first1=Jinbing| last2=Chen| first2=Changhong| last3=Wu| first3=Fengyan| last4=Zhao| first4=Liangzhong| year=2013| journal=Chem. Biol. Drug. Des.| volume=82| issue=1| doi=10.1111/cbdd.12126| pmid=23461881}} {{lref|nf}}</ref> [[sodium hydrogen sulfite]],<ref>{{cite journal| title=The antibrowning agent sulfite inactivates Agaricus bisporus tyrosinase through covalent modification of the copper-B site| last1=Kuijpers| first1=Tomas F. M.| last2=Gruppen| first2=Harry| last3=Sforza| first3=Stefano| last4=van Berkel| first4=Willem J. H.| last5=Vincken| first5=Jean-Paul| year=2013| journal=FEBS J.| volume=280| issue=23| doi=10.1111/febs.12539| pmid=24112416}} {{lref|nf}}</ref> structural analogues of [[coumarin]],<ref>{{cite journal| title=Biological evaluation of coumarin derivatives as mushroom tyrosinase inhibitors| authors=Liu, Jinbing| year=2012| journal=Food Chem.| volume=135| issue=4| doi=10.1016/j.foodchem.2012.07.055| pmid=22980884}} Restricted access.</ref> structural analogues of the following 2 compounds: [[benzene-1,2-diamine]] and [[2-Aminophenol|2-aminophenol]], and [[2,3-Dihydroxybenzoic acid|2,3-dihydroxybenzoic acid]] itself,<ref>{{cite journal| title=Kinetic characterisation of o-aminophenols and aromatic o-diamines as suicide substrates of tyrosinase| authors=Muñoz-Muñoz, Jose Luis et. al.| year=2012| journal=Biochim. Biophys. Acta.| volume=1824| issue=4| doi=10.1016/j.bbapap.2012.02.001| pmid=22342555}} Restricted access.</ref> [[tetrahydrofolic acid]],<ref>{{cite journal| title=Tetrahydrofolic Acid is a potent suicide substrate of mushroom tyrosinase| authors=García-Molina, Francisco et. al.| year=2011| journal=J. Agric. Food Chem.| volume=59| issue=4| doi=10.1021/jf1035433| pmid=21265541}} Restricted access.</ref> analogues of [[pyrimidine]] and [[rhodanine]],<ref>{{cite journal| title=Evaluation of dihydropyrimidin-(2H)-one analogues and rhodanine derivatives as tyrosinase inhibitors| authors=Liu, Jinbing et. al.| year=2011| journal=Bioorg. Med. Chem. Lett.| volume=21| issue=8| doi=10.1016/j.bmcl.2011.02.076| pmid=21411319}} Restricted access.</ref> tetrahydro[[pterin]]es,<ref>{{cite journal| title=Suicide inactivation of tyrosinase in its action on tetrahydropterines| authors=Muñoz-Muñoz, Jose Luis et. al.| year=2010| journal=J. Enzyme Inhib. Med. Chem.| volume=26| issue=5| doi=10.3109/14756366.2010.548811| pmid=21299451}} Restricted access.</ref> [[cardol triene]] (a triene analogue of [[cardol]] extracted from [[cashew]]),<ref>{{cite journal| title=Irreversible competitive inhibitory kinetics of cardol triene on mushroom tyrosinase| authors=Zhuang, Jiang-Xing et. al.| year=2010| journal=J. Agric. Food Chem.| volume=58| issue=24| doi=10.1021/jf103723k| pmid=21121650}} Restricted access.</ref> ''N''-(3,5-dihydroxybenzoyl)-6-hydroxy[[tryptamine]],<ref>{{cite journal| title=N-(3,5-dihydroxybenzoyl)-6-hydroxytryptamine as a novel human tyrosinase inhibitor that inactivates the enzyme in cooperation with l-3,4-dihydroxyphenylalanine| url=https://www.jstage.jst.go.jp/article/cpb/58/11/58_11_1536/_article| last1=Yamazaki| first1=Yoshimitsu| last2=Kawano| first2=Yasuhiro| year=2010| journal=Chem. Pharm. Bull.| volume=58| issue=11| doi=10.1248/cpb.58.1536| pmid=21048351}} {{lref|nf}}</ref> aminoethyliso[[thiourea]],<ref>{{cite journal| title=Kinetic Evaluation of Aminoethylisothiourea on Mushroom Tyrosinase Activity| last1=Li| first1=Shu-Bai| last2=Nie| first2=Hua-Li| last3=Zhang| first3=Hai-Tao| last4=Xue| first4=Yong| last5=Zhu| first5=Li-Min| year=2010| journal=Appl. Biochem. Biotechnol.| volume=162| issue=3| doi=10.1007/s12010-009-8760-3| pmid=19763898}} {{lref|r}}</ref> 8-hydroxy[[naringenin]],<ref>{{cite journal| title=Identifying 8-hydroxynaringenin as a suicide substrate of mushroom tyrosinase| url=http://journal.scconline.org/pdf/cc2010/cc061n03/p00205-p00210.pdf| last1=Chang| first1=Te-Sheng| last2=Lin| first2=Meng-Yi| last3=Lin| first3=Hsuan-Jung| year=2010|journal=J. Cosmet. Sci.| volume=61| issue=3| doi=10.1111/j.1468-2494.2010.00619_1.x| pmid=20587349}} {{lref|nf}}</ref> [[NADH]],<ref>{{cite journal| title=Melanogenesis Inhibition Due to NADH| url=https://www.jstage.jst.go.jp/article/bbb/74/9/74_90965/_article| authors=Garcia-Molina, Francis et. al.| year=2010| journal=Biosci. Biotechnol. Biochem.| volume=74| issue=9| doi=10.1271/bbb.90965| pmid=20834177}} {{lref|nf}}</ref> 8-hydroxy[[daidzein]]<ref>{{cite journal| title=Evaluation of Depigmenting Activity by 8-Hydroxydaidzein in Mouse B16 Melanoma Cells and Human Volunteers| last1=Tai| first1=Sorgan Shou-Ku| last2=Lin| first2=Ching-Gong| last3=Wu| first3=Mon-Han| last4=Chang| first4=Te-Sheng| year=2009| journal=Int. J. Mol. Sci.| volume=10| issue=10| doi=10.3390/ijms10104257| pmc=2790106| pmid=20057943}} {{lref|f|CC BY 3.0}}</ref> and [[captopril]].{{r|Espín2001}}
+===Inhibition of the expression or activation of tyrosinase===
+{{see also|transcription factor|hormone|receptor (biochemistry)}}
+'''[[Microphthalmia-associated transcription factor]]''' (MITF) is the master [[transcription factor]] that controls the expression of TYR, TRP1 and TRP2, [[MART1]], [[PMEL17]] and many other important proteins involved in the function of melanocytes.{{refn|group=notes|name=MITF|"The transcriptional level is the first stage by which the expression of tyrosinase and related melanogenic enzymes may be modulated. Influential in this process, the microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor that regulates melanocyte cellular differentiation as well as the transcription of melanogenic enzymes (tyrosinase, TYRP1 and TYRP2) and melanosome structural proteins (MART-1 and PMEL17) [''references omitted'']."{{r|Ebanks2009}}<br /><br />"In addition to being involved in the survival, proliferation, and differentiation of melanocytes, MITF is the master regulator of melanogenesis in melanocytes via binding to the M box of a promoter region and regulating the gene expression of tyrosinase, TRP-1, and TRP-2 [''references omitted'']. The up-regulation of MITF activity activates the expression of the melanogenesis-related enzymes, thus stimulating melanogenesis. In contrast, the down-regulation of MITF activity depresses the expression of the related enzymes, thereby inhibiting melanogenesis."{{r|Chang2012}}}} Downregulation of MITF decreases melanogenesis{{r|group=notes|MITF}} and is a mechanism of action of some skin whitening agents.{{r|Chang2012}}{{r|Smit2009}} As an heuristic rule, agents acting through downregulation of MITF are more likely to have side effects that selective tyrosinase inhibitors.{{refn|group=notes|"Because tyrosinase is produced only by melanocytic cells, tyrosinase inhibitors have highly specific targeting to melanogenesis in the cells without other side effects. In contrast, those melanogenesis inhibitors targeting to the tyrosinase gene expressions or protein degradations are rarely used as clinical hypopigmenting agents, due to their non-specific and global effects ''via'' intracellular signaling pathways."{{r|Chang2012}}}} Various signaling pathways and genetic mutations mutations influence the expression of MITF.{{refn|group=notes|name=Signaling pathways|Many papers have described the signaling pathways affecting melanogenesis and other functions of melanocytes. The following reviews are suggested reading (all of which are available online at no cost):<br /><br />For a description with emphasis on the relation with skin whitening, see Chang (2012){{r|Chang2012}} or Smit, Vicanova, Pavel (2009).{{r|Smit2009}} For a description with emphasis on [[physiology]], see Yamaguchi, Hearing (2009){{r|Yamaguchi2009}} or Kondo (2011).{{r|Kondo2011}} For a description of intra-melanocyte signaling pathways, see Imokawa, Ishida (2014).{{r|Imokawa2014}} An extensive and detailed review was written by Slominski et. al. (2004).{{r|Slominski2004}}}}<ref>{{cite journal| title=A systems-biological study on the identification of safe and effective molecular targets for the reduction of ultraviolet B-induced skin pigmentation| authors=Lee, Ho-Sung et. al.| year=2015| journal=Sci. Rep.| volume=5| doi=    10.1038/srep10305| pmc=4434836| pmid=25980672}} {{lref|f|CC BY 4.0}}</ref><ref>{{cite journal| title=UVB Stimulates the Expression of Endothelin B Receptor in Human Melanocytes via a Sequential Activation of the p38/MSK1/CREB/MITF Pathway Which Can Be Interrupted by a French Maritime Pine Bark Extract through a Direct Inactivation of MSK1| authors=Tagashira, Hideki et. al.| year=2015| journal=PLOS ONE| volume=10| issue=6| doi=10.1371/journal.pone.0128678| pmc=4452497| pmid=26030901}} {{lref|f|CC BY 4.0}}</ref>
+Inhibitors of melanogenesis whose mechanism of action includes reducing the genetic expression of melanogenic enzymes include [[caffeoylserotonin]],<ref>{{cite journal| title=The effects of Caffeoylserotonin on inhibition of melanogenesis through the downregulation of MITF via the reduction of intracellular cAMP and acceleration of ERK activation in B16 murine melanoma cells| last1=Kim| first1=Hye-Eun| last2=Ishihara| first2=Atsushi| last3=Lee| first3=Seong-Gene| year=2012| journal=BMB Rep.| volume=45| issue=12| doi=10.5483/BMBRep.2012.45.12.039| pmc=4133815| pmid=23261059}} {{lref|nc|CC BY-NC 3.0}}</ref> [[AP736]],<ref>{{cite journal| title=A novel adamantyl benzylbenzamide derivative, AP736, inhibits melanogenesis in B16F10 mouse melanoma cells via glycogen synthase kinase 3β phosphorylation| authors=Shin, Hong-Ju et. al.| year=2015| journal=Int. J. Mol. Med.| doi=10.3892/ijmm.2015.2348| pmid=26398893}} {{lref|r}}</ref> [[pomegranate]] extract,<ref>{{cite journal| title=Inhibitory Effect of Dried Pomegranate Concentration Powder on Melanogenesis in B16F10 Melanoma Cells; Involvement of p38 and PKA Signaling Pathways| authors=Kang, Su Jin et. al.| year=2015| journal=Int. J. Mol. Sci.| volume=16| issue=10| doi=10.3390/ijms161024219| pmc=4632747| pmid=26473849}} {{lref|f|CC BY 4.0}}</ref> [[betulinic acid]] (extracted from [[Vitis amurensis]] root),<ref>{{cite journal| title=Betulinic acid isolated from Vitis amurensis root inhibits 3-isobutyl-1-methylxanthine induced melanogenesis via the regulation of MEK/ERK and PI3K/Akt pathways in B16F10 cells| last1=Jin| first1=Kyong-Suk| last2=Oh| first2=You Na| last3=Hyun| first3=Sook Kyung| last4=Kwon| first4=Hyun Ju| last5=Kim| first5=Byung Woo| year=2014| journal=Food Chem. Toxicol. | volume=68| doi=10.1016/j.fct.2014.03.001| pmid=24632067}}</ref> and
+====The MC1R receptor and cAMP====
+The '''[[melanocortin 1 receptor]]''' (MC1R) is a [[transmembrane receptor|transmembrane]] and [[G-protein coupled receptor|G-protein coupled]] receptor expressed in melanocytes. MC1R is an important target for the regulation of melanogenesis.{{r|Chen2014}}{{r|Rodríguez2014}}{{r|Yamaguchi2009}} [[Agonist|Agonism]] (i.e: activation) of MC1R increases the ratio of eumelanin to pheomelanin and increases the generation of melanin overall.
+'''MC1R/cAMP signaling pathway:'''{{r|group=notes|Signaling pathways}}{{r|group=notes|MC1R}}{{r|Chen2014}}{{r|Rodríguez2014}}{{r|Lee2013}} Activation of MC1R causes activation of [[adenylyl cyclase]] (AC), which produces [[cyclic adenosine monophosphate]] (cAMP), which activates [[protein kinase A]] (PKA), which activates (by [[protein phosphorylation]]) [[cAMP response element-binding protein]] (CREB), which upregulates MITF (CREB is a transcription factor of MITF). Whitening agents that interfere with the MC1R/cAMP signaling pathway have been reviewed by Chang (2012).{{r|Chang2012}}
+cAMP is degraded by [[phosphodiesterase]]s (PDE). The PDE5 inhibitors [[sildenafil]] and [[vardenafil]], the cAMP-promoter [[IBMX]] and [[8-CPT-cGMP]] (a [[cyclic guanosine monophosphate]] (cGMP) analogue) increase melanin synthesis.<ref>{{cite journal| title=PDE5 inhibitor promotes melanin synthesis through the PKG pathway in B16 melanoma cells| authors=Zhang, Xiaodong et. al| year=2012| journal=J. Cell Biochem.| volume=113| issue=8| doi=10.1002/jcb.24147| pmid=22441938}} {{lref|r}}</ref>
+'''MC1R ligands:''' [[alpha-melanocyte stimulating hormone]] (α-MSH),{{refn|group=notes|name=MC1R|"Alpha melanocyte-stimulating hormone (α-MSH), a peptide derived from proopiomelanocortin (POMC), regulates melanogenesis ''via'' a cyclic adenosine monophosphate (cAMP)-dependent pathway [''references omitted'']. When binding to its receptor, melanocortin receptor 1 (MC1R), on the membrane of melanocytes, the hormone activates adenylate cyclase (AC) to produce cAMP as an intracellular second message ''via'' a G-protein-coupled receptor (GPCR)-type activation. cAMP activates protein kinase A (PKA), which then activates the gene expression of MITF ''via'' phosphorylation of the cAMP response element-binding protein (CREB). Finally, MITF efficiently activates the melanogenesis-related enzymes and stimulates melanogenesis. Once α-MSH binds to MC1R, up to a 100-fold increase in melanogenesis attends. In addition to α-MSH, other POMC-derived peptides, such as β-MSH and adrenocorticotropic hormone (ACTH), also stimulate melanogenesis ''via'' the same pathway."{{r|Chang2012}}<br /><br />"α-MSH binding to melanocortin 1 receptor (MC1R) on melanocytes in the basal epidermis generates the second messenger cAMP via interactions between MC1R and adenylyl cyclase, and leads to activation of protein kinase A and the cAMP responsive binding element (CREB) and microphthalmia (Mitf) transcription factors. CREB and Mitf directly enhance melanin production by raising levels of tyrosinase and other melanin biosynthetic enzymes. Thus, MSH-MC1R signaling leads to enhanced pigment synthesis by melanocytes and accumulation of melanin by epidermal keratinocytes.<br />[''etcetera'']<br />The MC1R is found on the surface of melanocytes where it binds to α-melanocyte stimulating hormone (MSH) and transmits differentiation signals into the cell through activation of adenylyl cyclase and generation of cAMP [''references omitted'']. cAMP signaling leads to activation of the protein kinase A (PKA) cascade which, in turn, leads to increased levels and/or activity of many melanogenic enzymes to enhance production and export of melanin by melanocytes [''references and figure omitted'']."{{r|D'Orazio2013}}}} [[beta-melanocyte stimulating hormone]] (β-MSH) and [[adrenocorticotropic hormone]] are endogenous [[agonist]]s of MC1R.{{r|Slominski2004|p=1175}} [[Agouti signaling protein]] (ASIP) appears to be the only endogenous [[receptor antagonist|antagonist]] of MC1R.{{refn|group=notes|The assertion that ASIP is the only endogenous antagonist is found in Yamaguchi, Hearing (2009).{{r|Yamaguchi2009}}}} Synthetic MC1R agonists have been designed; examples include the peptides [[afamelanotide]] and [[melanotan II]].{{r|Chen2014}}
+'''Mutations of the MC1R gene''' [[correlation|correlate]], and in some individuals are at least partially responsible for [[red hair]], [[white skin]] and an increased risk for [[skin cancer]].{{refn|group=notes|"Loss-of-signaling MC1R polymorphisms are commonly found among fair-skinned, sun-sensitive and skin cancer-prone populations (e.g., Northern Europeans). The most prevalent MC1R mutations (D84E, R151C, R160W and D294H) are commonly referred to as “RHC” (red hair color) alleles because of their association with red hair color, freckling and tendency to burn after UV exposure [''references omitted'']."{{r|D'Orazio2013}}}}{{r|Chen2014}}<ref>{{cite journal| title=Melanoma susceptibility genes and risk assessment| last1=Marzuka-Alcalá| first1=Alexander| last2=Gabree| first2=Michele Jacobs| last3=Tsao| first3=Hensin| year=2014| journal=Methods Mol. Biol.| doi=10.1007/978-1-62703-727-3_20| pmid=24258989}} Restricted access.</ref>{{r|Rodríguez2014}}<ref>{{cite journal| title=Melanoma Genetics: Recent Findings Take Us Beyond Well-Traveled Pathways| last1=Law| first1=Matthew H.| last2=MacGregor| first2=Stuart| last3=Hayward| first3=Nicholas K.| year=2012| journal=J. Invest. Dermatol.| volume=132| issue=7| doi=10.1038/jid.2012.75| pmid=22475760}} {{lref|nf}}</ref>{{r|Nelson2009}}<ref>{{cite journal| title=Molecular genetics of human pigmentation diversity| last=Sturm| first=Richard A.| year=2009| journal=Hum. Mol. Genet.| volume=19| issue=R1| doi=10.1093/hmg/ddp003| pmid=19297406}} {{lref|nf}}</ref><ref>{{cite journal| title=Genetic determinants of hair, eye and skin pigmentation in Europeans| url=https://www.researchgate.net/profile/Snaebjoern_Palsson/publication/5893814_Sulem_P._Gudbjartsson_D._F._Stacey_S._N._Helgason_A._Rafnar_T._Magnusson_K._P._et_al._Genetic_determinants_of_hair_eye_and_skin_pigmentation_in_Europeans._Nat._Genet._39_1443-1452/links/0fcfd505c6ba7c4988000000.pdf| authors=Sulem. Patrick et. al.| year=2007| journal=Nat. Genet.| volume=39| issue=12| doi=10.1038/ng.2007.13| pmid=17952075}} {{lref|nf}}</ref><ref>{{cite journal| title=What Controls Variation in Human Skin Color?| last=Barsh| first=Gregory S.| year=2003| journal=PLoS Biology| doi=10.1371/journal.pbio.0000027| pmc=212702| pmid=14551921}} {{font color|brown|No-cost access, unknown license.}}</ref>{{r|Slominski2004|p=1175}}
+====Serotonin signaling====
+Melanocytes express [[serotonin receptor]]s and are capable of producing [[serotonin]]. Pharmacological interference with the serotonin system of melanocytes can result in either increased or decreased melanin synthesis. Serotonin itself is a weak inhibitor of tyrosinase<ref name=Yamazaki2009>{{cite journal| title=N-[(Dihydroxyphenyl)acyl]serotonins as potent inhibitors of tyrosinase from mouse and human melanoma cells| last1=Yamazaki| first1=Yoshimitsu| last2=Kawano| first2=Yasuhiro| last3=Yamanaka| first3=Akiko| last4=Maruyama| first4=Susumu| year=2009| journal=Bioorg. Med. Chem. Lett.| volume=19| issue=15| doi=10.1016/j.bmcl.2009.05.115| pmid=19524439}} Restricted access.</ref> with 0.11 times the potency of kojic acid.{{refn|group=notes|1=Computed from the data reported by Yamazaki et. al. (2009):{{r|Yamazaki2009}} IC<sub>50</sub>(serotonin)=550&nbsp;µmol/l. IC<sub>50</sub>(kojic acid)=68&nbsp;µmol/l.}} Nonetheless, serotonin increases synthesis of melanin when its ''overall effect'' on melanocytes (as opposed to ''isolated tyrosinase'') is evaluated.<ref>{{cite journal| title=Cross-talk between 5-hydroxytryptamine and substance P in the melanogensis and apoptosis of B16F10 melanoma cells| last1=Zhou| first1=Jia| last2=Geng| first2=Kun-kun| last3=Ping| first3=Feng-feng| last4=Gao| first4=Yue-ying| last5=Liu| first5=Lei| last6=Feng| first6=Bai-nian| year=2016| journal=Eur. J. Pharmacol.| doi=10.1016/j.ejphar.2016.02.026| pmid=26872989}} Restricted access.</ref> Activation of [[5-HT2B receptor|5-HT<sub>2B</sub> receptors]] with [[BW-723C86]] ''inhibits'' melanogenesis<ref>{{cite journal| title=A Novel Role of Serotonin Receptor 2B Agonist as an Anti-Melanogenesis Agent| authors=Oh, Eun Ju, et. al.| year=2016| journal=Int. J. Mol. Sci.| volume=17| issue=4| doi=10.3390/ijms17040546| pmc=4849002| pmid=27077852}} {{lref|f|CC BY 4.0}}</ref> while activation of [[5-HT2A receptor|5-HT<sub>2A</sub> receptors]] with the amphetamine structural analog [[2,5-Dimethoxy-4-iodoamphetamine|DOI]] ''promotes'' melanogenesis.<ref>{{cite journal| title=Serotonin induces melanogenesis via serotonin receptor 2A| last1=Lee| first1=H. J.| last2=Park| first2=M. K.| last3=Kim| first3=S. Y.| last4=Park Choo| first4=H. Y.| last5=Lee| first5=A. Y.| last6=Lee| first6=C. H.| year=2011| journal=Br. J. Dermatol. | volume=165| issue=6| doi=10.1111/j.1365-2133.2011.10490.x| pmid=21711335}} {{lref|r}}</ref> The [[serotonin uptake inhibitor|serotonin reuptake inhibitor]] (SRI) [[6-Nitroquipazine|6-nitroquipazine]] inhibits melanogenesis in-vitro.<ref>{{cite journal| title=Inhibition of melanization in human melanoma cells by a serotonin uptake inhibitor| url=http://www.sciencedirect.com/science/article/pii/S0022202X87900194/pdf?md5=3de25ec9fbadfa4aa11b3274a3bc145d&pid=1-s2.0-S0022202X87900194-main.pdf| last1=Max| first1=McEwan| last2=Persons| first2= Peter G.| year=1987| journal=J. Invest. Dermatol.| volume=89| issue=1| doi=10.1111/1523-1747.ep12580425| pmid=3110297}} {{lref|nf}}</ref>
+===Preventing the transfer of melanosomes to keratinocytes===
+{{see also|human skin#Structure|epidermis}}
+:''For an overview of the interaction between keratinocytes and melanocytes see Yamaguchi, Hearing (2009).{{r|Yamaguchi2009}}''
+'''Keratinocytes in the skin:''' Within the skin, melanocytes are present in the basal layer of the [[epidermis]]; from these melanocytes originate dendrites that reach [[keratinocytes]].{{refn|group=notes|name=Keratinocytes|"In the skin, melanocytes are situated on the basal layer which separates dermis and epidermis. One melanocyte is surrounded by approximately 36 keratinocytes. Together, they form the so-called epidermal melanin unit. The melanin produced and stored inside the melanocyte in the melanosomal compartment is transported via dendrites to the overlaying keratinocytes."{{r|Smit2009}}<br /><br />"Each melanocyte resides in the basal epithelial layer and, by virtue of its dendrites, interacts with approximately 36 keratinocytes to transfer melanosomes and protect the skin from photo-induced carcinogenesis. Furthermore, the amount and type of melanin produced and transferred to the keratinocytes with subsequent incorporation, aggregation and degradation influences skin complexion coloration [''reference omitted'']."{{r|Ebanks2009}}<br /><br />Wu, Hammer (2014) describe the number of keratinocytes per melanocyte as above 40.{{r|Wu2014}}}} Keratinocytes are the most abundant cell type in the epidermis.{{refn|group=notes|"Keratinocytes are the most abundant cells in the epidermis and are characterized by their expression of cytokeratins and formation of desmosomes and tight junctions with each other to form an effective physicochemical barrier."{{r|D'Orazio2013}}}} In the skin, there are approximately 36 keratinocytes per melanocyte.{{r|group=notes|Keratinocytes}} Keratinocytes are continuously generated in the basal layer of the epidermis and displace older keratinocytes of the skin towards the surface.
+'''Melanosome transfer:''' Melanosomes along with the melanin they contain is transferred from melanocytes to keratinocytes when keratinocytes are low in the epidermis.{{refn|group=notes|Research about the mechanism of melanosome transfer has been reviewed by Wu, Hammer (2014).{{r|Wu2014}}}} Keratinocytes carry the melanosomes with them as they move towards the surface. Keratinocytes contribute to skin pigmentation holding the melanin originated in melanocytes and induce melanogenesis through chemical signals directed at melanocytes.{{r|group=notes|Signaling pathways}} The transfer of melanosomes to keratinocytes is a [[necessary condition]] for the visible pigmentation of the skin.{{r|Wu2014}} Blocking this transfer is a mechanism of action of some skin whitening agents.{{r|Smit2009}}{{r|Ebanks2009}} Skin whitening agents that block melanocyte transfer include [[#Niacinamide|niacinamide]], [[heparin]],{{r|Makino-Okamura2014}} [[madecassoside]],{{r|Jung2013}} [[soybean]]<ref>{{cite journal| title=The mechanism of action and clinical benefits of soy for the treatment of hyperpigmentation| last1=Leyden| first1=James| last2=Wallo| first2=Warren| year=2011| journal=Int. J. Dermatol.| volume=50| issue=4| doi=10.1111/j.1365-4632.2010.04765.x| pmid=21332714}} Restricted access.</ref> and [[Saccharomyces cerevisiae]] (a species of yeast).<ref>{{cite journal| title=The natural yeast extract isolated by ethanol precipitation inhibits melanin synthesis by modulating tyrosinase activity and downregulating melanosome transfer| authors=Lee, Woo Jin et. al.| year=2015| journal=Biosci. Biotechnol. Biochem.| volume=79| issue=9| doi=10.1080/09168451.2015.1032880| pmid=25943301}} Restricted access.</ref>
+The '''[[protease-activated receptor 2]]''' (PAR2) is a [[transmembrane receptor|transmembrane]] and [[G-protein coupled]] receptor expressed in keratinocytes and involved in melanocyte transfer.{{refn|group=notes|"Protease-activated receptor (PAR)-2 is a member of a novel G-protein-coupled seven-transmembrane receptor family. In epidermis, PAR-2 is expressed in keratinocytes [''references omitted''], but not melanocytes [''references omitted'']. A central role for PAR-2 in keratinocyte uptake of melanosomes has been established [''references omitted'']. PAR-2 has been linked to the upregulation of COX-2 and the release of arachidonic acid and secretion of PGE2 and PGF2α [''references omitted'']. Several reports have suggested that PAR-2 mediates cutaneous pigmentation through increased uptake of melanosomes by keratinocytes and by the release of PGE2 and PGF2α that stimulate melanocyte dendricity [''references omitted'']."{{r|Jung2013}}}}{{refn|group=notes|name=PAR2|References about PAR2 and its role in skin pigmentation: Kim (2016),<ref>{{cite journal| title=PAR-2 is involved in melanogenesis by mediating stem cell factor production in keratinocytes| last1=Kim| first1=Ji Young| last2=Kim| first2=Dae Suk| last3=Sohn| first3=Hyojung| last4=Lee| first4=Eun Jung| last5=Oh| first5=Sang Ho| year=2016| journal=Exp. Dermatol.| volume=25| issue=6| doi=10.1111/exd.12982| pmid=26909822}} {{lref|nf}}</ref> Choi (2014),<ref>{{cite journal| title=Melanosome uptake is associated with the proliferation and differentiation of keratinocytes| url=https://www.researchgate.net/profile/Young_Lee7/publication/258203476_Melanosome_uptake_is_associated_with_the_proliferation_and_differentiation_of_keratinocytes/links/56bc31d908ae2481ab6aec0f.pdf| authors=Choi, Hye-In et. al.| year=2014| journal=Arch. Dermatol. Res.| volume=306| doi=10.1007/s00403-013-1422-x| pmid=24173125}} {{lref|nf}}</ref> Makino-Okamura (2014),{{r|Makino-Okamura2014}} Wu, Hammer (2014),{{r|Wu2014}} Ando (2012),<ref>{{cite journal| title=Melanosomes are transferred from melanocytes to keratinocytes through the processes of packaging, release, uptake, and dispersion| url=https://www.researchgate.net/profile/Mary_Matsui/publication/51906561_Melanosomes_Are_Transferred_from_Melanocytes_to_Keratinocytes_through_the_Processes_of_Packaging_Release_Uptake_and_Dispersion/links/00b7d529fa602b183e000000.pdf| authors=Ando, Hideya et. al.| year=2012| journal=J. Invest. Dermatol.| volume=132| issue=4| doi=10.1038/jid.2011.413| pmid=22189785}} {{lref|nf}}</ref> Ando (2010).<ref>{{cite journal| title=Keratinocytes in culture accumulate phagocytosed melanosomes in the perinuclear area| url=https://www.researchgate.net/profile/Mary_Matsui/publication/26819132_Keratinocytes_in_culture_accumulate_phagocytosed_melanosomes_in_the_perinuclear_area/links/543fb43d0cf2be1758cf24ec.pdf| authors=Ando, Hideya et. al.| year=2010| journal=Pigment Cell Melanoma Res.| volume=23| issue=1| doi=10.1111/j.1755-148X.2009.00640.x| pmid=19761520}} {{lref|nf}}</ref>}} Antagonists of PAR2 inhibit the transfer of melanosomes and have a skin whitening affects while agonists of PAR2 have the opposite effect, as expected.{{r|group=notes|PAR2}} The common endogenous agonists of PAR2 are [[serine protease]]s which irreversibly activate PAR2 by cleaving a part of the extracellular terminal of this receptor thereby exposing a part of it that subsequently works as a ligand tethered to the reset of the receptor at the molecular scale. Some synthetic agonists of PAR2 are short peptides that imitate the aforesaid tethered ligand but do not cleave the extracellular terminal.
+===Directly destroying existing melanin===
+Several species of fungi produce enzymes that reduce pigmentation by degrading melanin.<ref name=Nagasaki2008>{{cite journal| title=Purification, characterization, and gene cloning of Ceriporiopsis sp. strain MD-1 peroxidases that decolorize human hair melanin| last1=Nagasaki| first1=Kenji| last2=Kumazawa| first2=Masaro| last3=Murakami| first3=Shuichiro| last4=Takenaka| first4=Shinji| last5=Koike| first5=Kenzo| last6=Aoki| first6=Kenji| year=2008| journal=Appl. Environ. Microbiol.| volume=74| issue=16| doi=10.1128/AEM.00253-08| pmc=2519264| pmid=18586974}} {{lref|nf}}</ref> These enzymes often require the presence of [[hydrogen peroxide]] and sometimes the presence of Mg<sup>+2</sup> ions to work.{{r|Nagasaki2008}} They have been proposed as a safer alternative to hydrogen peroxide for cosmetic [[hair coloring|hair depigmentation]].{{r|Nagasaki2008}}
+The enzyme [[lignin peroxidase]] produced by the fungus [[phanerochaete chrysosporium]] has been studied as an ingredient suitable for skin-whitening: A double-blind placebo-controlled split-face randomized study found this enzyme to be effective and superior to hydroquinone in skin whitening.<ref>{{cite journal| title=A randomized and placebo-controlled study to compare the skin-lightening efficacy and safety of lignin peroxidase cream vs. 2% hydroquinone cream| last1=Mauricio| first1=Tess| last2=Karmon| first2=Yoram| last3=Khaiat| first3=Alain| year=2011| journal=J. Cosmet. Dermatol.| volume=10| issue=4| doi=10.1111/j.1473-2165.2011.00581.x| pmid=22151932}} Restricted access.</ref> In a non-controlled study, this enzyme was applied to volunteers with facial melasma during 8 weeks; the treatment was found effective in reducing pigmentation in both skin affected by melasma and skin unaffected by melasma.<ref>{{cite journal|title=Reduction of facial pigmentation of melasma by topical lignin peroxidase: A novel fast-acting skin-lightening agent|last1=Zhong|first1=Shao-Min|last2=Sun|first2=Nan|last3=Liu|first3=Hui-Xian|last4=Niu|first4=Yue-Qing|last5=Wu|first5=Yan|year=2015|journal=Exp. Ther. Med.|volume=9|issue=2|doi=10.3892/etm.2014.2118|pmc=4280934|pmid=25574195}} {{lref|nc|CC BY-NC 3.0}}</ref>
+===Destroying melanocytes===
+Some compounds are known to destroy melanocytes; this mechanism of action is often used to remove the remaining pigmentation in cases of [[vitiligo]].<ref>{{cite journal| title=The Monobenzone-induced depigmentation: from enzymatic blockade to autoimmunity| url=https://www.researchgate.net/profile/Rosalie_Luiten/publication/51234742_Monobenzone-induced_depigmentation_from_enzymatic_blockade_to_autoimmunity_Pigment_Cell_Mel_Res/links/5694db0408aeab58a9a43efb.pdf| last1=van den Boorn| first1=Jasper G.| last2=Melief| first2=Cornelis J.| last3=Luiten| first3=Rosalie M.| journal=Pigment Cell Melanoma Res.| volume=24| issue=4| doi=10.1111/j.1755-148X.2011.00878.x| pmid=21689385}} {{lref|nf}}</ref><ref>{{cite journal| title=A convenient screening method to differentiate phenolic skin whitening tyrosinase inhibitors from leukoderma-inducing phenols| url=https://www.researchgate.net/profile/Kazumasa_Wakamatsu/publication/280582596_A_convenient_screening_method_to_differentiate_phenolic_skin_whitening_tyrosinase_inhibitors_from_keukoderma-inducing_phenols/links/572beb6f08aef5d48d32822b.pdf| last1=Ito| first1=Shosuke| last2=Wakamatsu| first2=Kazumasa| year=2015| journal=J. Dermatol. Sci.| volume=80| issue=1| doi=10.1016/j.jdermsci.2015.07.007| pmid=26228294}} {{lref|nf}}</ref>
+===Non-pharmacological treatments===
+Most skin-lightening treatments, which can reduce or block some amount of melanin production, are aimed at inhibiting [[tyrosinase]]. Many treatments use a combination of topical lotions or gels containing melanin-inhibiting ingredients along with a sunscreen, and a prescription [[retinoid]]. Depending on how the skin responds to these treatments, [[exfoliant]]s ‒either in the form of topical cosmetic or chemical peels‒ and [[laser]]s may be used. New development using [[LED]] systems are also showing good results.<ref name="Rendon" /><ref name="DermatologicSurgery2006" /><ref>{{cite journal|journal=Journal of Drugs in Dermatology|year=2004|pages=27–34}}</ref><ref>{{cite journal|journal=International Journal of Dermatology|year=2003|pages=966–972|doi=10.1111/j.1365-4632.2003.02017.x|volume=42|title=Safety and efficacy of 4% hydroquinone combined with 10% glycolic acid, antioxidants, and sunscreen in the treatment of melasma}}</ref><ref>{{cite journal|journal=Archives of Dermatology|date=December 2002|pages=1578–1582|doi=10.1001/archderm.138.12.1578|volume=138|title=Efficacy of Glycolic Acid Peels in the Treatment of Melasma}}</ref>
+==Whitening agents==
+===Pre-melanin synthesis===
 ====Tretinoin====
 Research has shown that the use of [[tretinoin]] (also known as all-trans retinoic acid) can only be somewhat effective in treating skin discolorations.<ref name="DermatologicSurgery2006">{{cite journal|journal=Dermatologic Surgery|date=March 2006|pages=365–371|doi=10.1097/00042728-200603000-00005|volume=32|title=Repeated Treatment Protocols for Melasma and Acquired Dermal Melanocytosis}}</ref><ref>{{cite journal|journal=Acta Dermato-Venereologica|date=July 1999|pages=305–310|doi=10.1080/000155599750010724|volume=79|title=Hypopigmented Macules of Photodamaged Skin and Their Treatment with Topical Tretinoin}}</ref><ref>{{cite journal|journal=International Journal of Dermatology|date=April 1998|pages=286–292|doi=10.1046/j.1365-4362.1998.00433.x|volume=37|title=Short- and long-term histologic effects of topical tretinoin on photodamaged skin}}</ref><ref>{{cite journal|journal=Journal of the American Academy of Dermatology|date=March 1997|pages=S27–S36|doi=10.1016/s0190-9622(97)70058-6|title =  Treatment of photodamage with topical tretinoin: An overview|volume=36}}</ref> Users of tretinoin have to avoid sunlight, as the skin can tan. Using tretinoin always makes the skin more sensitive to UVA and UVB rays.
@@ Line 47: / Line 113: @@
 [[Glutathione]] is a tripeptide molecule found in mammalian bodies. It is an [[antioxidant]] that plays an important role in preventing [[oxidative damage]] to the skin. In addition to its many recognized biological functions, glutathione has also been associated with skin lightening ability.
-A double-blind placebo-controlled study found glutathione to be effective as a skin whitening agent and in reducing dark spots; the dose regime was 500&nbsp;mg per day (split in 2 equal doses per day) for 4 weeks.<ref>{{cite journal| title=Glutathione as an oral whitening agent: a randomized, double-blind, placebo-controlled study| last1=Arjinpathana| first1=Nutthavuth| last2=Asawanonda| first2=Pravit| year=2012| journal=J. Dermatolog. Treat.| volume=23| issue=2| doi=10.3109/09546631003801619| pmid=20524875}}</ref> In contrast, a study that examined the effect of glutathione and related compounds in-vitro found that glutathione monoethyl ester but not glutathione had a depigmenting effect.<ref>{{cite journal| title=The Glutathione Derivative, GSH Monoethyl Ester, May Effectively Whiten Skin but GSH Does Not| last1=Chung| first1=Bo Young| last2=Choi| first2=So Ra| last3=Moon| first3=Ik Jun| last4=Park| first4=Chun Wook| last5=Kim| first5=Young-Hoon| last6=Chang| first6=Sung Eun| year=2016| journal=Int. J. Mol. Sci.| volume=17| issue=5| doi=10.3390/ijms17050629| pmc=4881455| pmid=27128906}} {{font color|green|No-cost access and free license (CC-BY 4.0).}}</ref> A review of the use of glutathione for skin whitening was published in 2016.<ref>{{cite journal| title=Glutathione as a skin whitening agent: Facts, myths, evidence and controversies| url=https://dx.doi.org/10.4103/0378-6323.179088| last1=Sonthalia| first1=Sidharth| last2=Daulatabad| first2=Deepashree| last3=Sarkar| first3=Rashmi| year=2016| journal=Indian J. Dermatol. Venereol. Leprol.| volume=82| issue=3| doi=10.4103/0378-6323.179088| pmid=27088927}} {{font color|brown|No cost access but non-free license.}}</ref>
+A double-blind placebo-controlled study found glutathione to be effective as a skin whitening agent and in reducing dark spots; the dose regime was 500&nbsp;mg per day (split in 2 equal doses per day) for 4 weeks.<ref>{{cite journal| title=Glutathione as an oral whitening agent: a randomized, double-blind, placebo-controlled study| last1=Arjinpathana| first1=Nutthavuth| last2=Asawanonda| first2=Pravit| year=2012| journal=J. Dermatolog. Treat.| volume=23| issue=2| doi=10.3109/09546631003801619| pmid=20524875}}</ref> In contrast, a study that examined the effect of glutathione and related compounds in-vitro found that glutathione monoethyl ester but not glutathione had a depigmenting effect.<ref>{{cite journal| title=The Glutathione Derivative, GSH Monoethyl Ester, May Effectively Whiten Skin but GSH Does Not| last1=Chung| first1=Bo Young| last2=Choi| first2=So Ra| last3=Moon| first3=Ik Jun| last4=Park| first4=Chun Wook| last5=Kim| first5=Young-Hoon| last6=Chang| first6=Sung Eun| year=2016| journal=Int. J. Mol. Sci.| volume=17| issue=5| doi=10.3390/ijms17050629| pmc=4881455| pmid=27128906}} {{lref|f|CC BY 4.0}}</ref> A review of the use of glutathione for skin whitening was published in 2016.<ref>{{cite journal| title=Glutathione as a skin whitening agent: Facts, myths, evidence and controversies| url=https://dx.doi.org/10.4103/0378-6323.179088| last1=Sonthalia| first1=Sidharth| last2=Daulatabad| first2=Deepashree| last3=Sarkar| first3=Rashmi| year=2016| journal=Indian J. Dermatol. Venereol. Leprol.| volume=82| issue=3| doi=10.4103/0378-6323.179088| pmid=27088927}} {{lref|nf}}</ref>
 Glutathione is an ingredient in some cosmetics preparations. Glutathione for skin whitening is available in cream, soap, lotion, nasal spray and injectable form. Glutathione that is applied on the skin in the form of lotion is not efficiently absorbed by the skin cells as the [[thiol group]] undergoes rapid formation of disulfide. When taken orally, glutathione is hydrolyzed by enzymes in the gastrointestinal tract resulting in reduced bioavailability. The level of glutathione increased in smalls amounts temporarily when large oral doses were administered.<ref name="pmid1362956">{{cite journal| title=The systemic availability of oral glutathione| author1=Witschi| first1=A.| last2=Reddy| first2=S.| last3=Stofer| first3=B.| last4=Lauterburg| first4=B. H.| year=1992| journal=European journal of clinical pharmacology| volume=43| issue=6| doi=10.1007/BF02284971| pmid=1362956}}</ref> As a result, the effectiveness of externally administered glutathione is slowed down by its inability to cross cell membranes efficiently and its rapid degradation by enzymes in the gastrointestinal tract. On the contrary, intravenous glutathione delivers very high doses directly into the systemic circulation and is the preferred mode of administering glutathione. However, this method of administrating the antioxidant might flood the cells with glutathione that may cause reductive stress. This might expose people to potential health risks associated with long-term use of high dose of glutathione.
 Glutathione can be combined with many other agents like vitamin C to increase its absorption, [[N-acetyl cysteine]] to boost its level, and other antioxidants like vitamin E. Some oral intake of glutathione could have dangerous effect when combined with other skin whitening agents such as hydroquinone which is a carcinogenic element and [[monobenzone]] which causes irreversible depigmentation.
-====Cinnamomum subavenium====
-''[[Cinnamomum subavenium]]'', a Chinese herb, has been suggested for use as a skin whitening agent. The plant contains substances which inhibit production of tyrosinase, an enzyme which catalyzes the production of melanin. The herb has not been established as either effective or safe but is being researched by Hui-Min Wang and his colleagues at Kaohsiung Medical University in Taiwan where experiments shown that it was effective at causing Zebrafish to lose their stripes.<ref>{{cite news |last=Bhanoo |first=Sindya N. |title=An Herbal Alternative to Creams for Pale Skin |url=http://www.nytimes.com/2011/03/29/science/29obskin.html |accessdate=March 30, 2011|newspaper=[[New York Times]] |date=December 15, 2011}}</ref>
 ===Post-melanin synthesis===
@@ Line 72: / Line 135: @@
 ====Mercury====
-Many skin whiteners contain toxic [[mercury (element)|mercury]], such as [[mercury(II) chloride]] or [[ammoniated mercury]] as the [[active ingredient]].  However, mercury has been banned in most countries for use in skin whitening (1976 in Europe, 1990 in the USA) because it accumulates on skin and it can have the opposite results in the long term.  As late as January 2016, the FDA published a warning not to use a particular brand of whitener - Viansilk’s "Crema Piel De Seda" ("Silky Skin Cream"), sold in the United States due to its mercury content.<ref>{{Cite web|title = Drug Safety and Availability - FDA Warns Consumers Not to Use Viansilk’s "Crema Piel De Seda" ("Silky Skin Cream")|url = http://www.fda.gov/Drugs/DrugSafety/ucm483831.htm|website = Drugs: Drug Safety and Availability|access-date = January 30, 2016|date = January 29, 2016|publisher = USFDA}}</ref> Some studies suggest that long-term use could cause systemic absorption that leads to tissue accumulation of the substance.<ref>{{cite web
+Many skin whiteners contain toxic [[mercury (element)|mercury]], such as [[mercury(II) chloride]] or [[ammoniated mercury]] as the [[active ingredient]].  However, mercury has been banned in most countries for use in skin whitening (1976 in Europe, 1990 in the USA) because it accumulates on skin and it can have the opposite results in the long term.  As late as January 2016, the FDA published a warning not to use a particular brand of whitener - Viansilk’s "Crema Piel De Seda" ("Silky Skin Cream"), sold in the United States due to its mercury content.<ref>{{Cite web|title = Drug Safety and Availability - FDA Warns Consumers Not to Use Viansilk’s "Crema Piel De Seda" ("Silky Skin Cream")|url = http://www.fda.gov/Drugs/DrugSafety/ucm483831.htm|website = Drugs: Drug Safety and Availability|access-date = January 30, 2016|date = January 29, 2016|publisher = USFDA}}</ref>
-|title=Skin Whitening Treatment
-|url=http://www.dubailasertreatment.com/treatments/skin-whitening/
-}}</ref>
 ====Other====
@@ Line 92: / Line 152: @@
 There is evidence to suggest that some types of skin-whitening products use active ingredients (such as mercurous chloride) and [[hydroquinone]] which can be harmful.<ref>Counter, S. Allen, [http://www.boston.com/news/globe/health_science/articles/2003/12/16/whitening_skin_can_be_deadly/ Whitening skin can be deadly], [[Boston Globe]], 16 Dec 2003</ref> Hydroquinone had been banned in Europe. However, it is now available again but only when prescribed by a medical doctor. This is also the case in many other countries, where hydroquinone can only be prescribed by a doctor for certain skin conditions.
-A test of common skin lightening creams available in [[Nigeria]] showed that they caused [[mutations]] in bacteria and were possibly [[carcinogenic]].<ref>{{cite journal|last=Akortha|first=E.E. |author2=Niemogha, M.T. |author3=Edobor, O.|title=MUTAGENIC AND GENOTOXIC SCREENING OF EIGHT COMMONLY USED SKIN WHITENING CREAMS IN NIGERIA|journal=Bayero Journal of Pure and Applied Sciences|date=1 June 2012|volume=5|issue=1|pages=5–10|url=http://www.ajol.info/index.php/bajopas/article/view/80929/71155|accessdate=25 December 2012|doi=10.4314/bajopas.v5i1.2}}</ref> A study that examined skin whitening creams in [[Mexico]] found an high concentration of mercury in several of them.<ref>{{cite journal|title=Mercury Levels in Locally Manufactured Mexican Skin-Lightening Creams|author1=Peregrino, C. P.|author2=Moreno, M. V.|author3=Miranda, S. V.|author4=Rubio, A. D.|author5=Leal, L. O.|date=11 June 2011|journal=Int. J. Environ. Res. Public Health|doi=10.3390/ijerph8062516|pmid=21776243|pmc=3138038}} Free access and license (CC-BY 3.0)</ref>
+A test of common skin lightening creams available in [[Nigeria]] showed that they caused [[mutations]] in bacteria and were possibly [[carcinogenic]].<ref>{{cite journal|last=Akortha|first=E.E. |author2=Niemogha, M.T. |author3=Edobor, O.|title=MUTAGENIC AND GENOTOXIC SCREENING OF EIGHT COMMONLY USED SKIN WHITENING CREAMS IN NIGERIA|journal=Bayero Journal of Pure and Applied Sciences|date=1 June 2012|volume=5|issue=1|pages=5–10|url=http://www.ajol.info/index.php/bajopas/article/view/80929/71155|accessdate=25 December 2012|doi=10.4314/bajopas.v5i1.2}}</ref> A study that examined skin whitening creams in [[Mexico]] found an high concentration of mercury in several of them.<ref>{{cite journal|title=Mercury Levels in Locally Manufactured Mexican Skin-Lightening Creams|author1=Peregrino, C. P.|author2=Moreno, M. V.|author3=Miranda, S. V.|author4=Rubio, A. D.|author5=Leal, L. O.|date=11 June 2011|journal=Int. J. Environ. Res. Public Health|doi=10.3390/ijerph8062516|pmid=21776243|pmc=3138038}} {{lref|f|CC BY 3.0}}</ref>
 ==See also==
+* Procedures
-* [[Depigmentation]]
-** Diseases
-*** [[Vitiligo]]
-*** [[Albinism]]
-*** [[Hypopigmentation]]
-** Agents
-*** [[Hydroquinone]]
-*** [[Monobenzone]]
 ** [[Anal bleaching]]
-** [[Hyperpigmentation]]
+** [[Tooth bleaching]]
+** [[Depigmentation]]
 ** [[Taxifolin]]
+** [[Facial]]
+** [[Sun tanning]]
+* Diseases
+** [[Vitiligo]]
+** [[Albinism]]
+** [[Hypopigmentation]]
+** [[Hyperpigmentation]]
+* Culture
+** [[White skin]]
 ** [[Colorism]]
 ** [[Shadism]]
-** [[Venetian Ceruse]] - white lead based cosmetic worn by [[Elizabeth I of England]].
+** [[Venetian Ceruse]] ‒white lead based cosmetic worn by [[Elizabeth I of England]]‒.
-** [[Sun tanning]]
-** [[Facial]]
 ** [[Racial whitening]]
-** [[Pale (skin tone)]]
-** [[Tooth bleaching]]
 ** [[Whiteness in Japanese culture]]
 ** [[Colonial mentality]]
 ** [[Michael Jackson]]
-== References ==
+==Notes==
+Italics have been preserved whenever they appear in quotations. Text between square brackets are additional notes not present in the source.
-{{reflist|2}}
+{{reflist|group=notes}}
+==References==
+{{reflist|refs=
+<ref name=Chang2009>{{cite journal|title=An Updated Review of Tyrosinase Inhibitors
+|first1=Te-Sheng|last1=Chang|year=2009|journal=Int. J. Mol. Sci.|volume=10|issue=6|doi=10.3390/ijms10062440|pmc=2705500|pmid=19582213}} {{lref|f|CC BY 3.0}}</ref>
+<ref name=Chang2012>{{cite journal| title=Natural Melanogenesis Inhibitors Acting Through the Down-Regulation of Tyrosinase Activity| year=2012| last1=Chang| first1=Te-Sheng| journal=Materials| volume=5| issue=9| doi=10.3390/ma5091661}} {{lref|f|CC BY 3.0}}</ref>
+<ref name=Chen2014>{{cite journal| title=UV Signaling Pathways within the Skin| url=https://dx.doi.org/10.1038/jid.2014.161| last1=Chen| first1=Hongxiang| last2=Weng| first2=Qing Y.| last3=Fisher| first3=David E.| year=2014| journal=J. Invest. Dermatol.| volume=134| issue=4| doi=10.1038/jid.2014.161| pmc=4102648| pmid=24759085}} {{lref|nf}}</ref>
+<ref name="D'Orazio2013">{{cite journal| title=UV Radiation and the Skin| last1=D’Orazio| first1=John| last2=Jarrett| first2=Stuart| last3=Amaro-Ortiz| first3=Alexandra| last4=Scott| first4=Timothy| year=2013| journal=Int. J. Mol. Sci.| volume=14| issue=6| doi=10.3390/ijms140612222| pmc=3709783| pmid=23749111}} {{lref|f|CC BY, version apparently not specified}}</ref>
+<ref name=Ebanks2009>{{cite journal|title=Mechanisms Regulating Skin Pigmentation: The Rise and Fall of Complexion Coloration|last1=Ebanks
+|first1=Jody P.|last2=Wickett|first2=R. Randall|last3=Boissy|first3=Raymond E.|year=2009|journal=Int. J. Mol. Sci.|volume=10|issue=9|doi=10.3390/ijms10094066|pmc=2769151|pmid=19865532}} {{lref|f|CC BY 3.0}}</ref>
+<ref name=Espín2001>{{cite journal| title=Effect of captopril on mushroom tyrosinase activity in vitro| last1=Espín| first1=Juan Carlos| last2=Wichers| first2=Harry J.| year=2001| journal=Biochim. Biophys. Acta.| volume=1544| issue=1-2| doi=10.1016/s0167-4838(00)00230-2| pmid=11341938}} Restricted access.</ref>
+<ref name=Imokawa2014>{{cite journal|title=Inhibitors of Intracellular Signaling Pathways that Lead to Stimulated Epidermal Pigmentation: Perspective of Anti-Pigmenting Agents|url=http://www.mdpi.com/1422-0067/15/5/8293|last1=Imokawa|first1=Genji|last2=Ishida|first2=Koichi|year=2014|journal=Int. J. Mol. Sci.|volume=15|issue=5|doi=10.3390/ijms15058293|pmc=4057732|pmid=24823877}} {{lref|f|CC BY 3.0}}</ref></ref><ref name=Nelson2009>{{cite journal| title=Melanoma and genetics| last1=Nelson| first1=Andrew A.| last2=Tsao| first2=Hensin| year=2009| journal=Clin. Dermatol.| volume=27| issue=1| doi=10.1016/j.clindermatol.2008.09.005| pmid=19095153}} Restricted access.</ref>
+<ref name=Jung2013>{{cite journal| title=Madecassoside Inhibits Melanin Synthesis by Blocking Ultraviolet-Induced Inflammation| last1=Jung| first1=Eunsun| last2=Lee| first2=Jung-A| last3=Shin| first3=Seoungwoo| last4=Roh| first4=Kyung-Baeg| last5=Kim| first5=Jang-Hyun| last6=Park| first6=Deokhoon| year=2013| journal=Molecules| volume=18| issue=12| doi=10.3390/molecules181215724| pmid=24352025}} {{lref|f|CC BY 3.0}}</ref>
+<ref name=Kondo2011>{{cite journal| title=Update on the regulation of mammalian melanocyte function and skin pigmentation| last1=Kondo| first1=Taisuke| last2=Hearing| first2=Vincent J.| year=2011| journal=Expert. Rev. Dermatol.| volume=6| issue=1| doi=10.1586/edm.10.70| pmc=3093193| pmid=21572549}} {{lref|nf}}</ref>
+<ref name=Lee2013>{{cite journal| title=The regulation of epidermal melanogenesis via cAMP and/or PKC signaling pathways: insights for the development of hypopigmenting agents| last1=Lee| first1=Ai-Young| last2=Noh| first2=Minsoo| year=2013| journal=Arch. Pharm. Res.| volume=36| issue=7| doi=10.1007/s12272-013-0130-6| pmid=23604723}} Restricted access.</ref>
+<ref name=Makino-Okamura2014>{{cite journal| title=Heparin inhibits melanosome uptake and inflammatory response coupled with phagocytosis through blocking PI3k/Akt and MEK/ERK signaling pathways in human epidermal keratinocytes| url=https://www.researchgate.net/profile/Naoaki_Saito/publication/263432448_Heparin_inhibits_melanosome_uptake_and_inflammatory_response_coupled_with_phagocytosis_through_blocking_PI3kAkt_and_MEKERK_signaling_pathways_in_human_epidermal_keratinocytes/links/544594b50cf22b3c14dde953.pdf| authors=Makino-Okamura, Chieko et. al.| year=2014| journal=Pigment Cell Melanoma Res.| volume=27| issue=6| doi=10.1111/pcmr.12287| pmid=24961476}} {{lref|nf}}</ref>
+<ref name=Rodríguez2014>{{cite journal|title=Cyclic AMP (cAMP) signaling in melanocytes and melanoma| last1=Rodríguez| first1=Carlos Iván| last2=Setaluri| first2=Vijayasaradhi| year=2014| journal=Arch. Biochem. Biophys.| volume=563| doi=10.1016/j.abb.2014.07.003| pmid=25017568}} Restricted access.</ref>
+<ref name=Slominski2004>{{cite journal|title=Melanin Pigmentation in Mammalian Skin and its Hormonal Regulation|last1=Slominski|first1=Andrzej|last2=Tobin|first2=Desmond J.|last3=Shibahara|first3=Shigeki|last4=Wortsman|first4=Jacobo|year=2004|journal=Physiol. Rev.|volume=84|issue=4|doi=10.1152/physrev.00044.2003|pmid=15383650}} {{lref|nf}}</ref>
+<ref name=Smit2009>{{cite journal| title=The Hunt for Natural Skin Whitening Agents| last1=Smit| first1=Nico| last2=Vicanova| first2=Jana| last3=Pavel| first3=Stan| year=2009| journal=Int. J. Mol. Sci.| volume=10| issue=12| doi=10.3390/ijms10125326| pmc=2801997| pmid=20054473}} {{lref|f|CC BY 3.0}}</ref>
+<ref name=Wu2014>{{cite journal| title=Melanosome transfer: It is best to give and receive| last1=Wu| first1=Wufeng| last2=Hammer| first2=John A.| year=2014| journal=Curr. Opin. Cell Biol.| volume=29| doi=10.1016/j.ceb.2014.02.003| pmc=4130791| pmid=24662021}} {{font color|brown|Manuscript in PMC.}}</ref>
+<ref name=Yamaguchi2009>{{cite journal| title=Physiological factors that regulate skin pigmentation| last1=Yamaguchi| first1=Yuji| last2=Hearing| first2=Vincent J.| year=2009| journal=Biofactors| volume=35| issue=2| doi=10.1002/biof.29| pmc=2793097| pmid=19449448}} {{lref|nf}}</ref>
+}}
 {{Japanese cosmetics}}