Resveratrol
342649
226147072
2008-07-17T01:04:27Z
Paul gene
3683516
/* Cancer prevention */ added the conclusion that resveratrol has poor bioavailability in humans
{{Chembox new
| Name = Resveratrol
| ImageFile = resveratrol.svg
| ImageSize = 250px
| ImageName = Chemical structure of ''trans''-resveratrol
| ImageFile1 = Resveratrol3d.png
| ImageSize1 = 180px
| ImageName1 = Chemical structure of ''trans''-resveratrol
| OtherNames = ''trans''-3,5,4'-Trihydroxystilbene;<br />3,4',5-Stilbenetriol;<br />''trans''-Resveratrol;<br />(''E'')-5-(''p''-Hydroxystyryl)resorcinol
| Section1 = {{Chembox Identifiers
| CASNo = 501-36-0
| SMILES = Oc2ccc(C=Cc1cc(O)cc(O)c1)cc2
| InChI=1/C14H12O3/c15-<br/>12-5-3-10(4-6-12)<br/>1-2-11-7-13(16)9-<br/>14(17)8-11/h1-9,15-<br/>17H/b2-1+
}}
| Section2 = {{Chembox Properties
| Formula = C<sub>14</sub>H<sub>12</sub>O<sub>3</sub>
| MolarMass = 228.25
| Appearance = white powder with<br /> slight yellow cast
| Solubility1 = 0.03 g/L
| Solvent1 = water
| Solubility2 = 16 g/L
| Solvent2 = Dimethyl sulfoxide{{!}}DMSO
| Solubility3 = 50 g/L
| Solvent3 = ethanol
}}
}}
[[Image:Resveratrol.pdb.gif|thumb|right|The ''cis''-isomer of resveratrol]]
'''Resveratrol''' is a [[phytoalexin]] produced naturally by several [[plant]]s when under attack by [[pathogen]]s such as [[bacteria]] or [[fungi]]. Resveratrol has also been produced by chemical synthesis<ref name="pmid16401555">{{cite journal
| author=Farina A, Ferranti C, Marra C
| title=An improved synthesis of resveratrol
| journal=Nat. Prod. Res.
| volume=20
| issue=3
| pages=247–52
| year=2006
| pmid=16401555
| doi=10.1080/14786410500059532
| issn=
}}</ref>, and is sold as a [[nutritional supplement]] derived primarily from [[Japanese knotweed]]. Resveratrol extends the life span of several short-living species of animals; however, this effect have not yet been demonstrated in mammals. In mouse and rat experiments, anti-cancer, [[anti-inflammatory]], blood-sugar-lowering and other beneficial cardiovascular effects of resveratrol have been reported. As of July 2008, most of these results are yet to be confirmed in humans. In the only positive human trial, extremely high doses (3–5g) of resveratrol in a special proprietary formulation have been necessary to significantly lower blood sugar. Resveratrol is found in the skin of red [[grape]]s and is a constituent of [[red wine]] but apparently not in sufficient amounts to explain the "[[French paradox]]" that the incidence of [[coronary heart disease]] is relatively low in southern [[France]] despite high dietary intake of [[saturated fat]]s.<ref name="pmid7994864">{{cite journal
| author=Renaud S, Ruf JC
| title=The French paradox: vegetables or wine
| journal=Circulation
| volume=90
| issue=6
| pages=3118–9
| year=1994
| pmid=7994864
| doi=
| issn=
}}</ref>
== Physiological effects ==
=== Life extension ===
The groups of Howitz and Sinclair reported in 2003 in the journal ''[[Nature (journal)|Nature]]'' that resveratrol significantly extends the lifespan of the [[yeast]] ''[[Saccharomyces cerevisiae]]''.<ref>Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. "Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan". ''Nature''. 2003 Sep 11;425(6954):191-6. Epub 2003 Aug 24. PMID 12939617 [http://www.fiestaterrace.com/dlamming/nature2003.pdf]</ref> Later studies conducted by Sinclair showed that resveratrol also prolongs the lifespan of the worm ''[[Caenorhabditis elegans]]'' and the fruit fly ''[[Drosophila melanogaster]]''.<ref>Wood JG, Rogina B, Lavu1 S, Howitz K, Helfand SL, Tatar M, Sinclair D. "Sirtuin activators mimic caloric restriction and delay ageing in metazoans". ''Nature''. 2004 Aug 5; 430(7000):686–689. Epub 2004 Jul 14. PMID 15254550 [http://sinclairfs.med.harvard.edu/pdfs/nature2004.pdf]</ref> In 2007 a different group of researchers was able to reproduce the Sinclair's results with C. elegans<ref>JAN GRUBER et al, "Evidence for a Trade-Off between Survival and Fitness Caused by Resveratrol Treatment of Caenorhabditis elegans" Ann. N.Y. Acad. Sci. 1100: 530–542 (2007).</ref> but a third group could not achieve consistent increases in lifespan of ''Drosophila'' or ''C. elegans''.<ref>{{cite journal
| author = Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L.
| title = Effects of resveratrol on lifespan in ''Drosophila melanogaster'' and ''Caenorhabditis elegans''
| journal = Mechanisms of ageing and development
| volume = 128
| issue = 10
| pages = 546–552
| date = 2007
| pmid = 17875315
| doi = 10.1016/j.mad.2007.07.007
}}</ref>
In 2006, Italian scientists obtained the first positive result of resveratrol supplementation in a vertebrate. Using a short-lived fish, ''Nothobranchius furzeri'', with a median life span of nine weeks, they found that a maximal dose of resveratrol increased the median lifespan by 56%. Compared with the control fish at nine weeks, that is by the end of the latter's life, the fish supplemented with resveratrol showed significantly higher general swimming activity and better learning to avoid an unpleasant stimulus. The authors noted a slight increase of mortality in young fish caused by resveratrol and hypothesized that it is its weak toxic action that stimulated the defense mechanisms and resulted in the life span extension.<ref>Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A "Resveratrol Prolongs Lifespan and Retards the Onset of Age-Related Markers in a Short-Lived Vertebrate." ''Current Biology'' 2006 Feb 7;16 (3):296–300 PMID 16461283</ref> Later the same year, Sinclair reported that resveratrol counteracted the detrimental effects of a high-fat diet in mice. The high fat diet was compounded by adding hydrogenated coconut oil to the standard diet; it provided 60% of energy from fat, and the mice on it consumed about 30% more calories then the mice on standard diet. Both the mice fed the standard diet and the high-fat diet plus 22 mg/kg resveratrol had a 30% lower risk of death than the mice on the high-fat diet. Gene expression analysis indicated the addition of resveratrol opposed the alteration of 144 out of 155 gene pathways changed by the high-fat diet. Insulin and glucose levels in mice on the high-fat+resveratrol diet were closer to the mice on standard diet than to the mice on the high-fat diet. However, addition of resveratrol to the high-fat diet did not change the levels of free fatty acids and cholesterol, which were much higher than in the mice on standard diet. <ref>Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA. "Resveratrol improves health and survival of mice on a high-calorie diet" ''Nature'' 2006 advanced publication</ref>
=== Cancer prevention ===
In 1997 Jang reported that topical resveratrol applications prevented the skin cancer development in mice treated with a [[carcinogen]].<ref name="pmid8985016">{{cite journal |author=Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM |title=Cancer chemopreventive activity of resveratrol, a natural product derived from grapes |journal=Science |volume=275 |issue=5297 |pages=218–20 |year=1997 |pmid=8985016|doi=10.1126/science.275.5297.218}}</ref> There have since been dozens of studies of the anti-cancer activity of resveratrol in animal models<ref name="pmid16732220">See review:{{cite journal |author=Baur JA, Sinclair DA |title=Therapeutic potential of resveratrol: the in vivo evidence |journal=Nat Rev Drug Discov |volume=5 |issue=6 |pages=493–506 |year=2006 |pmid=16732220 |doi=10.1038/nrd2060}}</ref> but no results of human clinical trials for cancer have been reported.<ref name="pmid17306316">See review:{{cite journal |author=Athar M, Back JH, Tang X, Kim KH, Kopelovich L, Bickers DR, Kim AL |title=Resveratrol: a review of preclinical studies for human cancer prevention |journal=Toxicol. Appl. Pharmacol. |volume=224 |issue=3 |pages=274–83 |year=2007 |pmid=17306316|doi=10.1016/j.taap.2006.12.025|url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2083123 }}</ref> [[In vitro]] resveratrol interacts with multiple molecular targets (see [[Resveratrol#mechanisms of action]]), and has positive effects on the cells of breast, skin, gastric, colon, esophageal, prostate, and pancreatic cancer, and leukemia.<ref name="pmid16732220"/> However, the study of pharmacokinetics of resveratrol in humans concluded that even high doses of resveratrol might be insufficient to achieve resveratrol concentrations required for the systemic prevention of cancer.<ref name="pmid17548692">{{cite journal |author=Boocock DJ, Faust GE, Patel KR, ''et al'' |title=Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent |journal=Cancer Epidemiol. Biomarkers Prev. |volume=16 |issue=6 |pages=1246–52 |year=2007 |month=June |pmid=17548692 |doi=10.1158/1055-9965.EPI-07-0022 |url=}}</ref> This is consistent with the results from the animal cancer models, which indicate that the [[in vivo]] effectiveness of resveratrol is limited by its poor bioavailability.<ref name="pmid16988123">{{cite journal |author=Niles RM, Cook CP, Meadows GG, Fu YM, McLaughlin JL, Rankin GO |title=Resveratrol is rapidly metabolized in athymic (nu/nu) mice and does not inhibit human melanoma xenograft tumor growth |journal=J. Nutr. |volume=136 |issue=10 |pages=2542–6 |year=2006 |month=October |pmid=16988123 |pmc=1612582 |doi= |url=http://jn.nutrition.org/cgi/pmidlookup?view=long&pmid=16988123}}</ref><ref name="pmid17306316"/> The strongest evidence of anti-cancer action of resveratrol exists for tumors it can come into direct contact with, such as skin and gastrointestinal tract tumors. For other cancers, the evidence is equivocal, even if massive doses of resveratrol are used.<ref name="pmid17306316"/>
Thus, topical application of resveratrol in mice, both before and after the UVB exposure, inhibited the skin damage and decreased skin cancer incidence. However, oral resveratrol was ineffective in treating mice inoculated with melanoma cells. Resveratrol given orally also had no effect on lung and pancreatic cancers, and leukemia.<ref name="pmid17306316"/><ref name="pmid12097696">{{cite journal |author=Gao X, Xu YX, Divine G, Janakiraman N, Chapman RA, Gautam SC |title=Disparate in vitro and in vivo antileukemic effects of resveratrol, a natural polyphenolic compound found in grapes |journal=J. Nutr. |volume=132 |issue=7 |pages=2076–81 |year=2002 |month=July |pmid=12097696 |doi= |url=http://jn.nutrition.org/cgi/pmidlookup?view=long&pmid=12097696}}</ref> Resveratrol (1 mg/kg orally) reduced the number and size of the esophageal tumors in rats treated with a carcinogen.<ref name="pmid12189197">{{cite journal |author=Li ZG, Hong T, Shimada Y, Komoto I, Kawabe A, Ding Y, Kaganoi J, Hashimoto Y, Imamura M |title=Suppression of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats by resveratrol |journal=Carcinogenesis |volume=23 |issue=9 |pages=1531–6 |year=2002 |pmid=12189197|doi=10.1093/carcin/23.9.1531}}</ref> In several studies, small doses (0.02-8 mg/kg) of resveratrol, given prophylactically, reduced or prevented the development of intestinal and colon tumors in rats given different carcinogens.<ref name="pmid17306316"/>
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 pre-pubertal mice with high doses of resveratrol enhanced formation of tumors. Injected in high doses into mice, resveratrol slowed the growth of neuroblastomas and metastatic Lewis lung carcinomas.<ref name="pmid17306316"/>
=== Athletic performance ===
Johan Auwerx (at the Institute of Genetics and Molecular and Cell Biology in Illkirch, France) and coauthors published an online article in the journal CELL in November 2006. Mice fed resveratrol for 15 weeks had better treadmill endurance than controls. The study supported Sinclair's hypothesis that the effects of resveratrol are indeed due to the activation of SIRT1.
Nicholas Wade's interview-article with Dr. Auwerx<ref name="Red Wine Ingredient Increases Endurance, Study Shows">{{cite journal|title=Red Wine Ingredient Increases Endurance, Study Shows|author=Wade, Nicholas|year=2006|date=November 16 2006|journal=New York Times}}</ref> states that the dose was 400 mg/kg of body weight (much higher than the 22 mg/kg of the Sinclair study). For an 80 kg (176 lb) person, the 400 mg/kg of body weight amount used in Dr. Auwerx's mouse study would come to 32,000 mg/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to roughly 4571 mg/day. Again, there is no published evidence anywhere in the scientific literature of any clinical trial for efficacy in humans. There is limited human safety data (see above). It is premature to take resveratrol and expect any particular results. Long-term safety has not been evaluated in humans.
In a study of 123 Finnish adults, those born with certain increased variations of the SIRT1 gene had faster metabolisms, helping them to burn energy more efficiently—indicating that the same pathway shown in the lab mice works in humans.<ref>{{cite journal
| author=Lagouge M, Argmann C, Gerhart-Hines Z, ''et al''
| title=Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha
| journal=Cell
| volume=127
| issue=6
| pages=1109–22
| year=2006
| pmid=17112576
| doi=10.1016/j.cell.2006.11.013
| issn=
}}</ref>
==Pharmacokinetics==
The most efficient way of administering resveratrol in humans appears to be [[buccal mucosa|buccal]] delivery, that is without swallowing, by direct absorption through the inside of the mouth. When 1 mg of resveratrol in 50 mL solution was retained in the mouth for 1 min before swallowing, 37 ng/ml of free resveratrol were measured in plasma 2 minutes later. This level of unchanged resveratrol in blood can only be achieved with 250 mg of resveratrol taken in a pill form.<ref name="pmid12126761">{{cite journal |author=Asensi M, Medina I, Ortega A, ''et al'' |title=Inhibition of cancer growth by resveratrol is related to its low bioavailability |journal=Free Radic. Biol. Med. |volume=33 |issue=3 |pages=387–98 |year=2002 |month=August |pmid=12126761 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0891584902009115}}</ref>
About 70% of the resveratrol dose given orally as a pill is absorbed; nevertheless, oral [[bioavailability]] of resveratrol is low because it is rapidly metabolized in intestines and liver into [[conjugate]]d forms: [[glucuronate]] and [[sulfonate]].<ref name="Walle">{{cite journal
| author=Walle T, Hsieh F, DeLegge MH, Oatis JE, Walle UK
| title=High absorption but very low bioavailability of oral resveratrol in humans
| journal=Drug Metab. Dispos.
| volume=32
| issue=12
| pages=1377–82
| year=2004
| pmid=15333514
| doi=10.1124/dmd.104.000885
| issn=
}}</ref> Only trace amounts (below 5 ng/mL) of unchanged resveratrol could be detected in the blood after 25 mg oral dose.<ref name="Walle"/> Even when a very large dose of resveratrol (2.5 and 5 g) was given as uncoated pill, the concentration of resveratrol in blood failed to reach the level necessary for the systemic cancer prevention.<ref name="Boocock"/> However, resveratrol given in a a proprietary formulation SRT-501 (3 or 5 g), developed by Sirtris Pharmaceuticals, reached 5-8 times higher blood levels. These levels did approach the concentration necessary to exert the effects shown in animal models and in vitro experiments.<ref name="PMID 18393104">{{cite journal
| author=Elliott PJ, Jirousek, M.
| title=Sirtuins: Novel targets for metabolic disease
| journal=Current Opinion in Investigational Drugs
| volume=9
| issue=4
| pages=1472–4472
| year=2008
| pmid=18393104
| doi=
| issn=
}}</ref>
In humans<ref name="Walle" /> <ref name="Boocock">{{cite journal
| author=David J. Boocock, et al
| title=Phase I Dose Escalation Pharmacokinetic Study in Healthy Volunteers of Resveratrol, a Potential Cancer Chemopreventive Agent
| journal=Cancer Epidemiology Biomarkers & Prevention
| volume=16
| issue=6
| pages=1246–1252
| year=2007
| pmid=17548692
| doi=10.1158/1055-9965.EPI-07-0022
| issn=
}}</ref> and rats,<ref name="pmid12065739">{{cite journal
| author=Marier JF, Vachon P, Gritsas A, Zhang J, Moreau JP, Ducharme MP
| title=Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model
| journal=J. Pharmacol. Exp. Ther.
| volume=302
| issue=1
| pages=369–73
| year=2002
| pmid=12065739
| doi=10.1124/jpet.102.033340
| issn=}}</ref> <ref>[http://www.ncbi.nlm.nih.gov/pubmed/16869992 Distribution of [3H]trans-resveratrol in rat tissu...[Br J Nutr. 2006] - PubMed Result<!-- Bot generated title -->]</ref> <ref>[http://www.ncbi.nlm.nih.gov/pubmed/15779067 Bioactivity and metabolism of trans-resveratrol or...[Mol Nutr Food Res. 2005] - PubMed Result<!-- Bot generated title -->]</ref> less than 5% of the oral dose is being observed as free resveratrol in blood plasma. The most abundant resveratrol metabolites in humans, rats, and mice are trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate.<ref>[http://www.ncbi.nlm.nih.gov/pubmed/12523673 Human, rat, and mouse metabolism of resveratrol. [Pharm Res. 2002] - PubMed Result<!-- Bot generated title -->]</ref> Walle suggests sulfate conjugates are the primary source of activity<ref name="Walle" />, Wang et al suggests the glucuronides,<ref>[http://www.ncbi.nlm.nih.gov/pubmed/15349955 Resveratrol glucuronides as the metabolites of res...[J Pharm Sci. 2004] - PubMed Result<!-- Bot generated title -->]</ref> 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 that "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."<ref name="pmid12554065"/>
The hypothesis that resveratrol from wine could have higher bioavailability than resveratrol from a pill,<ref name="pmid16732220">See review:{{cite journal |author=Baur JA, Sinclair DA |title=Therapeutic potential of resveratrol: the in vivo evidence |journal=Nat Rev Drug Discov |volume=5 |issue=6 |pages=493–506 |year=2006 |pmid=16732220 |doi=10.1038/nrd2060}}</ref><ref name="pmid15779070">{{cite journal |author=Wenzel E, Somoza V |title=Metabolism and bioavailability of trans-resveratrol |journal=Mol Nutr Food Res |volume=49 |issue=5 |pages=472–81 |year=2005 |month=May |pmid=15779070 |doi=10.1002/mnfr.200500010 |url=}}</ref> has been disproved by experimental data.<ref name="pmid15830336">{{cite journal |author=Vitaglione P, Sforza S, Galaverna G, ''et al'' |title=Bioavailability of trans-resveratrol from red wine in humans |journal=Mol Nutr Food Res |volume=49 |issue=5 |pages=495–504 |year=2005 |month=May |pmid=15830336 |doi=10.1002/mnfr.200500002 |url=}}</ref><ref name="pmid12554065">{{cite journal |author=Goldberg DM, Yan J, Soleas GJ |title=Absorption of three wine-related polyphenols in three different matrices by healthy subjects |journal=Clin. Biochem. |volume=36 |issue=1 |pages=79–87 |year=2003 |month=February |pmid=12554065 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0009912002003971}}</ref> 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 mg/mL resveratrol; total dose about 0.5 mg) was taken with meal: trace amounts (1–6 ng/mL) were found in four out of ten subjects.<ref name="pmid15830336"/> In another study, the pharmacokinetics of resveratrol (25 mg) did not change whether it was taken with vegetable juice, white vine 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 4 hours.<ref name="pmid12554065"/> The authors of both studies concluded that the trace amounts of resveratrol reached in the blood are insufficient to explain the French paradox. They concluded that the beneficial effects of wine could be explained by the effects of alcohol<ref name="pmid12554065"/> or the whole complex of substances it contains.<ref name="pmid15830336"/>
=== Adverse effects and unknowns ===
While the health benefits of resveratrol seem promising, one study has theorized that it may stimulate the growth of human breast cancer cells, possibly because of resveratrol's chemical structure, which is similar to a [[phytoestrogen]].<ref>Gehm BD, McAndrews JM, Chien P, Jameson JL. Resveratrol, a [http://en.wiktionary.org/wiki/polyphenolic polyphenolic] compound found in grapes and wine, is an agonist for the estrogen receptor. ''Proc. National. Academy of Sciences'' 1997 Dec 9;94(25):14138-43. PMID 9391166</ref><ref>Bowers JL, Tyulmenkov VV, Jernigan SC, Klinge CM. Resveratrol acts as a mixed agonist/antagonist for estrogen receptors alpha and beta. ''Endocrinology'' 2000 Oct;141(10):3657-67. PMID 11014220</ref> However, other studies have found that resveratrol actually fights breast cancer.<ref>Levi, Pasche, Lucchini, Ghidoni, Ferraroni, La Vecchia. Resveratrol and breast cancer risk. ''European Journal of Cancer Prevention'' 14(2):139–142, April 2005.[http://www.eurjcancerprev.com/pt/re/ejcp/abstract.00008469-200504000-00009.htm;jsessionid=G3GJqVvCY4cg6ply0srM3lxnwdNMhpqkBZGnmS1fksNydvR2h6mX!-170133123!181195628!8091!-1]</ref><ref>Garvina, Öllingerb, Dabrosin.Resveratrol induces [http://en.wiktionary.org/wiki/apoptosis apoptosis] and inhibits [[wiktionary:angiogenesis|angiogenesis]] in human breast cancer xenografts in vivo. ''Cancer Letters'' Volume 231, Issue 1, 8 January 2006, Pages 113-122.[http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T54-4FPYWW1-8&_user=10&_coverDate=01%2F08%2F2006&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=4b11cd83d6581a92cd26debad3e21408]</ref>
Citing the evidence that resveratrol is [[wiktionary:estrogenic|estrogenic]], 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 18, as no studies have shown how it affects their natural development.<ref name="revgenetics">More resveratrol information, ''What is Resveratrol?''.[http://www.revgenetics.com/resveratrol.html]</ref> A small study found that a single dose of up to 5 g of ''trans''-resveratrol caused no serious adverse effects in healthy volunteers.<ref name="pmid17548692">{{cite journal |author=Boocock DJ, Faust GE, Patel KR, Schinas AM, Brown VA, Ducharme MP, Booth TD, Crowell JA, Perloff M, Gescher AJ, Steward WP, Brenner DE |title=Phase I dose escalation [http://en.wiktionary.org/wiki/pharmacokinetic pharmacokinetic] study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent |journal=Cancer Epidemiol. Biomarkers Prev. |volume=16 |issue=6 |pages=1246–52 |year=2007 |pmid=17548692 |doi=10.1158/1055-9965.EPI-07-0022}}</ref>
==Mechanisms of action==
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]]. A new report indicates that resveratrol activates [[SIRT1]] and PGC-1α and improve functioning of the [[mitochondria]].<ref>Cell, Vol 127, 1109–1122, 15 December 2006; Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1α</ref> Other research calls into question the theory connecting resveratrol, [[SIRT1]], and [[calorie restriction]].<ref>Kaeberlein M ''et al.'' Sir2-independent life span extension by calorie restriction in yeast. ''PLoS Biol.'' 2004 Sep;2(9):E296. PMID 15328540</ref><ref>Kaeberlein ''et al.'' Substrate-specific activation of sirtuins by resveratrol. ''J Biol Chem.'' 2005 Apr 29; 280(17):17038-45. PMID 15684413.</ref>
An article in press as of January 2008 discusses resveratrol action in cells. It reports a 14-fold increase in the action of MnSOD.<ref>Ellen L. Robb, Melissa M. Page, Brent E. Wiens, Jeffrey A. Stuart, Molecular mechanisms of oxidative stress resistance induced by resveratrol: Specific and progressive induction of MnSOD, Biocehm and Biophys Res Comm, 2008</ref> MnSOD reduces superoxide to H2O2, but H2O2 is not increased due to other cellular activity. Superoxide O<sub>2</sub><sup>-</sup> is a byproduct of respiration in complex 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 is it essential for the cell to keep superoxide anions in check."<ref>Zsolt Radák, Free Radicals in Exercise and Aging, 2000, p39</ref> MnSOD reduces superoxide and thereby confers resistance to mitochondrial dysfunction, permeability transition, and apoptotic death in various diseases.<ref>L.A. MacMillan-Crow, D.L. Cruthirds, Manganese superoxide dismutase in disease, Free Rad. Res. 34 (2001) 325–336.</ref> It has been implicated in lifespan extension, inhibits cancer (e.g. pancreatic cancer <ref>Mamta Kanwar, Pooi-See Chan, Timothy S. Kern, and Renu A. Kowluru, The Role of Manganese Superoxide Dismutase in the Growth of Pancreatic Adenocarcinoma, Cancer Research 63, 1297-1303, March 15, 2003</ref><ref>{{cite news | first= | last= | coauthors= Weimin Sun, Wei Wang, Jung Kim, Peter Keng, Shanmin Yang, Hengshan Zheng, Chaomei Liu, Lurong Zhang, Jacqueline P. Williams, Steven Swarts and Amy K. Huser. | title=Mounting Evidence Shows Red Wine Antioxidant Kills Cancer | date=2008-03-26 | publisher=Department of Radiation Oncology, University of Rochester Medical Center. | url =http://www.eurekalert.org/pub_releases/2008-03/uorm-mes032508.php# | work = | pages = | accessdate = 2008-03-26 | language = }}</ref>), and provides resistance to reperfusion injury and irradiation damage <ref>J. Sun, D. Folk, T.J. Bradley, J. Tower, Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster, Genetics 161 (2002) 661–672</ref> <ref>D. Hu, P. Cao, E. Thiels, C.T. Chu, G.Y. Wu, T.D. Oury, E. Klann, Hippocampal long-term potentiation, memory, and longevity in mice that overexpress mitochondrial superoxide dismutase, Neurobiol. Learn. Mem. 87 (2007) 372–384.</ref> <ref>G.H.W. Wong, Protective roles of cytokines against radiation: Induction of mitochondrial MnSOD, Biochim. Biophys. Acta 1271 (1995) 205–209.</ref>. These effects have also been observed with resveratrol. Ellen 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 <ref>M. Stefani, A. Markus, R.C.Y. Lin, M. Pinese, I.W. Dawes, B.J. Morris, The effect of resveratrol on a cell model of human aging, Annals N.Y. Acad. Sci. 1114 (2007) 407–418.</ref> which stimulates FOXO3a transcriptional activity <ref>A. Brunet, L.B. Sweeney, J.F. Sturgill, K.F. Chua, P.L. Greer, Y. Lin, H. Tran, S.E. Ross, R. Mostoslavsky, H.Y. Cohen, L.S. Hu, H.-L. Cheng, M.P. Jedrychowski, S.P. Gygi, D.A. Sinclair, F.W. Alt, M.E. Greenberg, Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase, Science 303 (2004) 2011–2015.</ref> 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 <ref>G.J.P.L. Kops, T.B. Dansen, P.E. Polderman, I. Saarloos, K.W.A. Wirtz, P.J. Coffer, T.-T. Huang, J.L. Bos, R.H. Medema, B.M.T. Burgering, Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress, Nature 419 (2002) 316–321.</ref>.
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-kB]],<ref>{{cite journal
| author=Leiro J, Arranz JA, Fraiz N, Sanmartín ML, Quezada E, Orallo F
| title=Effect of cis-resveratrol on genes involved in nuclear factor kappa B signaling
| journal=Int. Immunopharmacol.
| volume=5
| issue=2
| pages=393–406
| year=2005
| pmid=15652768
| doi=10.1016/j.intimp.2004.10.006
| issn=
}}</ref> inhibition of the [[cytochrome P450]] isoenzyme [[CYP1A1]]<ref>{{cite journal
| author=Chun YJ, Kim MY, Guengerich FP
| title=Resveratrol is a selective human cytochrome P450 1A1 inhibitor
| journal=Biochem. Biophys. Res. Commun.
| volume=262
| issue=1
| pages=20–4
| year=1999
| pmid=10448061
| doi=10.1006/bbrc.1999.1152
| issn=
}}</ref> (although this may not be relevant to the CYP1A1-mediated bioactivation of the procarcinogen [[benzo(a)pyrene]]<ref>{{cite journal
| author=Schwarz D, Roots I
| title=In vitro assessment of inhibition by natural polyphenols of metabolic activation of procarcinogens by human CYP1A1
| journal=Biochem. Biophys. Res. Commun.
| volume=303
| issue=3
| pages=902–7
| year=2003
| pmid=12670496
| doi=10.1016/S0006-291X(03)00435-2
| issn=}}</ref>), alterations in [[androgenic]]<ref name="Benitez_2006">{{cite journal|title=Mechanisms involved in resveratrol-induced apoptosis and cell cycle arrest in prostate cancer-derived cell lines|author=Benitez DA, Pozo-Guisado E, Alvarez-Barrientos A, Fernandez-Salguero PM, Castellon EA|year=2006|date=October 18 2006|journal=Journal of Andrology|pmid=17050787|volume=28|pages=282|doi=10.2164/jandrol.106.000968}}</ref> 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.<ref name="Benitez_2006" /><ref name="Faber 2006">{{cite journal|title=Resveratrol induces apoptosis in transformed follicular lymphoma OCI-LY8 cells: Evidence for a novel mechanism involving inhibition of BCL6 signaling|date=Dec 2006|author=Faber AC, Chiles TC|journal=International Journal of Oncology|pmid=17088997|volume=29|issue=6|pages=1561–6}}</ref><ref name="Riles_2006">{{cite journal|title=Resveratrol engages selective apoptotic signals in gastric adenocarcinoma cells|author=Riles WL, Erickson J, Nayyar S, Atten MJ, Attar BM, Holian O|date=21 Sep 2006|pmid=17007014|journal=World Journal of Gastroenterology|volume=12|issue=35}}</ref><ref name="Sareen 2006">{{cite journal|title=Mitochondria as the primary target of resveratrol-induced apoptosis in human retinoblastoma cells|date=September 2006|pmid=16936077|author=Sareen D, van Ginkel PR, Takach JC, Mohiuddin A, Darjatmoko SR, Albert DM, Polans AS|journal=Investigative Ophthamology & Visual Science|volume=47|issue=9}}</ref><ref name="Tang 2006">{{cite journal|title=Resveratrol-induced cyclooxygenase-2 facilitates p53-dependent apoptosis in human breast cancer cells|date=Aug 2006|pmid=16928824|author=Tang HY, Shih A, Cao HJ, Davis FB, Davis PJ, Lin HY|volume=5|issue=8}}</ref><ref name="aziz 2006">{{cite journal|title=Resveratrol-caused apoptosis of human prostate carcinoma LNCaP cells is mediated via modulation of phosphatidylinositol 3'-kinase/Akt pathway and Bcl-2 family proteins|date=May 2006|pmid=16731767|author=Aziz MH, Nihal M, Fu VX, Jarrard DF, Ahmad N|journal=Molecular Cancer Therapeutics|volume=5|issue=5|pages=1335|doi=10.1158/1535-7163.MCT-05-0526}}</ref> Resveratrol has been shown to induce Fas/Fas [[ligand]] mediated [[apoptosis]], [[p53]] and [[cyclin]]s A, B1 and [[cyclin-dependent kinase]]s cdk 1 and 2. Resveratrol also possesses [[antioxidant]] and anti-[[angiogenic]] properties.<ref name="pmid15621628">{{cite journal
| author=Cao Y, Fu ZD, Wang F, Liu HY, Han R
| title=Anti-angiogenic activity of resveratrol, a natural compound from medicinal plants
| journal=Journal of Asian natural products research
| volume=7
| issue=3
| pages=205–13
| year=2005
| pmid=15621628
| doi=10.1080/10286020410001690190
| issn=
}}</ref><ref name="pmid10963727">{{cite journal
| author=Hung LM, Chen JK, Huang SS, Lee RS, Su MJ
| title=Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes
| journal=Cardiovasc. Res.
| volume=47
| issue=3
| pages=549–55
| year=2000
| pmid=10963727
| doi=10.1016/S0008-6363(00)00102-4
| issn=}}</ref>
Resveratrol was reported effective against [[neuron]]al cell dysfunction and cell death, and in theory could help against diseases such as [[Huntington's disease]] and [[Alzheimer's disease]].<ref>Parker JA, Arango M, Abderrahmane S, Lambert E, Tourette C, Catoire H, Néri C. Resveratrol rescues mutant polyglutamine cytotoxicity in C. elegans and mammalian neurons. Nature Genetics 2005 ; 4 : 349-50. PMID 15793589</ref><ref>Philippe Marambaud et al., Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides. ''Journal of Biological Chemistry'' 2005 ; 280(45):37377-82 PMID 16162502</ref> Again, this has not yet been tested in humans for any disease.
Research at the [[Northeastern Ohio Universities College of Medicine]] and [[Ohio State University]] indicates that resveratrol has direct inhibitory action on cardiac fibroblasts and may inhibit the progression of [[heart|cardiac]] [[fibrosis]].<ref>Olson ER, Naugle JE, Zhang X, Bomser JA, Meszaros JG. Inhibition of cardiac fibroblast proliferation and myofibroblast differentiation by resveratrol. ''Am J Physiol Heart Circ Physiol'' 2005 Mar;288(3):H1131-8. PMID 15498824</ref>
According to [[Patrick Arnold]] it also [http://anabolicminds.com/forum/809122-post19.html significantly] increases natural testosterone production from being both a [[selective estrogen receptor modulator]]<ref>{{cite journal|author=Juan ME, González-Pons E, Munuera T, Ballester J, Rodríguez-Gil JE, Planas JM|title=trans-Resveratrol, a natural antioxidant from grapes, increases sperm output in healthy rats|journal=J Nutr.|volume=135|issue=4|pages=757–60|year=2005|pmid=15795430|doi=|issn=}}</ref><ref>{{cite journal|author=Bhat KP, Lantvit D, Christov K, Mehta RG, Moon RC, Pezzuto JM|title=Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models|journal= Cancer Res.|volume=61|issue=20|pages=7456–63|year=2001|pmid=11606380|doi=|issn=}}</ref> and an [[aromatase inhibitor]].<ref>{{cite journal|author=Wang Y, Lee KW, Chan FL, Chen S, Leung LK|title=The red wine polyphenol resveratrol displays bilevel inhibition on aromatase in breast cancer cells|journal= Toxicol Sci.|volume=92|issue=1|pages=71–7|year=2006|pmid=16611627|doi=10.1093/toxsci/kfj190|issn=}}</ref><ref>{{cite journal|author=Leder BZ, Rohrer JL, Rubin SD, Gallo J, Longcope C|title=Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels|journal= J Clin Endocrinol Metab|volume=89|issue=3|pages=1174–80|year=2004|pmid=15001605|doi=10.1210/jc.2003-031467|issn=}}</ref>
In December, 2007, work from Irfan Rahman's laboratory at the University of Rochester demonstrated that [http://www.ncbi.nlm.nih.gov/pubmed/18162601?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum 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. <ref>{{cite journal|author=Kode A, Rajendrasozhan S, Caito S, Yang SR, Megson IL, Rahman I|title=Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells|journal= Am J Physiol Lung Cell Mol Physiol.|volume=|issue=|pages=|year=2007|pmid=18162601|doi=10.1152|issn=|doi_brokendate=2008-06-20}}</ref>
== Chemical and physical properties ==
Resveratrol (3,5,4'-trihydroxystilbene) is a [[polyphenol]]ic [[phytoalexin]]. It is a [[stilbenoid]], a derivate of [[stilbene]], and is produced in plants with the help of the enzyme stilbene synthase.
It exists as two [[cis-trans isomerism|geometric isomers]]: ''cis-'' (''Z'') and ''trans-'' (''E''), with the ''trans''-isomer shown in the top image. The ''trans-'' form can undergo isomerisation to the ''cis-'' form when exposed to [[ultraviolet]] irradiation.<ref>{{cite journal
| last =Lamuela-Raventos
| first =RM
| authorlink =
| coauthors =
| title = Direct HPLC Analysis of cis- and trans-Resveratrol and Piceid Isomers in Spanish Red Vitis vinifera Wines
| journal = J. Agric. Food Chem.
| volume =
| issue = 43
| pages = 281–283
| publisher = pubs.acs.org
| date = 1995
| url = http://pubs.acs.org/cgi-bin/abstract.cgi/jafcau/1995/43/i02/f-pdf/f_jf00050a003.pdf?sessid=6006l3
| doi =
| id =
| accessdate = }}</ref> ''Trans''-resveratrol in the powder form was found to be stable under "accelerated stability" conditions of 75% humidity and 40 degrees C in the presence of air.<ref name="pmid16579722">{{cite journal |author=Prokop J, Abrman P, Seligson AL, Sovak M |title=Resveratrol and its glycon piceid are stable polyphenols |journal=J Med Food |volume=9 |issue=1 |pages=11–4 |year=2006 |pmid=16579722 |doi=10.1089/jmf.2006.9.11}}</ref> Resveratrol content also stayed stable in the skins of grapes and [[pomace]] taken after fermentation and stored for a long period.<ref name="pmid10051967">{{cite journal |author=Bertelli AA, Gozzini A, Stradi R, Stella S, Bertelli A |title=Stability of resveratrol over time and in the various stages of grape transformation |journal=Drugs Exp Clin Res |volume=24 |issue=4 |pages=207–11 |year=1998 |pmid=10051967 |doi=}}</ref>
== Plants and foods ==
Resveratrol was originally isolated by Takaoka from the roots of [[white hellebore]] in 1940, and later, in 1963, from the roots of [[Japanese knotweed]]. However, it attracted wider attention only in 1992, when its presence in wine was suggested as the explanation for cardioprotective effects of wine.<ref name="pmid16732220">See review:{{cite journal |author=Baur JA, Sinclair DA |title=Therapeutic potential of resveratrol: the in vivo evidence |journal=Nat Rev Drug Discov |volume=5 |issue=6 |pages=493–506 |year=2006 |pmid=16732220 |doi=10.1038/nrd2060}}</ref>
In grapes, resveratrol is found primarily in the skin,<ref name="PNS">Roy, H., Lundy, S., [http://www.pbrc.edu/Division_of_Education/pdf/PNS_resveratrol.pdf Resveratrol], Pennington Nutrition Series, 2005 No. 7</ref> and -— in muscadine grapes —- also in the seeds.<ref name="LeBlanc">{{cite web|url=http://etd.lsu.edu/docs/available/etd-01202006-082858/ |title=Cultivar, Juice Extraction, Ultra Violet Irradiation and Storage Influence the Stilbene Content of Muscadine Grapes (Vitis Rotundifolia Michx.) |accessdate=2007-08-15 |last=LeBlanc |first=Mark Rene |date=2005-12-13 }}</ref> 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.<ref name="PNS">Roy, H., Lundy, S., [http://www.pbrc.edu/Division_of_Education/pdf/PNS_resveratrol.pdf Resveratrol], Pennington Nutrition Series, 2005 No. 7</ref>
The levels of resveratrol found in food varies greatly. Red wine contains between 0.2 and 5.8 mg/L,<ref name="Gu"> Gu X, Creasy L, Kester A, et al., Capillary electrophoretic determination of resveratrol in wines. J Agric Food Chem 47:3323–3277, 1999</ref> depending on the grape variety, while white wine has much less — the reason being that red wine is [[fermentation (wine)|fermented]] with the skins, allowing the wine to absorb the resveratrol, whereas [[white wine]] is fermented after the skin has been removed.<ref name="PNS">Roy, H., Lundy, S., [http://www.pbrc.edu/Division_of_Education/pdf/PNS_resveratrol.pdf Resveratrol], Pennington Nutrition Series, 2005 No. 7</ref> A number of reports have indicated that [[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.<ref name="Ector">Ector BJ, Magee JB, Hegwood CP, Coign MJ., [http://www.ajevonline.org/cgi/content/abstract/47/1/57 Resveratrol Concentration in Muscadine Berries, Juice, Pomace, Purees, Seeds, and Wines.]</ref><ref name="LeBlanc"/> However, subsequent studies have found no or little resveratrol in different varieties of muscadine grapes.<ref>Pastrana-Bonilla E, Akoh CC, Sellappan S, Krewer G. "Phenolic content and antioxidant capacity of muscadine grapes". J Agric Food Chem. 2003 Aug 27;51(18):5497-503. PMID 12926904. quote: "Contrary to previous results, ellagic acid and not resveratrol was the major phenolic in muscadine grapes. The HPLC solvent system used coupled with fluorescence detection allowed separation of ellagic acid from resveratrol and detection of resveratrol." "trans-resveratrol had the lowest concentrations of the detected phenolics, ranging from not detected in two varieties to 0.2 mg/ 100 g of FW (Tables 1 and 2). Our result for resveratrol differed from previous results [Ector et al., 1996] indicating high concentrations. These researchers apparently were not able to separate ellagic acid from resveratrol with UV detection alone."</ref><ref>Hudson TS, Hartle DK, Hursting SD, Nunez NP, Wang TT, Young HA, Arany P, Green JE. "Inhibition of Prostate Cancer Growth by Muscadine Grape Skin Extract and Resveratrol through Distinct Mechanisms". Cancer Res. 2007 Sep 1;67(17):8396-405. PMID 17804756. quote: "MSKE [muscadine grape skin extract] does not contain significant quantities of resveratrol and differs from MSEE. To determine whether MSKE contains significant levels of resveratrol and to compare the chemical content of MSKE (skin) with MSEE (seed), HPLC analyses were done. As depicted in Supplementary Fig. S1A and B, MSKE does not contain significant amounts of resveratrol (<1 ?g/g by limit of detection)."</ref>
=== Content in wines and grape juice ===
{| class="wikitable"
|-
! Beverage
! Total resveratrol (mg/L)<ref name="PNS" /><ref name="LeBlanc"/>
! Total resveratrol in a 5 ounce glass (mg)<ref name="PNS" /><ref name="LeBlanc"/>
|-
| [[Muscadine]] Wines
| 14.1 - 40
| 2.12 - 6
|-
| Red Wines (Global)
| 1.98 - 7.13
| 0.30 - 1.07
|-
| Red Wines (Spanish)
| 1.92 - 12.59
| 0.29 - 1.89
|-
| Red grape juice (Spanish)
| 1.14 - 8.69
| 0.17 - 1.30
|-
| Rose Wines (Spanish)
| 0.43 - 3.52
| 0.06 - 0.53
|-
| Pinot Noir
| 0.40 - 2.0
| 0.06 - 0.30
|-
| White Wines (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.<ref name="Ref24">{{cite journal
| last = Mozzon
| first = M.
| authorlink =
| coauthors =
| title = Resveratrol content in some Tuscan wines
| journal = Ital. j. food sci.
| volume = 8
| issue = 2
| pages = 145–152
| publisher = Chiriotti, Pinerolo, ITALIE
| date = 1996
| url = http://cat.inist.fr/?aModele=afficheN&cpsidt=3123149
| doi =
| id =
| accessdate = 2007-06-18 }}</ref>
In a review of published resveratrol concentrations, the average resveratrol concentration in red wines is 1.9 ± 1.7 mg trans-resveratrol/l (8.2 ± 7.5 μM), ranging from non-detectable levels to 14.3 mg/l (62.7 μM) trans-resveratrol. Levels of cis-resveratrol follow the same trend as trans-resveratrol.<ref name=Stervbo2007>{{cite journal
| author = Stervbo, U.
| coauthors = Vang, O.; Bonnesen, C.
| year = 2007
| title = A review of the content of the putative chemopreventive phytoalexin resveratrol in red wine
| journal = Food Chemistry
| volume = 101
| issue = 2
| pages = 449–457
| doi = 10.1016/j.foodchem.2006.01.047
}}</ref>
Reports suggest that 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.<ref name="LeBlanc"/>
"All of the muscadine table wines sampled had greater trans and cis resveratrol concentrations than any other wines sampled. The muscadine
table wines varied between 9.2 and 31.9 mg/L ''cis''-resveratrol and between 4.9 and 13.4 mg/L ''trans''-resveratrol."<ref name="LeBlanc"/>
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 resveratrol concentrations than any other wine or region.<ref name=Stervbo2007/>
=== Content in selected foods ===
{| class="wikitable"
|-
! Food
! Serving
! Total resveratrol (mg)<ref name="Ref5">{{cite web
| last = Higdon
| first = Jane
| authorlink =
| coauthors =
| title = Resveratrol
| work = Oregon State University
| publisher = The Linus Pauling Institute Micronutrient Information Center
| date = 2005
| url = http://lpi.oregonstate.edu/infocenter/phytochemicals/resveratrol/
| format =
| doi =
| accessdate = 2007-06-18 }}</ref>
|-
| 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
|}
Ounce for ounce, peanuts have about half the amount of resveratrol as that found in red wine. The average amount of resveratrol in one ounce of peanuts in the marketplace (about 15 whole) is 79.4 µg/ounce.
In comparison, some red wines contain approximately 160 µg/fluid ounce.<ref name="Ref6">{{cite web
| last =
| first =
| authorlink =
| coauthors =
| title = Resveratrol
| work =
| publisher = The Peanut Institute
| date = 1999
| url = http://www.peanut-institute.org/kidsFFT.html
| format =
| doi =
| accessdate = 2008-01-28 }}</ref> 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 micromol/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.<ref name="Ref7">{{cite journal
| author=Wang Y, Catana F, Yang Y, Roderick R, van Breemen RB
| title=An LC-MS method for analyzing total resveratrol in grape juice, cranberry juice, and in wine
| journal=J. Agric. Food Chem.
| volume=50
| issue=3
| pages=431–5
| year=2002
| pmid=11804508
| doi=
| issn=
}}</ref>
[[Blueberries]] have about twice as much resveratrol as [[bilberries]], but there is great regional variation. These fruits have less than ten percent 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.
<ref name="Lyons">{{cite journal
| author=Lyons MM, Yu C, Toma RB, ''et al''
| title=Resveratrol in raw and baked blueberries and bilberries
| journal=J. Agric. Food Chem.
| volume=51
| issue=20
| pages=5867–70
| year=2003
| pmid=13129286
| doi=10.1021/jf034150f
| issn=
}}</ref>
== Supplementation ==
Resveratrol [[nutritional supplements]], first sourced from ground dried grape skins and seeds (sometimes from residual byproducts of winemaking),{{fact|date=February 2008}} are now primarily derived from the cheaper, more concentrated [[Japanese knotweed]] which contains up to 187 mg/kg in the dried root.{{fact|date=February 2008}}
As a result of extensive news coverage,<ref>{{cite news | first=Andrew | last=Rimas | coauthors= | title=MOLECULAR BIOLOGIST DAVID SINCLAIR, MEETING THE MINDS | date=[[2006-12-11]] | publisher=boston.com | url =http://www.boston.com/news/globe/health_science/articles/2006/12/11/his_research_targets_the_aging_process/ | work =Boston Globe | pages = | accessdate = 2007-06-22 | language = }}</ref><ref>{{cite news | first=David | last=Stipp | coauthors= | title=Can red wine help you live forever? | date=[[2007-01-19]] | publisher=[[CNN]] | url=http://money.cnn.com/2007/01/18/magazines/fortune/Live_forever.fortune/index.htm?postversion=2007011912 | work =[[Fortune magazine]] | pages =3 | accessdate = 2007-08-15 | language = }}</ref> sales of supplements greatly increased in 2006,<ref>{{cite news | first= | last= | coauthors= | title= MM2 Group Announces Record Sales of Its Resveratrol Grape Powder | date=[[2006-11-29]] | publisher=Earthtimes.org | url =http://www.earthtimes.org/articles/show/news_press_release,27694.shtml | work =MM2 Group | pages = | accessdate = 2007-06-22 | language = }}</ref><ref name=wsj>{{cite web |url=http://www.post-gazette.com/pg/06334/742471-114.stm |title=Quest for youth drives craze for 'wine' pills |accessdate=2008-02-02 |author=Zachary M. Seward |authorlink= |coauthors= |date=2006-11-30 |format=htm |work= |publisher=The Wall Street Journal |pages= |language= |archiveurl= |archivedate= |quote=}}</ref> despite cautions that benefits to humans are unproven.<ref>{{cite news | first= | last= | coauthors= | title=Caution urged with resveratrol | date=[[2006-11-30]] | publisher=Upi.com | url =http://www.upi.com/NewsTrack/Science/2006/11/30/caution_urged_with_resveratrol/9504/ | work =United Press International | pages = | accessdate = 2007-06-21 | language = }}</ref><ref name=wsj>{{cite web |url=http://www.post-gazette.com/pg/06334/742471-114.stm |title=Quest for youth drives craze for 'wine' pills |accessdate=2008-02-02 |author=Zachary M. Seward |authorlink= |coauthors= |date=2006-11-30 |format=htm |work= |publisher=The Wall Street Journal |pages= |language= |archiveurl= |archivedate= |quote=}}</ref> There is also concern in the scientific community that many of the currently-available resveratrol supplements contain little or none of the active ingredient. <ref>{{cite news | first=JoNel | last=Aleccia | coauthors= | title=Longevity quest moves slowly from lab to life | date=[[2008-04-22]] | publisher=msnbc.com | url =http://www.msnbc.msn.com/id/23359040/ | work =MSNBC | pages = | accessdate = 2008-04-22 | language = }}</ref>
== Related compounds ==
Scientists are also studying three other synthetic compounds based on resveratrol which more effectively activate the same biological mechanism.<ref>[http://www.npr.org/templates/story/story.php?storyId=16727282 Scientists Develop Life-Extending Compounds]</ref>
The compound called SRT 1720 seems to be 1000 times more effective than resveratrol, although it only increases SIRT1 activation by 6 times. No data has been publicly produced by Sirtris regarding this difference in SIRT1 efficiency for the new compound.<ref>[http://www.physorg.com/news115657505.html Scientists Locate Revved Up Chemical That Mimics Red Wine]</ref>
A study by Professor Roger Corder has identified a particular group of [[polyphenols]], known as oligomeric [[Proanthocyanidin|procyanidins]], which they believe offer the greatest degree of protection to human blood-vessel cells. These are found in greatest concentration in European red wines from certain areas, which correlates with longevity in those regions, though a causal effect is still unclear. This new data may impact the supplement market.<ref name=Corder>R. Corder et al., [http://www.nature.com/nature/journal/v444/n7119/abs/444566a.html Oenology: Red wine procyanidins and vascular health.], Nature vol. 444, p. 566; 30 November 2006.</ref> Because they are present in red wine in more significant quantities, they could offer an alternate explanation of the [[French paradox]].
== References ==
{{reflist|2}}
== Further reading ==
* Gescher AJ, Steward WP. [http://cebp.aacrjournals.org/cgi/content/full/12/10/953 Relationship between mechanisms, bioavailibility, and preclinical chemopreventive efficacy of resveratrol: a conundrum.], Cancer Epidemiol Biomarkers Prev. 2003;12(10):953–957.
* Sinclair, David A., et al. "Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase." Science 305 (July 16 2004): 309–392.
* Wolf, George. "Calorie Restriction Increases Life Span: A Molecular Mechanism." Nutrition Reviews 64.2 (Feb. 2006): 89–92
== See also ==
* [[French paradox]]
* [[Japanese knotweed]]
* [[List of emerging technologies]]
* [[Mulberry]]
* [[Muscadine]]
* [[Piceatannol]], an active [[metabolite]] of resveratrol.
* [[Proanthocyanidin]]
== External links ==
* [http://ctd.mdibl.org/detail.go?type=chem&acc=C059514&bq=resveratrol CTD's Resveratrol page] from the [[Comparative Toxicogenomics Database]]
* [http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/res_0224.shtml PDRHealth Resveratrol]
* [http://science-library.blogspot.com/search/label/Resveratrol Resveratrol in Human Health and Disease: Books and Discussion]
* [http://www.sirtrispharma.com/ Sirtris Pharmaceuticals]
{{Phenylpropanoids}}
{{Stilbenoids}}
{{Dietary supplement}}
[[Category:Chemopreventive agents]]
[[Category:Phytochemicals]]
[[Category:Stilbenoids]]
[[Category:Phenols]]
[[Category:Antioxidants]]
[[cs:Resveratrol]]
[[de:Resveratrol]]
[[es:Resveratrol]]
[[eo:Resveratrolo]]
[[fr:Resvératrol]]
[[ko:레스베라트롤]]
[[it:Resveratrolo]]
[[nl:Resveratrol]]
[[pl:Resweratrol]]
[[pt:Resveratrol]]
[[fi:Resveratroli]]
[[sv:Resveratrol]]
[[uk:Резвератрол]]
[[zh:白藜芦醇]]