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==Sources==
==Sources==
[[File:Carrots.JPG|thumb|upright|right|250px|[[Carrot]]s are a source of beta-carotene]]
[[File:Carrots.JPG|thumb|upright|right|250px|[[Carrot]]s are a rich source of beta-carotene]]
Vitamin A is found in many foods, including the following list.<ref>{{cite web |url=https://ndb.nal.usda.gov/ndb/nutrients/report/nutrientsfrm?max=25&offset=0&totCount=0&nutrient1=318&nutrient2=&nutrient3=&subset=0&sort=c&measureby=g |title=Rank order of vitamin A content in foods per 100 g |publisher=USDA National Nutrient Database |date=29 March 2017 |access-date=26 April 2017}}</ref> For the animal-sourced foods it is retinol. For the plant-sourced it is carotenoids (primarily beta-carotene). Conversion of carotenes to retinol varies from person to person depending on their vitamin status.<ref>{{cite journal |vauthors=Borel P, Drai J, Faure H, Fayol V, Galabert C, Laromiguière M, Le Moël G |title= [Recent knowledge about intestinal absorption and cleavage of carotenoids] |language=fr |journal=Annales de Biologie Clinique |volume=63 |issue=2 |pages=165–177 |year=2005 |pmid=15771974}}</ref><ref>{{cite journal |vauthors=Tang G, Qin J, Dolnikowski GG, Russell RM, Grusak MA |title=Spinach or carrots can supply significant amounts of vitamin A as assessed by feeding with intrinsically deuterated vegetables |journal=The American Journal of Clinical Nutrition |volume=82 |issue=4 |pages=821–828 |date=October 2005 |pmid=16210712 |doi=10.1093/ajcn/82.4.821|doi-access=free }}</ref> According to the vitamin A chapter in the Dietary Reference Intakes book, a vegetarian or vegan diet can provide sufficient vitamin A in the form of beta-carotene if the diet contains green leafy vegetables, carrots, sweet potatoes and other deeply colored foods (see table). There are also vitamin A fortified foods and dietary supplements.<ref name="DRI VitA"/>
Vitamin A is found in many foods, including the following list.<ref>{{cite web |url=https://fdc.nal.usda.gov/fdc-app.html#/?component=1106 |title=Rank order of vitamin A content in foods, retinol activity equivalent (RAE) in ug per 100 g |publisher=FoodData Central, US Department of Agriculture |date=1 October 2021 |access-date=20 December 2021}}</ref> Vitamin A content in animal-sourced foods derives from retinol, while in plant-sourced foods, it derives from beta-carotene and [[Β-Cryptoxanthin|beta-cryptoxanthin]] which are converted to retinol in the body.{{medical citation needed|date=December 2021}} Conversion of carotenoids to retinol varies from person to person depending on their vitamin status.<ref>{{cite journal |vauthors=Borel P, Drai J, Faure H, Fayol V, Galabert C, Laromiguière M, Le Moël G |title= [Recent knowledge about intestinal absorption and cleavage of carotenoids] |language=fr |journal=Annales de Biologie Clinique |volume=63 |issue=2 |pages=165–177 |year=2005 |pmid=15771974}}</ref><ref>{{cite journal |vauthors=Tang G, Qin J, Dolnikowski GG, Russell RM, Grusak MA |title=Spinach or carrots can supply significant amounts of vitamin A as assessed by feeding with intrinsically deuterated vegetables |journal=The American Journal of Clinical Nutrition |volume=82 |issue=4 |pages=821–828 |date=October 2005 |pmid=16210712 |doi=10.1093/ajcn/82.4.821|doi-access=free }}</ref> According to the vitamin A chapter in the Dietary Reference Intakes book, a vegetarian or vegan diet can provide sufficient vitamin A in the form of beta-carotene if the diet contains green leafy vegetables, carrots, sweet potatoes and other carotenoid-rich foods (see table). There are also [[food fortification|manufactured foods]] and dietary supplements which supply vitamin A or beta-carotene.<ref name="DRI VitA"/>


{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
! Source || Retinol activity equivalences<br> (RAEs), μg/100g
! Source || Retinol activity equivalents<br> (RAEs), μg/100g
|-
|-
| [[cod liver oil]] || 30000
| [[cod liver oil]] || 30000
|-
|-
| [[liver (food)|liver]] turkey || 8058
| [[liver (food)|liver]] beef (cooked) || 21145
|-
|-
| [[liver (food)|liver]] beef, pork, fish || 6500
| [[liver (food)|liver]] turkey (cooked) || 10751
|-
|-
| [[liver (food)|liver]] chicken || 3296
| [[liver (food)|liver]] chicken || 4296
|-
|-
| [[sweet potato]]{{refn|group=food|Content in sweet potatoes depend on flesh color.}} || 961
| [[sweet potato]] (cooked in skin) || 961
|-
|-
| [[carrot]] || 835
| [[carrot]] (raw) || 835
|-
|-
| [[broccoli]] leaf || 800
| [[pumpkin]] (canned) || 778
|-
|-
| [[butter]] || 684
| [[butter]] (stick) || 684
|-
|-
| [[kale]] || 681
| [[spinach]] (cooked) || 603
|-
|-
| [[collard greens]] frozen then boiled || 575
| [[cheddar cheese]] || 316
|-
| [[butternut squash]] || 532
|-
| [[Taraxacum|dandelion greens]] || 508
|-
| [[spinach]] || 469
|-
| [[pumpkin]] || 426
|-
| [[collard greens]] || 333
|-
| [[ghee]] || 300
|-
| [[cheddar cheese]] || 265
|-
|-
| [[cantaloupe melon]] || 169
| [[cantaloupe melon]] || 169
Line 192: Line 178:
| [[Bell pepper|bell pepper/capsicum]], red || 157
| [[Bell pepper|bell pepper/capsicum]], red || 157
|-
|-
| [[egg (food)|egg]] || 140
| [[egg (food)|egg]] (cooked) || 140
|-
| [[apricot]] || 96
|-
| [[papaya]] || 55
|-
| [[tomato]]es || 42
|-
| [[mango]] || 38
|-
| [[pea]] || 38
|-
| [[broccoli]] florets || 31
|-
| [[milk]] || 28
|-
| [[Bell pepper|bell pepper/capsicum]], green || 18
|-
|-
| [[spirulina (dietary supplement)|spirulina]] || 3
|}
|}
<references group=food/>
<references group=food/>

Revision as of 18:08, 20 December 2021

"ATAV" redirects here. For the telenovela, see Argentina, tierra de amor y venganza.
This article is about the family of vitamers. For the form usually used as a supplement, see Retinol.

Chemical structure of retinol, one of the major forms of vitamin A

Vitamin A is a group of unsaturated nutritional organic compounds that includes retinol, retinal, and several provitamin A carotenoids (most notably beta-carotene).[1][2][3] Vitamin A has multiple functions: it is important for growth and development, for the maintenance of the immune system, and for good vision.[4][5] Vitamin A is needed by the retina of the eye in the form of retinal, which combines with protein opsin to form rhodopsin, the light-absorbing molecule[6] necessary for both low-light (scotopic vision) and color vision.[4]

In foods of animal origin, the major form of vitamin A is an ester, primarily retinyl palmitate, which is converted to retinol (chemically an alcohol) in the small intestine. The retinol form functions as a storage form of the vitamin, and can be converted to and from its visually active aldehyde form, retinal.[3]

All forms of vitamin A have a beta-ionone ring to which an isoprenoid chain is attached, called a retinyl group.[1] Both structural features are essential for vitamin activity.[3] The orange pigment of beta-carotene can be represented as two connected retinyl groups, which are used in the body to contribute to vitamin A levels.[3] Alpha-carotene and gamma-carotene also have a single retinyl group, which give them some vitamin activity. None of the other carotenes have vitamin activity. The carotenoid beta-cryptoxanthin possesses an ionone group and has vitamin activity in humans.

Vitamin A can be found in two principal forms in foods:

Definition

Medical uses

Treating deficiency

Main article: Vitamin A deficiency

Vitamin A deficiency is estimated to affect approximately one third of children under the age of five around the world.[8] It is estimated to claim the lives of 670,000 children under five annually.[9] Between 250,000 and 500,000 children in developing countries become blind each year owing to vitamin A deficiency, with the highest prevalence in Africa and southeast Asia.[4] Vitamin A deficiency is "the leading cause of preventable childhood blindness", according to UNICEF.[10][11] It also increases the risk of death from common childhood conditions such as diarrhea. UNICEF regards addressing vitamin A deficiency as critical to reducing child mortality, the fourth of the United Nations' Millennium Development Goals.[10]

Vitamin A deficiency can occur as either a primary or a secondary deficiency. A primary vitamin A deficiency occurs among children and adults who do not consume an adequate intake of provitamin A carotenoids from fruits and vegetables or preformed vitamin A from animal and dairy products. Early weaning from breastmilk can also increase the risk of vitamin A deficiency.

Secondary vitamin A deficiency is associated with chronic malabsorption of lipids, impaired bile production and release, and chronic exposure to oxidants, such as cigarette smoke, and chronic alcoholism. Vitamin A is a fat-soluble vitamin and depends on micellar solubilization for dispersion into the small intestine, which results in poor use of vitamin A from low-fat diets. Zinc deficiency can also impair absorption, transport, and metabolism of vitamin A because it is essential for the synthesis of the vitamin A transport proteins and as the cofactor in conversion of retinol to retinal. In malnourished populations, common low intakes of vitamin A and zinc increase the severity of vitamin A deficiency and lead to physiological signs and symptoms of deficiency.[12]

Due to the unique function of retinal as a visual chromophore, one of the earliest and specific manifestations of vitamin A deficiency is impaired vision, particularly in reduced light – night blindness. Persistent deficiency gives rise to a series of changes, the most devastating of which occur in the eyes. Some other ocular changes are referred to as xerophthalmia. First there is dryness of the conjunctiva (xerosis) as the normal lacrimal and mucus-secreting epithelium is replaced by a keratinized epithelium. This is followed by the build-up of keratin debris in small opaque plaques (Bitot's spots) and, eventually, erosion of the roughened corneal surface with softening and destruction of the cornea (keratomalacia) and leading to total blindness. Other changes include impaired immunity (increased risk of ear infections, urinary tract infections, meningococcal disease), hyperkeratosis (white lumps at hair follicles), keratosis pilaris and squamous metaplasia of the epithelium lining the upper respiratory passages and urinary bladder to a keratinized epithelium. In relation to dentistry, a deficiency in vitamin A may lead to enamel hypoplasia.

Adequate supply, but not excess vitamin A, is especially important for pregnant and breastfeeding women for normal fetal development and in breastmilk.[13] Excess vitamin A, which is most common with high-dose vitamin supplements, can cause birth defects and therefore should not exceed recommended daily values.

Vitamin A supplementation

Vitamin A supplementation coverage rate (children ages 6–59 months), 2014[14]

In 2008, the World Health Organization estimated that vitamin A supplementation over a decade in 40 countries averted 1.25 million deaths due to vitamin A deficiency.[15] A 2012 review found no evidence that beta-carotene or vitamin A supplements increased longevity in healthy people or in people with various diseases.[16] A 2011 review found that vitamin A supplementation of children at risk of deficiency aged under five reduced mortality by up to 24%.[17] However, other reviews concluded there was insufficient evidence to recommend blanket vitamin A supplementation for all infants less than a year of age, as it did not reduce infant mortality or morbidity in low- and middle-income countries.[18][19]

Food fortification approaches are feasible, but cannot ensure adequate intake levels.[20] While strategies include intake of vitamin A through a combination of breast feeding and dietary intake, delivery of oral high-dose supplements remains the principal strategy for minimizing deficiency.[20] In 2016-7, about 75% of the vitamin A required for supplementation activity by developing countries was supplied by the Micronutrient Initiative, with support from the Canadian International Development Agency.[21]

Topical

Retinyl palmitate has been used in skin creams, where it is broken down to retinol and ostensibly metabolized to retinoic acid, which has potent biological activity, as described above. The retinoids (for example, 13-cis-retinoic acid) constitute a class of chemical compounds chemically related to retinoic acid, and are used in medicine to modulate gene functions in place of this compound. Like retinoic acid, the related compounds do not have full vitamin A activity, but do have powerful effects on gene expression and epithelial cell differentiation.[22] Pharmaceutics utilizing megadoses of naturally occurring retinoic acid derivatives are currently in use for cancer, HIV, and dermatological purposes.[23] At high doses, side-effects are similar to vitamin A toxicity.[citation needed]

Units of measurement

As some carotenoids can be converted into vitamin A, attempts have been made to determine how much of them in the diet is equivalent to a particular amount of retinol, so that comparisons can be made of the benefit of different foods. The situation can be confusing because the accepted equivalences have changed over time

For many years, a system of equivalencies in which an international unit (IU) was equal to 0.3 μg of retinol (~1 nmol), 0.6 μg of β-carotene, or 1.2 μg of other provitamin-A carotenoids was used.[24] This relationship was alternatively expressed by the retinol equivalent (RE): one RE corresponded to 1 μg retinol, to 2 μg β-carotene dissolved in oil, to 6 μg β-carotene in foods, and to 12 μg of either α-carotene, γ-carotene, or β-cryptoxanthin in food.

Newer research has shown that the absorption of provitamin-A carotenoids is only half as much as previously thought. As a result, in 2001 the US Institute of Medicine recommended a new unit, the retinol activity equivalent (RAE). Each μg RAE corresponds to 1 μg retinol, 2 μg of β-carotene in oil, 12 μg of "dietary" beta-carotene, or 24 μg of the three other dietary provitamin-A carotenoids.[2]

Substance and its chemical environment (per 1 μg) IU (1989) μg RE (1989) μg RAE (2001)
Retinol 3.33 1 1
beta-Carotene, dissolved in oil 1.67 1/2 1/2
beta-Carotene, common dietary 1.67 1/6 1/12
0.83 1/12 1/24

Because the conversion of retinol from provitamin carotenoids by the human body is actively regulated by the amount of retinol available to the body, the conversions apply strictly only for vitamin A-deficient humans. [citation needed]

Dietary recommendations

The US National Academy of Medicine updated Dietary Reference Intakes (DRIs) in 2001 for vitamin A, which included Recommended Dietary Allowances (RDAs) and Estimated Average Requirements (EARs).[2] For infants up to 12 months there was not sufficient information to establish a RDA, so Adequate Intake (AI) is shown instead. As for safety, tolerable upper intake levels (ULs) were also established. For RDAs, the calculation of retinol activity equivalents (RAE) is each μg RAE corresponds to 1 μg retinol, 2 μg of β-carotene in oil, 12 μg of "dietary" beta-carotene, or 24 μg of the three other dietary provitamin-A carotenoids.[2] For ULs, carotenoids are not added when calculating total vitamin A intake for safety assessments.[2]

Life stage group US RDAs or AIs
(μg RAE/day) 		US Upper limits
(μg/day)
Infants 0–6 months 400 (AI) 600
7–12 months 500 (AI) 600
Children 1–3 years 300 600
4–8 years 400 900
Males 9–13 years 600 1700
14–18 years 900 2800
>19 years 900 3000
Females 9–13 years 600 1700
14–18 years 700 2800
>19 years 700 3000
Pregnancy <19 years 750 2800
>19 years 770 3000
Lactation <19 years 1200 2800
>19 years 1300 3000

European Union

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL defined the same as in United States. For women and men of ages 15 and older, the PRIs are set respectively at 650 and 750 μg RE/day. PRI for pregnancy is 700 μg RE/day, for lactation 1300/day. For children of ages 1–14 years, the PRIs increase with age from 250 to 600 μg RE/day. These PRIs are similar to the US RDAs.[25] The EFSA reviewed the same safety question as the United States, and set ULs at 800 for ages 1-3, 1100 for ages 4-6, 1500 for ages 7-10, 2000 for ages 11-14, 2600 for ages 15-17 and 3000 μg/day for ages 18 and older for preformed vitamin A, i.e., not including dietary contributions from carotenoids.[26]

Safety

Main article: Hypervitaminosis A

Vitamin A toxicity hypervitaminosis A occurs when there is too much vitamin A accumulating in the body. It comes from consumption of retinol but not of carotenoids, as conversion of the latter to retinol is suppressed by the presence of retinol. There are historical reports of acute hypervitaminosis A from Artic explorers consuming seal or polar bear liver (very rich sources of stored retinol), but otherwise there is no risk from consuming too much via foods. Only consumption of retinol-containing dietary supplements can result in acute or chronic toxicity.[3] Acute toxicity occurs after a single or short-term doses of greater than 150,000 μg. Symptoms include blurred vision, nausea, vomiting, dizziness and headache witin 8 to 24 hours. Chronic toxicity may occur with long-term consumption of vitamin A at doses of 25,000–33,000 IU/day for several months.[1] Excessive consumption of alcohol can lead to chronic toxicity at lower intakes.[4] Symptoms may include nervous system effects, liver abnormalities, fatigue, muscle weakness, bone and skin changes and others. The asverse effects of both acute an chronic toxicity are reversed after consumption is stopped.[2]

In 2001, for the purpose of determining a Tolerable Upper Intake Level (UL) for adults, the US Institute of Medicine considered three primary adverse effects and settled on two: teratogenicity, i.e., causing birth defects, and liver abnormalities. Reduced bone mineral density was considered, but dismissed because the human evidence was contradictory.[2] During pregnancy, especially during the first trimester, consumption of retinol in amounts exceeding 4,500 μg/day increased the risk of birth defects, but not below that amount, thus setting a "No-Observed Adverse-Effect Level" (NOAEL). Given the quality of the clinical trial evidence, the NOAEL was divided by an uncertainty factor of 1.5 to set the ULfor women of reproductive age at 3,000 ug/day or preformed vitamin A. For all other adults, liver abnormalities were detected at intakes above 14,000 ug/day. Given the weak quality of the clinical trial evidence an uncertainty factor of 5 was used, and with rounding, the UL was set at 3,000 ug/day. For children ULs were extrapolated from the adult value, adjusted for relative body weight.[2]

β-carotene safety

No adverse effects other than carotenemia have been reported for consumption of β-carotene rich foods. Supplementation with β-carotene does not cause hypervitaminosis A. Two large clinical trials (ATBC and CARET) were conducted in tobacco smokers to see if years of β-carotene supplementation at 20 or 30 mg/day in oil-filled capsules would reduce the risk of lung cancer.[27] These trials were implemented because observational studies had reported a lower incidence of lung cancer in tobacco smokers who had diets higher in β-carotene.[26] Unexpectedly, β-carotene supplementation resulted in a higher incidence of lung cancer and of total mortality. Taking this and other evidence into consideration, the U.S. Institute of Medicine decided to not set a Tolerable Upper Intake Level (UL) for β-carotene.[27] The European Food Safety Authority, acting for the European Union, also decided to not set a UL for β-carotene.[26]

Carotenosis

Carotenoderma, also referred to as carotenemia, is a benign and reversible medical condition where an excess of dietary carotenoids results in orange discoloration of the outermost skin layer. It is associated with a high blood β-carotene value. This can occur after a month or two of consumption of beta-carotene rich foods, such as carrots, carrot juice, tangerine juice, or in Africa, red palm oil. β-carotene dietary supplements can have the same effect. The discoloration etends to palms and soles of feet, but not to the white of the eye, which helps distinguish the condition from jaundice.[28] Consumption of greater than 30 mg/day for a prolonged period has been confirmed as leading to carotenemia.[29]

U.S. labeling

For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For vitamin A labeling purposes 100% of the Daily Value was set at 5,000 IU, but it was revised to 900 μg RAE on 27 May 2016.[30][31] A table of the old and new adult daily values is provided at Reference Daily Intake.

Sources

Carrots are a rich source of beta-carotene

Vitamin A is found in many foods, including the following list.[32] Vitamin A content in animal-sourced foods derives from retinol, while in plant-sourced foods, it derives from beta-carotene and beta-cryptoxanthin which are converted to retinol in the body.[medical citation needed] Conversion of carotenoids to retinol varies from person to person depending on their vitamin status.[33][34] According to the vitamin A chapter in the Dietary Reference Intakes book, a vegetarian or vegan diet can provide sufficient vitamin A in the form of beta-carotene if the diet contains green leafy vegetables, carrots, sweet potatoes and other carotenoid-rich foods (see table). There are also manufactured foods and dietary supplements which supply vitamin A or beta-carotene.[2]

Source Retinol activity equivalents
(RAEs), μg/100g
cod liver oil 30000
liver beef (cooked) 21145
liver turkey (cooked) 10751
liver chicken 4296
sweet potato (cooked in skin) 961
carrot (raw) 835
pumpkin (canned) 778
butter (stick) 684
spinach (cooked) 603
cheddar cheese 316
cantaloupe melon 169
bell pepper/capsicum, red 157
egg (cooked) 140


Metabolic functions

Vitamin A plays a role in a variety of functions throughout the body,[4] such as:

Vision

The role of vitamin A in the visual cycle is specifically related to the retinal form. Within the eye, 11-cis-retinal is bound to the protein "opsin" to form rhodopsin in rods[6] and iodopsin (cones) at conserved lysine residues. As light enters the eye, the 11-cis-retinal is isomerized to the all-"trans" form. The all-"trans" retinal dissociates from the opsin in a series of steps called photo-bleaching. This isomerization induces a nervous signal along the optic nerve to the visual center of the brain. After separating from opsin, the all-"trans"-retinal is recycled and converted back to the 11-"cis"-retinal form by a series of enzymatic reactions. In addition, some of the all-"trans" retinal may be converted to all-"trans" retinol form and then transported with an interphotoreceptor retinol-binding protein (IRBP) to the pigment epithelial cells. Further esterification into all-"trans" retinyl esters allow for storage of all-trans-retinol within the pigment epithelial cells to be reused when needed.[12] The final stage is conversion of 11-cis-retinal will rebind to opsin to reform rhodopsin (visual purple) in the retina. Rhodopsin is needed to see in low light (contrast) as well as for night vision. Kühne showed that rhodopsin in the retina is only regenerated when the retina is attached to retinal pigmented epithelium,[6] which provides retinal. It is for this reason that a deficiency in vitamin A will inhibit the reformation of rhodopsin, and will lead to one of the first symptoms, night blindness.[35]

Gene transcription

Main article: Gene transcription

Vitamin A, in the retinoic acid form, plays an important role in gene transcription. Once retinol has been taken up by a cell, it can be oxidized to retinal (retinaldehyde) by retinol dehydrogenases; retinaldehyde can then be oxidized to retinoic acid by retinaldehyde dehydrogenases.[36] The conversion of retinaldehyde to retinoic acid is an irreversible step; this means that the production of retinoic acid is tightly regulated, due to its activity as a ligand for nuclear receptors.[12] The physiological form of retinoic acid (all-trans-retinoic acid) regulates gene transcription by binding to nuclear receptors known as retinoic acid receptors (RARs) which are bound to DNA as heterodimers with retinoid "X" receptors (RXRs). RAR and RXR must dimerize before they can bind to the DNA. RAR will form a heterodimer with RXR (RAR-RXR), but it does not readily form a homodimer (RAR-RAR). RXR, on the other hand, may form a homodimer (RXR-RXR) and will form heterodimers with many other nuclear receptors as well, including the thyroid hormone receptor (RXR-TR), the Vitamin D3 receptor (RXR-VDR), the peroxisome proliferator-activated receptor (RXR-PPAR) and the liver "X" receptor (RXR-LXR).[37]

The RAR-RXR heterodimer recognizes retinoic acid response elements (RAREs) on the DNA whereas the RXR-RXR homodimer recognizes retinoid "X" response elements (RXREs) on the DNA; although several RAREs near target genes have been shown to control physiological processes,[36] this has not been demonstrated for RXREs. The heterodimers of RXR with nuclear receptors other than RAR (i.e. TR, VDR, PPAR, LXR) bind to various distinct response elements on the DNA to control processes not regulated by vitamin A.[12] Upon binding of retinoic acid to the RAR component of the RAR-RXR heterodimer, the receptors undergo a conformational change that causes co-repressors to dissociate from the receptors. Coactivators can then bind to the receptor complex, which may help to loosen the chromatin structure from the histones or may interact with the transcriptional machinery.[37] This response can upregulate (or downregulate) the expression of target genes, including Hox genes as well as the genes that encode for the receptors themselves (i.e. RAR-beta in mammals).[12]

Immune function

Vitamin A plays a role in many areas of the immune system, particularly in T cell differentiation and proliferation.[38][39]

Vitamin A promotes the proliferation of T cells through an indirect mechanism involving an increase in IL-2.[39] In addition to promoting proliferation, vitamin A (specifically retinoic acid) influences the differentiation of T cells.[40][41] In the presence of retinoic acid, dendritic cells located in the gut are able to mediate the differentiation of T cells into regulatory T cells.[41] Regulatory T cells are important for prevention of an immune response against "self" and regulating the strength of the immune response in order to prevent host damage. Together with TGF-β, Vitamin A promotes the conversion of T cells to regulatory T cells.[40] Without Vitamin A, TGF-β stimulates differentiation into T cells that could create an autoimmune response.[40]

Hematopoietic stem cells are important for the production of all blood cells, including immune cells, and are able to replenish these cells throughout the life of an individual. Dormant hematopoietic stem cells are able to self-renew, and are available to differentiate and produce new blood cells when they are needed. In addition to T cells, Vitamin A is important for the correct regulation of hematopoietic stem cell dormancy.[42] When cells are treated with all-trans retinoic acid, they are unable to leave the dormant state and become active, however, when vitamin A is removed from the diet, hematopoietic stem cells are no longer able to become dormant and the population of hematopoietic stem cells decreases.[42] This shows an importance in creating a balanced amount of vitamin A within the environment to allow these stem cells to transition between a dormant and activated state, in order to maintain a healthy immune system.

Vitamin A has also been shown to be important for T cell homing to the intestine, effects dendritic cells, and can play a role in increased IgA secretion, which is important for the immune response in mucosal tissues.[38][43]

Dermatology

Vitamin A, and more specifically, retinoic acid, appears to maintain normal skin health by switching on genes and differentiating keratinocytes (immature skin cells) into mature epidermal cells.[44] Exact mechanisms behind pharmacological retinoid therapy agents in the treatment of dermatological diseases are being researched. For the treatment of acne, the most prescribed retinoid drug is 13-cis retinoic acid (isotretinoin). It reduces the size and secretion of the sebaceous glands. Although it is known that 40 mg of isotretinoin will break down to an equivalent of 10 mg of ATRA — the mechanism of action of the drug (original brand name Accutane) remains unknown and is a matter of some controversy. Isotretinoin reduces bacterial numbers in both the ducts and skin surface. This is thought to be a result of the reduction in sebum, a nutrient source for the bacteria. Isotretinoin reduces inflammation via inhibition of chemotactic responses of monocytes and neutrophils.[12] Isotretinoin also has been shown to initiate remodeling of the sebaceous glands; triggering changes in gene expression that selectively induce apoptosis.[45] Isotretinoin is a teratogen with a number of potential side-effects. Consequently, its use requires medical supervision.

Research

Fetal alcohol spectrum disorder

Fetal alcohol spectrum disorder (FASD), formerly referred to as fetal alcohol syndrome, presents as craniofacial malformations, neurobehavioral disorders and mental disabilities, all attributed to exposing human embryos to alcohol during fetal development.[46][47] The risk of FASD depends on the amount consumed, the frequency of consumption, and the points in pregnancy at which the alcohol is consumed.[48] Ethanol is a known teratogen, i.e, causes birth defects. Ethanol is metabolized by alcohol dehydrogenase enzymes into acetaldehyde.[49][50] The subsequent oxidation of acetaldehyde into acetate is performed by aldehyde dehydrogenase enzymes. Given that retinoic acid (RA) regulates numerous embryonic and differentiation processes, one of the proposed mechanisms for the teratogenic effects of ethanol is a competition for the enzymes required for the biosynthesis of RA from vitamin A. Animal research demonstrates that in the embryo, the competition takes place between acetaldehyde and retinaldehyde for aldehyde dehydrogenase activity. In this model, acetaldehyde inhibits the production of retinoic acid by retinaldehyde dehydrogenase. Ethanol-induced developmental defects can be ameliorated by increasing the levels of retinol, retinaldehyde, or retinaldehyde dehydrogenase. Thus, animal research supports the reduction of retinoic acid activity as an etiological trigger in the induction of FASD.[46][47][51][52]

Malaria

Malaria and vitamin A deficiency are both common among young children in sub-Saharan Africa. Vitamin A supplementation to children in regions where vitamin A deficiency is common has repeatedly been shown to reduce overall mortality rates, especially from measles and diarrhea.[53] For malaria, clinical trial results are mixed, either showing that vitamin A treatment did not reduce the incidence of probable malarial fever, or else did not affect incidence, but did reduce slide-confirmed parasite density and reduced the number of fever episodes.[53] The question was raised as to whether malaria causes vitamin A deficiency, or vitamin A deficiency contributes to the severity of malaria, or both. Researchers proposed several mechanisms by which malaria (and other infections) could contribute to vitamin A deficiency, including a fever-induced reduction in synthesis of retinal-binding protein (RBP) responsible for transporting retinol from liver to plasma and tissues, but reported finding no evidence fora transient depression or restoration of plasma RBP or retinol after a malarial infection was eliminated.[53]

History

In 1912, Frederick Gowland Hopkins demonstrated that unknown accessory factors found in milk, other than carbohydrates, proteins, and fats were necessary for growth in rats. Hopkins received a Nobel Prize for this discovery in 1929.[6][54] By 1913, one of these substances was independently discovered by Elmer McCollum and Marguerite Davis at the University of Wisconsin–Madison, and Lafayette Mendel and Thomas Burr Osborne at Yale University. McCollum and Davis ultimately received credit because they submitted their paper three weeks before Mendel and Osborne. Both papers appeared in the same issue of the Journal of Biological Chemistry in 1913.[55] The "accessory factors" were termed "fat soluble" in 1918 and later "vitamin A" in 1920. In 1919, Harry Steenbock (University of Wisconsin–Madison) proposed a relationship between yellow plant pigments (beta-carotene) and vitamin A. In 1931, Swiss chemist Paul Karrer described the chemical structure of vitamin A.[54] Vitamin A was first synthesized in 1947 by two Dutch chemists, David Adriaan van Dorp and Jozef Ferdinand Arens.

During World War II, German bombers would attack at night to evade British defenses. In order to keep the 1939 invention of a new on-board Airborne Intercept Radar system secret from German bombers, the British Ministry of Information told newspapers that the nighttime defensive success of Royal Air Force pilots was due to a high dietary intake of carrots rich in vitamin A, propagating the myth that carrots enable people to see better in the dark.[56][6]

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