Resveratrol

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Resveratrol
Chemical 9–69 structure of trans-resveratrol
Chemical structure of trans-resveratrol
Chemical structures of cis- and trans-resveratrols
Chemical structures of cis- ((Z)-resveratrol, left) and trans-resveratrol ((E)-resveratrol, right)[1]
Identifiers
CAS number 501-36-0 YesY
PubChem 445154
ChemSpider 392875 YesY
UNII Q369O8926L YesY
DrugBank DB02709
KEGG C03582 YesY
ChEBI CHEBI:45713 YesY
ChEMBL CHEMBL165 YesY
RTECS number CZ8987000
Jmol-3D images Image 1
Properties
Molecular formula C14H12O3
Molar mass 228.24 g mol−1
Appearance white powder with
slight yellow cast
Melting point 261 - 263°C / 501.8 - 505.4°F[2]
Solubility in water 0.03 g/L
Solubility in DMSO 16 g/L
Solubility in ethanol 50 g/L
λmax 304nm (trans-resveratrol, in water)
286nm (cis-resveratrol, in water)[1]
Hazards
MSDS Fisher Scientific[2]
Sigma Aldrich[3]
R-phrases R36 (irritating to eyes)[3]
S-phrases S26 (in case of contact with eyes, rinse immediately with plenty of water and

seek medical advice)[3]

LD50 23.2 µM (5,29 g)[4]
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 YesY (verify) (what is: YesY/N?)
Infobox references
UV visible spectrum of trans-resveratrol

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is produced in response to injury.[5] It is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi.

There is limited evidence of health effects in humans.

Health effects[edit]

Heart disease[edit]

There is little evidence of benefit from resveratrol in those who already have heart disease.[6]

Cancer[edit]

As of 2007, there is no evidence of an effect on cancer in humans.[7]

Metabolism[edit]

There is very little human evidence of an effect of resveratrol on metabolism.[8] There is some promising evidence in rodents.[8]

Lifespan[edit]

The effect of resveratrol on lifespan in humans is unclear as of 2011.[9] There is some evidence of benefit in yeast and mice.[9] However, no benefit has been shown for healthy non-obese mammals.[10][11]

Adverse effects[edit]

Long-term effects of using resveratrol are currently unknown.[12] Citing the evidence that resveratrol is estrogenantagonistic, some retailers of resveratrol advise that the compound may interfere with oral contraceptives and that women who are pregnant or intending to become pregnant should not use the product, while others advise that resveratrol should not be taken by children or young adults under eighteen, as no studies have shown how it affects their natural development. A small study found a single dose of up to 5 g of trans-resveratrol caused no serious adverse effects in healthy volunteers.[13]

Potential carcinogenicity[edit]

Resveratrol in common with other polyphenols, was found to be a strong topoisomerase inhibitor, sharing similarities to chemotherapeutic anticancer drugs, such as etoposide and doxorubicin.[14][15] This may simultaneously contribute to both the potential anticarcinogenic and carcinogenic properties of the substance in given circumstances. Harmful properties of resveratrol may be pronounced in the human fetus, as it has diminished detoxification systems. Therefore, resveratrol as commonly sold combined with other "bioflavonoids", should not be used by pregnant women.[16]

Natural occurrence[edit]

Resveratrol is found in the skin of red grapes and in other fruits as well as in the roots of Japanese knotweed (Polygonum cuspidatum). Red wine contains on the order of 0.1-14.3 mg/l.[17] Resveratrol also has been produced by chemical synthesis [18] and by biotechnological synthesis (metabolic engineered microorganisms),[19][20] and it is sold as a nutritional supplement derived primarily from Japanese knotweed.[21]

Resveratrol is also found in Gnetum cleistostachyum.[22]

Discovery and name[edit]

The first mention of resveratrol was in a Japanese article in 1939 by Michio Takaoka, who isolated it from the poisonous, but medicinal, Veratrum album, variety grandiflorum.[23] The name presumably comes from the fact that it is a resorcinol derivative coming from a Veratrum species.[24] In 2003, D. Sinclair from Harvard Medical School reported in Nature that resveratrol activated sirtuins in yeast cells. This as immediately followed by the launch of Sirtris Pharmaceuticals. While pharmacological effects of resveratrol did not turn out to be commercially viable, their discovery lead to efforts to develop other types of SIRT genes' activators.

Pharmacokinetics[edit]

One way of administering resveratrol in humans may be buccal delivery, that is without swallowing, by direct absorption through tissues on the inside of the mouth. When one milligram of resveratrol in 50 ml 50% alcohol/ water solution was retained in the mouth for one minute before swallowing, 37 ng/ml of free resveratrol were measured in plasma two minutes later. This level of unchanged resveratrol in blood can only be achieved with 250 mg of resveratrol taken in a pill form.[25] However, the viability of a buccal delivery method is called into question due to the low aqueous solubility of the molecule. For a drug to be absorbed transmucosally it must be in free-form or dissolved.[26][27] Resveratrol fits the criteria for oral transmucosal dosing, except for this caveat. The low aqueous solubility greatly limits the amount that can be absorbed through the buccal mucosa. Resveratrol that is attempted to be taken buccally was expected to pass through the mucous membrane of the mouth and be absorbed as an oral dose,[28] however, the need to explore buccal delivery in future pharmaceutical formulations was expressed.[27][29]

While 70% of orally administered resveratrol is absorbed its oral bioavailability is approximately 0.5% due to extensive hepatic gluconuridation and sulfation.[30] Only trace amounts (below 5 ng/ml) of unchanged resveratrol could be detected in the blood after 25 mg oral dose.[30] Even when a very large dose (2.5 and 5 g) was given as an uncoated pill, the concentration of resveratrol in blood failed to reach the level claimed to be necessary for the systemic cancer prevention.[13] A formulation of resveratrol in a chewing gum form is now in production, and this would be expected to achieve much higher blood levels than oral formulations. Resveratrol given in a proprietary formulation SRT-501 (3 or 5 g), developed by Sirtris Pharmaceuticals, reached five to eight times higher blood levels. These levels did approach the concentration necessary to exert the effects shown in animal models and in vitro experiments.[31] On May 5, 2010, however, GlaxoSmithKline (GSK) said it had suspended a small clinical trial of SRT501, a proprietary form of resveratrol, due to safety concerns, and terminated the study on December 2, 2010.[32] Sirtris Pharmaceuticals, which U.K.-based GlaxoSmithKline bought for $720 million in 2008, was developing the drug. GlaxoSmithKline is now focusing its efforts on more potent and selective SIRT1 activators—SRT2104 and SRT2379—both of which are involved in several exploratory clinical trials.[citation needed]

Full formal pharmacokinetics of oral resveratrol 2000 mg twice daily in humans, studying interaction with concurrent ethanol, quercetin, and fat meal has been published.[33] Mean peak serum resveratrol concentration was 1274 ng/ml at steady-state, which was reduced 46% by a fat meal at dosing. There was no effect of concurrent oral quercetin or ethanol. Healthy volunteers had frequently reported minor diarrhea, and laboratory measures identified slight changes in liver function tests and in serum potassium. No adverse effect on renal function was identified, although only eight healthy adults were observed in the two-week study.

In humans and rats less than 5% of the oral dose was observed as free resveratrol in blood plasma.[13][30][34][35][36] The most abundant resveratrol metabolites in humans, rats, and mice are trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate.[37] Walle suggests sulfate conjugates are the primary source of activity,[30] Wang et al. suggests the glucuronides,[38] and Boocock et al. also emphasized the need for further study of the effects of the metabolites, including the possibility of deconjugation to free resveratrol inside cells. Goldberd, who studied the pharmacokinetics of resveratrol, catechin and quercetin in humans, concluded "it seems that the potential health benefits of these compounds based upon the in vitro activities of the unconjugated compounds are unrealistic and have been greatly exaggerated. Indeed, the profusion of papers describing such activities can legitimately be described as irrelevant and misleading. Henceforth, investigations of this nature should focus upon the potential health benefits of their glucuronide and sulfate conjugates."[39]

The hypothesis that resveratrol from wine could have higher bioavailability than resveratrol from a pill [17][40] has been refuted by experimental data.[39][41] For example, after five men took 600 ml of red wine with the resveratrol content of 3.2 mg/l (total dose about 2 mg) before breakfast, unchanged resveratrol was detected in the blood of only two of them, and only in trace amounts (below 2.5 ng/ml). Resveratrol levels appeared to be slightly higher if red wine (600 ml of red wine containing 0.6 mcg(?)/ml resveratrol; total dose about 0.5 mg) was taken with a meal: trace amounts (1–6 ng/ml) were found in four out of ten subjects.[41] In another study, the pharmacokinetics of resveratrol (25 mg) did not change whether it was taken with vegetable juice, white wine, or white grape juice. The highest level of unchanged resveratrol in the serum (7–9 ng/ml) was achieved after 30 minutes, and it completely disappeared from blood after four hours.[39] The authors of both studies concluded the trace amounts of resveratrol reached in the blood are insufficient to explain the French paradox. The beneficial effects of wine apparently could be explained by the effects of alcohol [39] or the whole complex of substances wine contains;[41] for example, the cardiovascular benefits of wine appear to correlate with the content of procyanidins.[42]

Mechanisms of action[edit]

The mechanisms of resveratrol's apparent effects on life extension are not fully understood, but they appear to mimic several of the biochemical effects of calorie restriction. Some studies indicates resveratrol activates Sirtuin 1[43] and PGC-1α and improves the functioning of the mitochondria.[44] Resveratrol's ability to directly activate sirtuin 1 has been called into question,[45][46][47] however newer research has reconfirmed this link.[48]

In cells treated with resveratrol, a fourteen-fold increase in the action of MnSOD (SOD2) is observed.[49] MnSOD reduces superoxide to hydrogen peroxide (H2O2), but H2O2 is not increased due to other cellular activity. Superoxide O2 is a byproduct of respiration in complexes 1 and 3 of the electron transport chain. It is "not highly toxic, [but] can extract an electron from biological membrane and other cell components, causing free radical chain reactions. Therefore it is essential for the cell to keep superoxide anions in check."[50] MnSOD reduces superoxide and thereby, confers resistance to mitochondrial dysfunction, permeability transition, and apoptotic death in various diseases.[51] It has been implicated in lifespan extension, inhibits cancer, (e.g. pancreatic cancer) [52][53] and provides resistance to reperfusion injury and irradiation damage.[54][55][56] These effects have also been observed with resveratrol. Robb et al. propose MnSOD is increased by the pathway RESV → SIRT1 / NAD+ → FOXO3a → MnSOD. Resveratrol has been shown to cause SIRT1 to cause migration of FOXO transcription factors to the nucleus,[57] which stimulates FOXO3a transcriptional activity [58] and it has been shown to enhance the sirtuin-catalyzed deacetylation (activity) of FOXO3a. MnSOD is known to be a target of FOXO3a, and MnSOD expression is strongly induced in cells overexpressing FOXO3a.[59] It has been reported too that the disproportional up-regulation of superoxide dismutase (SOD), catalse (CAT) and glutathion peroxidase (GPX) expression (high expression of MnSOD, but mild change in CAT or GPX) and their enzymatic activity in cancer cells results in the mitochondrial accumulation of H2O2, which in turn induces cancer cell apoptosis.[60]

Resveratrol interferes with all three stages of carcinogenesis—initiation, promotion and progression. Experiments in cell cultures of varied types and isolated subcellular systems in vitro imply many mechanisms in the pharmacological activity of resveratrol. These mechanisms include modulation of the transcription factor NF-κB,[61] inhibition of the cytochrome P450 isoenzyme CYP1A1[62] (although this may not be relevant to the CYP1A1-mediated bioactivation of the procarcinogen benzo(a)pyrene),[63] alterations in androgenic [64] actions, and expression and activity of cyclooxygenase (COX) enzymes. In vitro, resveratrol "inhibited the proliferation of human pancreatic cancer cell lines." In some lineages of cancer cell culture, resveratrol has been shown to induce apoptosis, which means it kills cells and may kill cancer cells.[64][65][66][67][68][69] Resveratrol has been shown to induce Fas/Fas ligand mediated apoptosis, p53 and cyclins A, B1, and cyclin-dependent kinases cdk 1 and 2. Resveratrol also possesses antioxidant and anti-angiogenic properties.[70][71]

Resveratrol was reported to be effective against neuronal cell dysfunction and cell death, and, in theory, could be effective against diseases such as Huntington's disease and Alzheimer's disease.[72][73] Again, this has not yet been tested in humans for any disease.

Resveratrol has direct inhibitory action on cardiac fibroblasts, and may inhibit the progression of cardiac fibrosis.[74]

Resveratrol also significantly increases natural testosterone production from being both a selective estrogen receptor modulator [75][76] and an aromatase inhibitor.[77]

Resveratrol increased intracellular glutathione levels via Nrf2-dependent upregulation of gamma-glutamylcysteine ligase in lung epithelial cells, which protected them against cigarette smoke extract-induced oxidative stress.[78]

Another potentially important mechanism common to both resveratrol supplementation and caloric restriction is the modulation of autophagy.[79] SIRT1 is a hypothesized target of both resveratrol and caloric restriction, and has been shown to facilitate autophagy through the inhibition of mTOR, which itself negatively regulates autophagy.[80]

In 2012, it was shown that resveratrol is capable of competitively inhibiting various phosphodiesterases, which results in an increase in cytosolic concentration of cAMP, which acts as a second messenger for the activation of the pathway Epac1/CaMKKβ/AMPK/SIRT1/PGC-1α. This rise of cAMP concentration allows an increase in oxidation of fatty acids, mitochondrial biogenesis, mitochondrial respiration, and gluconeogenesis.[81][82]

Chemical and physical properties[edit]

Resveratrol (3,5,4'-trihydroxystilbene) is a stilbenoid, a derivate of stilbene.

It exists as two geometric isomers: cis- (Z) and trans- (E), with the trans-isomer shown in the top image. The trans- and cis-resveratrol can be either free or bound to glucose.[83]

The trans- form can undergo isomerisation to the cis- form when exposed to ultraviolet irradiation,[84] a process called photoisomerization:[85]

Resveratrol photoisomerization

Recently, it is noted that ultraviolet irradiation to cis-resveratrol induces further photochemical reaction, produces a fluorescent molecule named "Resveratrone".[86]

Trans-resveratrol in the powder form was found to be stable under "accelerated stability" conditions of 75% humidity and 40 °C in the presence of air.[87] The trans isomer is also stabilized by the presence of transport proteins.[88] Resveratrol content also was stable in the skins of grapes and pomace taken after fermentation and stored for a long period.[89] lH- and 13C-NMR data for the four most common forms of resveratrols are reported in literature.[83]

Metabolism[edit]

Resveratrol gets extensively metabolized in the body. Liver and gut are the major site of its metabolism. Lungs are also involved in its metabolism, with inter-species difference in its pulmonary metabolism.[90]

Biosynthesis[edit]

Resveratrol is produced in plants with the help of the enzyme, resveratrol synthase.[91]

Biotransformation[edit]

The grapevine fungal pathogen Botrytis cinerea is able to oxidise resveratrol into metabolites showing attenuated antifungal activities. Those include the resveratrol dimers restrytisol A, B, and C, resveratrol trans-dehydrodimer, leachinol F, and pallidol.[92] The soil bacterium Bacillus cereus can be used to transform resveratrol into piceid (resveratrol 3-O-beta-D-glucoside).[93]

Occurrences[edit]

In plants[edit]

Resveratrol was originally isolated by Takaoka from the roots of hellebore in 1940, and later, in 1963, from the roots of Japanese knotweed. It attracted wider attention only in 1992, however, when its presence in wine was suggested as the explanation for cardioprotective effects of wine.[17]

In grapes, trans-resveratrol is a phytoalexin produced against the growth of fungal pathogens such as Botrytis cinerea.[94] Its presence in Vitis vinifera grapes can also be constitutive, with accumulation in ripe berries of different levels of bound and free resveratrols, according to the genotype.[95] In grapes, resveratrol is found primarily in the skin,[96] and, in muscadine grapes, also in the seeds.[97] The amount found in grape skins also varies with the grape cultivar, its geographic origin, and exposure to fungal infection. The amount of fermentation time a wine spends in contact with grape skins is an important determinant of its resveratrol content.[83][96]

It is also found in Pinus strobus, the eastern white pine.

In foods[edit]

The levels of resveratrol found in food varies greatly. Red wine contains between 0.2 and 5.8 mg/l,[98] depending on the grape variety, while white wine has much less, because red wine is fermented with the skins, allowing the wine to extract the resveratrol, whereas white wine is fermented after the skin has been removed.[96][99] The composition of wine is different from that of grapes since the extraction of resveratrols from grapes depends on the duration of the skin contact, and the resveratrol 3-glucosides are in part hydrolised, yielding both trans- and cis-resveratrol.[83] A number of reports have indicated muscadine grapes may contain high concentrations of resveratrol, and that wines produced from these grapes, both red and white, may contain more than 40 mg/l,[97][100] however, subsequent studies have found little or no resveratrol in different varieties of muscadine grapes.[101][102]

One of the most promising sources is peanuts, especially sprouted peanuts where the content rivals that in grapes. Before sprouting, it was in the range of 2.3 to 4.5 μg/g, and after sprouting, in the range of 11.7 to 25.7 μg/g depending upon peanut cultivar.[103]

The fruit of the mulberry (esp. the skin)[104] is a source, and is sold as a nutritional supplement.

Cocoa powder, baking chocolate, and dark chocolate also have low levels of resveratrol in normal consumption quantities (0.35 to 1.85 mg/kg).[105]

Content in wines and grape juice[edit]

Beverage Total resveratrol (mg/l)[96][97] Total resveratrol (mg/150ml)[96][97]
Red wine (global) 1.98 – 7.13 0.30 – 1.07
Red wine (Spanish) 1.92 – 12.59 0.29 – 1.89
Red grape juice (Spanish) 1.14 – 8.69 0.17 – 1.30
Rose wine (Spanish) 0.43 – 3.52 0.06 – 0.53
Pinot noir 0.40 – 2.0 0.06 – 0.30
White wine (Spanish) 0.05 – 1.80 0.01 – 0.27

The trans-resveratrol concentration in 40 Tuscan wines ranged from 0.3 to 2.1 mg/l in the 32 red wines tested and had a maximum of 0.1 mg/l in the 8 white wines in the test. Both the cis- and trans-isomers of resveratrol were detected in all tested samples. cis-resveratrol levels were comparable to those of the trans-isomer. They ranged from 0.5 mg/l to 1.9 mg/l in red wines and had a maximum of 0.2 mg/l in white wines.[106]

In a review of published resveratrol concentrations, the average in red wines is 1.9 ± 1.7 mg trans-resveratrol/L (8.2 ± 7.5 μM), ranging from nondetectable levels to 14.3 mg/l (62.7 μM) trans-resveratrol. Levels of cis-resveratrol follow the same trend as trans-resveratrol.[107]

Reports suggest some aspect of the wine making process converts piceid to resveratrol in wine, as wine seems to have twice the average resveratrol concentration of the equivalent commercial juices.[97]

In general, wines made from grapes of the Pinot Noir and St. Laurent varieties showed the highest level of trans-resveratrol, though no wine or region can yet be said to produce wines with significantly higher concentrations than any other wine or region.[107]

Content in selected foods[edit]

Food Serving Total resveratrol (mg)[105][108]
Peanuts (raw) 1 c (146 g) 0.01 – 0.26
Peanuts (boiled) 1 c (180 g) 0.32 – 1.28
Peanut butter 1 c (258 g) 0.04 – 0.13
Red grapes 1 c (160 g) 0.24 – 1.25
Cocoa powder 1 c (200 g) 0.28 – 0.46

Ounce for ounce, peanuts have about half as much resveratrol as red wine. The average amount in peanuts in the marketplace is 79.4 µg/ounce.

In comparison, some red wines contain approximately 160 µg/fluid ounce.[109] Resveratrol was detected in grape, cranberry, and wine samples. Concentrations ranged from 1.56 to 1042 nmol/g in Concord grape products, and from 8.63 to 24.84 µmol/L in Italian red wine. The concentrations of resveratrol were similar in cranberry and grape juice at 1.07 and 1.56 nmol/g, respectively.[110]

Blueberries have about twice as much resveratrol as bilberries, but there is great regional variation. These fruits have less than 10% of the resveratrol of grapes. Cooking or heat processing of these berries will contribute to the degradation of resveratrol, reducing it by up to half.[111]

Supplementation[edit]

As a result of extensive news coverage,[112][113] sales of supplements greatly increased in 2006.[114] This was despite the existence of studies cautioning that benefits to humans are unproven.[114][115][116]

Supplements vary in purity and can contain anywhere from 50 percent to 99 percent resveratrol. Many brands consist of an unpurified extract of Japanese knotweed (Polygonum cuspidatum), an introduced species in many countries. These contain about 50 percent resveratrol by weight, as well as emodin, which, while considered safe in moderate quantities, can have a laxative effect in high amounts.[117] Resveratrol can be produced from its glucoside piceid from Japanese knotweed fermented by Aspergillus oryzae.[20]

Harvard University scientist and professor David Sinclair is often quoted in online ads for resveratrol supplements, many of which imply endorsement of the advertized product; however, Sinclair, who has studied resveratrol extensively, has gone on record in Bloomberg Businessweek to say he never uttered many of the statements attributed to him on these sites.[118]

Research[edit]

Cancer[edit]

As of 2007, no results of human clinical trials for cancer had been reported.[7] The strongest evidence of anticancer action of resveratrol exists for tumors it can contact directly, such as skin and gastrointestinal tract tumors. For other cancers, the evidence is uncertain, even if massive doses of resveratrol are used.[7] Resveratrol treatment appeared to prevent the development of mammary tumors in animal models; however, it had no effect on the growth of existing tumors. Paradoxically, treatment of prepubertal mice with high doses of resveratrol enhanced formation of tumors. Injected in high doses into mice, resveratrol slowed the growth of neuroblastomas.[7]

Cardioprotective effects[edit]

Moderate drinking of red wine has long been known to reduce the risk of heart disease.[119] This is best known as "the French paradox".[120][121]

Studies suggest resveratrol in red wine may play an important role in this phenomenon.[122] It appears to stimulate endothelial nitric oxide synthase (eNOS) activity;[123] and inhibition of platelet aggregation.[124]

The cardioprotective effects of resveratrol also are theorized to be a form of preconditioning—the best method of cardioprotection, rather than direct therapy.[125] Study into the cardioprotective effects of resveratrol is based on the research of Dipak K. Das. However, he has been found guilty of scientific fraud, and many of his publications related to resveratrol have been retracted.[126][127]

Antidiabetic effects[edit]

Other diabetic animal model studies by different researchers have also demonstrated the antidiabetic effects of resveratrol.[44][128]

Skin protection[edit]

The oxidative stress induced by ultraviolet radiation is one of the main causes for premature skin ageing. The photoprotective effects of several polyphenols known for their antioxidant properties, including resveratrol, have been investigated in silico and in topical application conditions.[129][130]

Neuroprotective effects[edit]

The neuroprotective effects have been confirmed in several animal model studies.[131]

Sirtuin activation[edit]

Some of the benefits demonstrated in previous studies were overstated,[132][133] however, this study was challenged immediately,[134] and a few experiments were suggested to be of inferior quality.[135]

Psychological[edit]

In a number of animal models resveratrol has had a antidepressant-like effect.[136] Whether or not there's any effect in humans is unclear.[136]

Related compounds[edit]

See also[edit]

References[edit]

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