Summary

  • Resveratrol is a polyphenolic compound found in grapes, red wine, purple grape juice, peanuts, and some berries. (More information)
  • When taken orally, resveratrol appears to be well-absorbed by humans, but its bioavailability is relatively low because it is rapidly metabolized and eliminated. (More information)
  • Scientists became interested in exploring potential health benefits of resveratrol when its presence was reported in red wine, leading to speculation that resveratrol might help explain the “French Paradox.” (More information)
  • Moderate alcohol consumption has been consistently associated with 20%-30% reductions in coronary heart disease risk, but it is not yet clear whether red wine polyphenols, such as resveratrol, confer any additional risk reduction. (More information)
  • Although resveratrol can inhibit the growth of cancer cells in culture and in some animal models, it is not known whether high intakes of resveratrol can prevent cancer in humans. (More information)
  • Resveratrol administration has increased the lifespans of yeast, worms, fruit flies, fish, and mice fed a high-calorie diet, but it is not known whether resveratrol will have similar effects in humans. (More information)
  • At present, relatively little is known about the effects of resveratrol in humans.

Introduction

Resveratrol (3,4',5-trihydroxystilbene) belongs to a class of polyphenolic compounds called stilbenes (1). Some types of plants produce resveratrol and other stilbenes in response to stress, injury, fungal infection, or ultraviolet (UV) radiation (2). Resveratrol is a fat-soluble compound that occurs in a trans and a cis configuration (Figure 1). Both cis- and trans-resveratrol also occur as glucosides (bound to a glucose molecule). Resveratrol-3-O-β-glucoside is called piceid (3). Scientists became interested in exploring potential health benefits of resveratrol in 1992 when its presence was first reported in red wine (4), leading to speculation that resveratrol might help explain the “French Paradox” (see Cardiovascular disease). More recently, reports on the potential for resveratrol to inhibit the development of cancer (5) and extend lifespan (6) in cell culture and animal models have continued to generate scientific interest. 

Figure 1. Chemical Structures of Resveratrol and Resveratrol Glucoside (Piceid).

Metabolism and Bioavailability

Although trans-resveratrol appears to be well-absorbed by humans when taken orally, its bioavailability is relatively low due to its rapid metabolism and elimination (7, 8). Resveratrol metabolites are primarily detected upon oral exposure to trans-resveratrol. When six healthy men and women took an oral dose of 25 mg of trans-resveratrol, only traces of the unchanged resveratrol were detected in plasma (blood). Plasma concentrations of resveratrol and metabolites peaked around 60 minutes later at concentrations around 2 micromoles/liter (491 micrograms/liter) (7). A study in 12 healthy men administered an oral dose of 25 mg of trans-resveratrol per 70 kg of body weight reported that serum concentration of resveratrol and metabolites peaked at 30 minutes after administration. The concentration of total resveratrol (resveratrol and metabolites) ranged from 416 to 471 micrograms/liter, depending on whether resveratrol was administered in wine, vegetable juice, or grape juice (9). Results of another study suggested that the bioavailability of resveratrol from grape juice, which contains mostly glucosides of resveratrol (piceid), may be even lower than that of trans-resveratrol (10). A recent study reported that bioavailability of trans-resveratrol from red wine did not differ when the wine was consumed with a meal (low- or high-fat) versus on an empty stomach (11).

Information about the bioavailability of resveratrol in humans is important because much of the basic research on resveratrol has been conducted in cultured cells exposed to unmetabolized resveratrol at concentrations that are often 10-100 times greater than peak concentrations observed in human plasma after oral consumption (12). Although cells that line the digestive tract are exposed to unmetabolized resveratrol, research in humans suggests that other tissues are exposed primarily to resveratrol metabolites. Little is known about the biological activity of resveratrol metabolites, and it is not known whether some tissues are capable of converting resveratrol metabolites back to resveratrol (7).

Biological Activities

Direct antioxidant activity

In the test tube, resveratrol effectively scavenges (neutralizes) free radicals and other oxidants (13) and inhibits low density lipoprotein (LDL) oxidation (14, 15). However, there is little evidence that resveratrol is an important antioxidant in vivo (16). Upon oral consumption of resveratrol, circulating and intracellular levels of resveratrol in humans are likely to be much lower than that of other important antioxidants, such as vitamin C, uric acid, vitamin E, and glutathione. Moreover, the antioxidant activity of resveratrol metabolites, which comprise most of the circulating resveratrol, may be lower than that of resveratrol.

Estrogenic and anti-estrogenic activities

Endogenous estrogens are steroid hormones synthesized by humans and other mammals; these hormones bind to estrogen receptors within cells. The estrogen-receptor complex interacts with unique sequences in DNA (estrogen response elements; EREs) to modulate the expression of estrogen-responsive genes (17). A compound that binds to estrogen receptors and elicits similar responses to endogenous estrogens is considered an estrogen agonist, while a compound that binds estrogen receptors but prevents or inhibits the response elicited by endogenous estrogens is considered an estrogen antagonist. The chemical structure of resveratrol is very similar to that of the synthetic estrogen agonist, diethylstilbestrol (Figure 2), suggesting that resveratrol might also function as an estrogen agonist. However, in cell culture experiments resveratrol acts as an estrogen agonist under some conditions and an estrogen antagonist under other conditions (18, 19). In estrogen receptor-positive breast cancer cells, resveratrol acted as an estrogen agonist in the absence of the endogenous estrogen, 17β-estradiol, but acted as an estrogen antagonist in the presence of 17β-estradiol (20, 21). At present, it appears that resveratrol has the potential to act as an estrogen agonist or antagonist depending on such factors as cell type, estrogen receptor isoform (ER α or ER β), and the presence of endogenous estrogens (17).

Figure 2. Chemical Structures of trans-Resveratrol, Diethylstilbestrol, and 17-Beta-Estradiol

Biological activities related to cancer prevention

Effects on biotransformation enzymes

Some compounds are not carcinogenic until they have been metabolized in the body by cytochrome P450 enzymes (2). By inhibiting the expression and activity of certain cytochrome P450 enzymes (22, 23), resveratrol could help prevent cancer by decreasing exposure to these activated carcinogens. In contrast, increasing the activity of phase II biotransformation enzymes generally promotes the excretion of potentially toxic or carcinogenic chemicals. Resveratrol has been found to increase the expression and activity of the phase II enzyme NAD(P)H:quinone reductase in cultured cells (5, 24).

Preservation of normal cell cycle regulation

Following DNA damage, the cell cycle can be transiently arrested to allow for DNA repair or activation of pathways leading to cell death (apoptosis) if the damage is irreparable (25). Defective cell cycle regulation may result in the propagation of mutations that contribute to the development of cancer. Resveratrol has been found to induce cell cycle arrest when added to cancer cells grown in culture (26).

Inhibition of proliferation and induction of apoptosis

Unlike normal cells, cancer cells proliferate rapidly and are unable to respond to cell death signals that initiate apoptosis. Resveratrol has been found to inhibit proliferation and induce apoptosis in a number of cancer cell lines (reviewed in 2, 27).

Inhibition of tumor invasion and angiogenesis

Cancerous cells invade normal tissue aided by enzymes called matrix metalloproteinases. Resveratrol has been found to inhibit the activity of at least one type of matrix metalloproteinase (28). To fuel their rapid growth, invasive tumors must also develop new blood vessels by a process known as angiogenesis. Resveratrol has been found to inhibit angiogenesis in vitro (29-31).

Anti-inflammatory effects

Inflammation promotes cellular proliferation and angiogenesis and inhibits apoptosis (32). Resveratrol has been found to inhibit the activity of several inflammatory enzymes in vitro, including cyclooxygenase and lipoxygenase (33, 34). Resveratrol may also inhibit pro-inflammatory transcription factors, such as NFκB or AP-1 (35, 36).

Biological activities related to cardiovascular disease prevention

Inhibition of vascular cell adhesion molecule expression

Atherosclerosis is now recognized as an inflammatory disease, and several measures of inflammation are associated with increased risk of myocardial infarction (heart attack) (37). One of the earliest events in the development of atherosclerosis is the recruitment of inflammatory white blood cells from the blood to the arterial wall by vascular cell adhesion molecules (38). Resveratrol has been found to inhibit the expression of adhesion molecules in cultured endothelial cells (39, 40).

Inhibition of vascular smooth muscle cell proliferation

The proliferation of vascular smooth muscle cells plays an important role in the progression of atherosclerosis (41). Resveratrol has been found to inhibit the proliferation of vascular smooth muscle cells in culture (42, 43).

Stimulation of endolethelial nitric oxide synthase (eNOS) activity

eNOS is an enzyme that catalyzes the formation of nitric oxide (NO) by vascular endothelial cells. NO is needed to maintain arterial relaxation (vasodilation), and impaired NO-dependent vasodilation is associated with increased risk of cardiovascular disease (44). Resveratrol has been found to stimulate eNOS activity in cultured endothelial cells (45, 46).

Inhibition of platelet aggregation

Platelet aggregation is one of the first steps in the formation of a blood clot that can occlude a coronary or cerebral artery, resulting in myocardial infarction or stroke, respectively. Resveratrol has been found to inhibit platelet aggregation in vitro (47, 48).

Note: It is important to keep in mind that many of the biological activities discussed above were observed in cells cultured in the presence of resveratrol at higher concentrations than those likely to be achieved in humans consuming resveratrol orally (see Metabolism and Bioavailability).

Disease Prevention

Cardiovascular disease

Red wine polyphenols

Significant reductions in cardiovascular disease risk have been associated with moderate consumption of alcoholic beverages (49, 50). The “French Paradox”—the observation that mortality from coronary heart disease is relatively low in France despite relatively high levels of dietary saturated fat and cigarette smoking—led to the idea that regular consumption of red wine might provide additional protection from cardiovascular disease (51, 52). Red wine contains resveratrol and even higher levels of flavonoids. These polyphenolic compounds have antioxidant, anti-inflammatory, and other potentially anti-atherogenic effects in the test tube and in some animal models of atherosclerosis (53). However, it is not yet known whether increased consumption of polyphenols from red wine provides any additional protection from cardiovascular disease beyond that associated with its alcohol content (see the article on Alcoholic Beverages). The results of epidemiological studies addressing this question have been inconsistent. While some large prospective studies found that wine drinkers were at lower risk of cardiovascular disease than beer or liquor drinkers (54-56), others found no difference (57-59). Socioeconomic and lifestyle differences between people who prefer wine and those who prefer beer or liquor may explain part of the additional benefit observed in some studies. Several studies have found that people who prefer wine tend to have higher incomes, more education, smoke less, and eat more fruit and vegetables and less saturated fat than people who prefer other alcoholic beverages (59-64). Although moderate alcohol consumption has been consistently associated with 20-30% reductions in coronary heart disease risk, it is not yet clear whether red wine polyphenols confer any additional risk reduction. Interestingly, studies that administered alcohol-free red wine to rodents noted improvements in various parameters related to cardiovascular disease (65, 66), and a placebo-controlled human study found that heart disease patients administered red grape polyphenol extract experienced acute improvements in endothelial function (67). However, more studies are needed to determine whether drinking red wine confers any cardiovascular benefit beyond that associated with its alcohol content.

Resveratrol

Resveratrol has been found to exert a number of potentially cardioprotective effects in vitro, including inhibition of platelet aggregation (47, 48, 68), promotion of vasodilation by enhancing the production of NO (46, 69) and inhibition of inflammatory enzymes (34, 70, 71). However, the concentrations of resveratrol required to produce these effects are often higher than those that have been measured in human plasma after oral consumption of resveratrol (7). The results of some animal studies suggest that high oral doses of resveratrol could decrease the risk of thrombosis (clot formation) and atherosclerosis (72, 73), but at least one study found increased atherosclerosis in animals fed resveratrol (74). Although its presence in red wine has stimulated a great deal of interest in the potential for resveratrol to prevent cardiovascular disease, there is currently no convincing evidence that resveratrol has cardioprotective effects in humans, particularly in the amounts present in 1-2 glasses of red wine.

Cancer

Resveratrol has been found to inhibit the proliferation of a variety of human cancer cell lines, including those from breast, prostate, stomach, colon, pancreatic, and thyroid cancers (2). In animal models, oral administration of resveratrol inhibited the development of esophageal (75), intestinal (76), and mammary (breast) cancer (20, 77) induced by chemical carcinogens. However, oral resveratrol was not effective in inhibiting the development of lung cancer induced by carcinogens in cigarette smoke (78, 79). The effects of oral resveratrol administration on mice that are genetically predisposed to colon cancer have been mixed (80, 81), and a few studies have documented that oral resveratrol protects against colon cancer development in rats administered the carcinogen, 1,2-dimethylhydrazine (82-84). It is not known whether high intakes of resveratrol can help prevent cancer in humans. Clinical trials are currently underway to address this question and to also determine whether resveratrol might be beneficial in cancer treatment (85). Studies on human metabolism of resveratrol suggest that even very high dietary intakes of resveratrol may not result in tissue levels that are high enough to realize most of the protective effects demonstrated in cell culture studies (7, 12).

Longevity

Caloric restriction is known to extend the lifespans of a number of species, including mammals (86). In yeast, caloric restriction stimulates the activity of an enzyme known as Sir2 (87). Providing resveratrol to yeast increased Sir2 activity in the absence of caloric restriction and extended the replicative lifespan of yeast by 70% (6). Resveratrol feeding also extended the lifespans of worms (C. elegans) and fruit flies (D. melanogaster) by a similar mechanism (88). Additionally, resveratrol dose-dependently increased the lifespan of a vertebrate fish (N. furzeri) (89). However, it is not known whether resveratrol will have similar effects in higher animals. A recent study reported that resveratrol extended lifespan of mice on a high-calorie diet such that their lifespan was similar to that of mice fed a standard diet (90). Although resveratrol increased the activity of the homologous human enzyme (Sirt1) in the test tube (6), it is not known whether resveratrol can extend the human lifespan. Moreover, the resveratrol concentrations required to increase human Sirt1 activity were considerably higher than concentrations that have been measured in human plasma after oral consumption. Interestingly, a recent aging study in mice found that a low dose of dietary resveratrol altered gene expression in heart, brain, and skeletal muscle similar to that induced by caloric restriction (91). Like caloric restriction, resveratrol also blunted the age-related decline in heart function in this study. Clinical trials will be needed to determine if these findings are relevant to humans.

Sources

Food sources

Resveratrol is found in grapes, wine, grape juice, peanuts, and berries of Vaccinum species, including blueberries, bilberries, and cranberries (92-94). In grapes, resveratrol is found only in the skins (95). The amount of resveratrol in grape skins varies with the grape cultivar, its geographic origin, and exposure to fungal infection (96). The amount of fermentation time a wine spends in contact with grape skins is an important determinant of its resveratrol content. Consequently, white and rosé wines generally contain less resveratrol than red wines (4). Red or purple grape juices may also be good sources of resveratrol (3). The predominant form of resveratrol in grapes and grape juice is trans-resveratrol glucoside (trans-piceid), but wines also contain significant amounts of resveratrol aglycones, thought to be the result of sugar cleavage during fermentation (92). Many wines also contain significant amounts of cis-resveratrol (see Figure 1 above), which may be produced during fermentation or released from viniferins (resveratrol polymers) (97). Red wine is a relatively rich source of resveratrol, but other polyphenols are present in red wine at considerably higher concentrations than resveratrol (see the article on Flavonoids) (98). The total resveratrol content of some beverages and foods are listed in Table 1 and Table 2. These values should be considered approximate since the resveratrol content of food and beverages can vary considerably.

Table 1. Total Resveratrol Content of Wines and Grape Juice (3, 99, 100)
Beverage Total Resveratrol (mg/liter) Total Resveratrol in a 5-oz Glass (mg)
White wines (Spanish) 0.05-1.80 0.01-0.27
Rosé wines (Spanish) 0.43-3.52 0.06-0.53
Red wines (Spanish) 1.92-12.59 0.29-1.89
Red wines (global) 1.98-7.13 0.30-1.07
Red grape juice (Spanish) 1.14-8.69 0.17-1.30
Table 2. Total Resveratrol Content of Selected Foods (92, 94, 101)
Food Serving Total Resveratrol (mg)
Peanuts (raw) 1 cup (146 g) 0.01-0.26
Peanuts (boiled) 1 cup (180 g) 0.32-1.28
Peanut butter 1 cup (258 g) 0.04-0.13
Red grapes 1 cup (160 g) 0.24-1.25

Supplements

Most resveratrol supplements available in the US contain extracts of the root of Polygonum cuspidatum, also known as Hu Zhang or kojo-kon (102). Red wine extracts and red grape extracts containing resveratrol and other polyphenols are also available in the US as dietary supplements. Resveratrol supplements may contain anywhere from 10-50 mg of resveratrol, but the effective doses for chronic disease prevention in humans are not known.

Safety

Adverse effects

Resveratrol is not known to be toxic or cause adverse effects in humans, but there have been only a few controlled clinical trials to date. A recent trial that evaluated the safety of oral resveratrol in ten subjects found a single dose up to 5 grams resulted in no serious adverse effects (103). In rats, daily oral administration of trans-resveratrol at doses up to 300 mg/kg of body weight for four weeks resulted in no apparent adverse effects (104, 105).

Pregnancy and lactation

The safety of resveratrol-containing supplements during pregnancy and lactation has not been established (102). Since no safe level of alcohol consumption has been established at any stage of pregnancy (106), pregnant women should avoid consuming wine as a source of resveratrol.

Estrogen-sensitive cancers

Until more is known about the estrogenic activity of resveratrol in humans, women with a history of estrogen-sensitive cancers, such as breast, ovarian, and uterine cancers, should avoid resveratrol supplements (see Estrogenic and anti-estrogenic activities).

Drug interactions

Anticoagulant and antiplatelet drugs

Resveratrol has been found to inhibit human platelet aggregation in vitro (48, 107). Theoretically, high intakes of resveratrol (e.g., from supplements) could increase the risk of bleeding when taken with anticoagulant drugs, such as warfarin (Coumadin); antiplatelet drugs, such as clopidogrel (Plavix) and dipyridamole (Persantine); and non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen, and others.

Drugs metabolized by Cytochrome P450 3A4

Resveratrol has been reported to inhibit the activity of cytochrome P450 3A4 (CYP3A4) in vitro (108, 109). Although this interaction has not been reported in humans, high intakes of resveratrol (e.g., from supplements) could theoretically increase the bioavailability and toxicity of drugs that undergo extensive first-pass metabolism by CYP3A4. Drugs known to be metabolized by CYP3A4 include but are not limited to HMG-CoA reductase inhibitors (atorvastatin, lovastatin, and simvastatin), calcium channel antagonists (felodipine, nicardipine, nifedipine, nisoldipine, nitrendipine, nimodipine, and verapamil), anti-arrhythmic agents (amiodarone), HIV protease inhibitors (saquinivir), immunosuppressants (cyclosporine and tacrolimus), antihistamines (terfenadine), benzodiazepines (midazolam and triazolam), and drugs used to treat erectile dysfunction (sildenafil).


Authors and Reviewers

Originally written in 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in May 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in May 2008 by:
William P. Steward, M.D., Ph.D.
Professor of Oncology
Co-Director of Cancer Biomarkers and Prevention Group
Department of Oncology
University of Leicester

Copyright 2005-2015  Linus Pauling Institute


References

1.  Soleas GJ, Diamandis EP, Goldberg DM. Resveratrol: a molecule whose time has come? And gone? Clin Biochem. 1997;30(2):91-113.  (PubMed)

2.  Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res. 2004;24(5A):2783-2840.  (PubMed)

3.  Romero-Perez AI, Ibern-Gomez M, Lamuela-Raventos RM, de La Torre-Boronat MC. Piceid, the major resveratrol derivative in grape juices. J Agric Food Chem. 1999;47(4):1533-1536.  (PubMed)

4.  Siemann EH, Creasey LL. Concentration of the phytoalexin resveratrol in wine. Am J Enol Vitic. 1992;43(1):49-52.

5.  Jang M, Cai L, Udeani GO, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 1997;275(5297):218-220.  (PubMed)

6.  Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003;425(6954):191-196.  (PubMed)

7.  Walle T, Hsieh F, Delegge MH, Oatis JE, Jr., Walle UK. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos. 2004;32(12):1377-1382.  (PubMed)

8.  Wenzel E, Somoza V. Metabolism and bioavailability of trans-resveratrol. Mol Nutr Food Res. 2005;49(5):472-481.  (PubMed)

9.  Goldberg DM, Yan J, Soleas GJ. Absorption of three wine-related polyphenols in three different matrices by healthy subjects. Clin Biochem. 2003;36(1):79-87.  (PubMed)

10.  Meng X, Maliakal P, Lu H, Lee MJ, Yang CS. Urinary and plasma levels of resveratrol and quercetin in humans, mice, and rats after ingestion of pure compounds and grape juice. J Agric Food Chem. 2004;52(4):935-942.  (PubMed)

11.  Vitaglione P, Sforza S, Galaverna G, et al. Bioavailability of trans-resveratrol from red wine in humans. Mol Nutr Food Res. 2005;49(5):495-504.  (PubMed)

12.  Gescher AJ, Steward WP. Relationship between mechanisms, bioavailibility, and preclinical chemopreventive efficacy of resveratrol: a conundrum. Cancer Epidemiol Biomarkers Prev. 2003;12(10):953-957.  (PubMed)

13.  Stojanovic S, Sprinz H, Brede O. Efficiency and mechanism of the antioxidant action of trans-resveratrol and its analogues in the radical liposome oxidation. Arch Biochem Biophys. 2001;391(1):79-89.  (PubMed)

14.  Brito P, Almeida LM, Dinis TC. The interaction of resveratrol with ferrylmyoglobin and peroxynitrite; protection against LDL oxidation. Free Radic Res. 2002;36(6):621-631.  (PubMed)

15.  Frankel EN, Waterhouse AL, Kinsella JE. Inhibition of human LDL oxidation by resveratrol. Lancet. 1993;341(8852):1103-1104.  (PubMed)

16.  Bradamante S, Barenghi L, Villa A. Cardiovascular protective effects of resveratrol. Cardiovasc Drug Rev. 2004;22(3):169-188.  (PubMed)

17.  Tangkeangsirisin W, Serrero G. Resveratrol in the chemoprevention and chemotherapy of breast cancer. In: Bagchi D, Preuss HG, eds. Phytopharmaceuticals in Cancer Chemoprevention. Boca Raton: CRC Press; 2005:449-463.

18.  Bowers JL, Tyulmenkov VV, Jernigan SC, Klinge CM. Resveratrol acts as a mixed agonist/antagonist for estrogen receptors alpha and beta. Endocrinology. 2000;141(10):3657-3667.  (PubMed)

19.  Gehm BD, McAndrews JM, Chien PY, Jameson JL. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci U S A. 1997;94(25):14138-14143.  (PubMed)

20.  Bhat KP, Lantvit D, Christov K, Mehta RG, Moon RC, Pezzuto JM. Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models. Cancer Res. 2001;61(20):7456-7463.  (PubMed)

21.  Lu R, Serrero G. Resveratrol, a natural product derived from grape, exhibits antiestrogenic activity and inhibits the growth of human breast cancer cells. J Cell Physiol. 1999;179(3):297-304.  (PubMed)

22.  Chen ZH, Hurh YJ, Na HK, et al. Resveratrol inhibits TCDD-induced expression of CYP1A1 and CYP1B1 and catechol estrogen-mediated oxidative DNA damage in cultured human mammary epithelial cells. Carcinogenesis. 2004;25(10):2005-2013.  (PubMed)

23.  Ciolino HP, Yeh GC. Inhibition of aryl hydrocarbon-induced cytochrome P-450 1A1 enzyme activity and CYP1A1 expression by resveratrol. Mol Pharmacol. 1999;56(4):760-767.  (PubMed)

24.  Yang SH, Kim JS, Oh TJ, et al. Genome-scale analysis of resveratrol-induced gene expression profile in human ovarian cancer cells using a cDNA microarray. Int J Oncol. 2003;22(4):741-750.  (PubMed)

25.  Stewart ZA, Westfall MD, Pietenpol JA. Cell-cycle dysregulation and anticancer therapy. Trends Pharmacol Sci. 2003;24(3):139-145.  (PubMed)

26.  Joe AK, Liu H, Suzui M, Vural ME, Xiao D, Weinstein IB. Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines. Clin Cancer Res. 2002;8(3):893-903.  (PubMed)

27.  Fulda S, Debatin KM. Resveratrol modulation of signal transduction in apoptosis and cell survival: a mini-review. Cancer Detect Prev. 2006;30(3):217-223.  (PubMed)

28.  Woo JH, Lim JH, Kim YH, et al. Resveratrol inhibits phorbol myristate acetate-induced matrix metalloproteinase-9 expression by inhibiting JNK and PKC delta signal transduction. Oncogene. 2004;23(10):1845-1853.  (PubMed)

29.  Igura K, Ohta T, Kuroda Y, Kaji K. Resveratrol and quercetin inhibit angiogenesis in vitro. Cancer Lett. 2001;171(1):11-16.  (PubMed)

30.  Lin MT, Yen ML, Lin CY, Kuo ML. Inhibition of vascular endothelial growth factor-induced angiogenesis by resveratrol through interruption of Src-dependent vascular endothelial cadherin tyrosine phosphorylation. Mol Pharmacol. 2003;64(5):1029-1036.  (PubMed)

31.  Chen Y, Tseng SH. Review. Pro- and anti-angiogenesis effects of resveratrol. In Vivo. 2007;21(2):365-370.  (PubMed)

32.  Steele VE, Hawk ET, Viner JL, Lubet RA. Mechanisms and applications of non-steroidal anti-inflammatory drugs in the chemoprevention of cancer. Mutat Res. 2003;523-524:137-144.  (PubMed)

33.  Donnelly LE, Newton R, Kennedy GE, et al. Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms. Am J Physiol Lung Cell Mol Physiol. 2004;287(4):L774-783.  (PubMed)

34.  Pinto MC, Garcia-Barrado JA, Macias P. Resveratrol is a potent inhibitor of the dioxygenase activity of lipoxygenase. J Agric Food Chem. 1999;47(12):4842-4846.  (PubMed)

35.  Shankar S, Singh G, Srivastava RK. Chemoprevention by resveratrol: molecular mechanisms and therapeutic potential. Front Biosci. 2007;12:4839-4854.  (PubMed)

36.  de la Lastra CA, Villegas I. Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications. Mol Nutr Food Res. 2005;49(5):405-430.  (PubMed)

37.  Blake GJ, Ridker PM. C-reactive protein and other inflammatory risk markers in acute coronary syndromes. J Am Coll Cardiol. 2003;41(4 Suppl S):37S-42S.  (PubMed)

38.  Stocker R, Keaney JF, Jr. Role of oxidative modifications in atherosclerosis. Physiol Rev. 2004;84(4):1381-1478.  (PubMed)

39.  Carluccio MA, Siculella L, Ancora MA, et al. Olive oil and red wine antioxidant polyphenols inhibit endothelial activation: antiatherogenic properties of Mediterranean diet phytochemicals. Arterioscler Thromb Vasc Biol. 2003;23(4):622-629.  (PubMed)

40.  Ferrero ME, Bertelli AE, Fulgenzi A, et al. Activity in vitro of resveratrol on granulocyte and monocyte adhesion to endothelium. Am J Clin Nutr. 1998;68(6):1208-1214.  (PubMed)

41.  Faxon DP, Fuster V, Libby P, et al. Atherosclerotic Vascular Disease Conference: Writing Group III: pathophysiology. Circulation. 2004;109(21):2617-2625.  (PubMed)

42.  Mnjoyan ZH, Fujise K. Profound negative regulatory effects by resveratrol on vascular smooth muscle cells: a role of p53-p21(WAF1/CIP1) pathway. Biochem Biophys Res Commun. 2003;311(2):546-552.  (PubMed)

43.  Haider UG, Sorescu D, Griendling KK, Vollmar AM, Dirsch VM. Resveratrol increases serine15-phosphorylated but transcriptionally impaired p53 and induces a reversible DNA replication block in serum-activated vascular smooth muscle cells. Mol Pharmacol. 2003;63(4):925-932.  (PubMed)

44.  Duffy SJ, Vita JA. Effects of phenolics on vascular endothelial function. Curr Opin Lipidol. 2003;14(1):21-27.  (PubMed)

45.  Klinge CM, Blankenship KA, Risinger KE, et al. Resveratrol and estradiol rapidly activate MAPK signaling through estrogen receptors alpha and beta in endothelial cells. J Biol Chem. 2005; 280(9):7460-7468.  (PubMed)

46.  Wallerath T, Deckert G, Ternes T, et al. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation. 2002;106(13):1652-1658.  (PubMed)

47.  Kirk RI, Deitch JA, Wu JM, Lerea KM. Resveratrol decreases early signaling events in washed platelets but has little effect on platalet in whole blood. Blood Cells Mol Dis. 2000;26(2):144-150.  (PubMed)

48.  Pace-Asciak CR, Hahn S, Diamandis EP, Soleas G, Goldberg DM. The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease. Clin Chim Acta. 1995;235(2):207-219.  (PubMed)

49.  Klatsky AL. Drink to your health? Sci Am. 2003;288(2):74-81.  (PubMed)

50.  Corrao G, Rubbiati L, Bagnardi V, Zambon A, Poikolainen K. Alcohol and coronary heart disease: a meta-analysis. Addiction. 2000;95(10):1505-1523.  (PubMed)

51.  Criqui MH, Ringel BL. Does diet or alcohol explain the French paradox? Lancet. 1994;344(8939-8940):1719-1723.  (PubMed)

52.  St Leger AS, Cochrane AL, Moore F. Factors associated with cardiac mortality in developed countries with particular reference to the consumption of wine. Lancet. 1979;1(8124):1017-1020.  (PubMed)

53.  German JB, Walzem RL. The health benefits of wine. Annu Rev Nutr. 2000;20:561-593.  (PubMed)

54.  Gronbaek M, Becker U, Johansen D, et al. Type of alcohol consumed and mortality from all causes, coronary heart disease, and cancer. Ann Intern Med. 2000;133(6):411-419.  (PubMed)

55.  Klatsky AL, Friedman GD, Armstrong MA, Kipp H. Wine, liquor, beer, and mortality. Am J Epidemiol. 2003;158(6):585-595.  (PubMed)

56.  Renaud SC, Gueguen R, Siest G, Salamon R. Wine, beer, and mortality in middle-aged men from eastern France. Arch Intern Med. 1999;159(16):1865-1870.  (PubMed)

57.  Mukamal KJ, Conigrave KM, Mittleman MA, et al. Roles of drinking pattern and type of alcohol consumed in coronary heart disease in men. N Engl J Med. 2003;348(2):109-118.  (PubMed)

58.  Rimm EB, Klatsky A, Grobbee D, Stampfer MJ. Review of moderate alcohol consumption and reduced risk of coronary heart disease: is the effect due to beer, wine, or spirits. BMJ. 1996;312(7033):731-736.  (PubMed)

59.  Wannamethee SG, Shaper AG. Type of alcoholic drink and risk of major coronary heart disease events and all-cause mortality. Am J Public Health. 1999;89(5):685-690.  (PubMed)

60.  Barefoot JC, Gronbaek M, Feaganes JR, McPherson RS, Williams RB, Siegler IC. Alcoholic beverage preference, diet, and health habits in the UNC Alumni Heart Study. Am J Clin Nutr. 2002;76(2):466-472.  (PubMed)

61.  McCann SE, Sempos C, Freudenheim JL, et al. Alcoholic beverage preference and characteristics of drinkers and nondrinkers in western New York (United States). Nutr Metab Cardiovasc Dis. 2003;13(1):2-11.  (PubMed)

62.  Mortensen EL, Jensen HH, Sanders SA, Reinisch JM. Better psychological functioning and higher social status may largely explain the apparent health benefits of wine: a study of wine and beer drinking in young Danish adults. Arch Intern Med. 2001;161(15):1844-1848.  (PubMed)

63.  Johansen D, Friis K, Skovenborg E, Gronbaek M. Food buying habits of people who buy wine or beer: cross sectional study. BMJ. 2006;332(7540):519-522.  (PubMed)

64.  Ruidavets JB, Bataille V, Dallongeville J, et al. Alcohol intake and diet in France, the prominent role of lifestyle. Eur Heart J. 2004;25(13):1153-1162.  (PubMed)

65.  Stocker R, O'Halloran RA. Dealcoholized red wine decreases atherosclerosis in apolipoprotein E gene-deficient mice independently of inhibition of lipid peroxidation in the artery wall. Am J Clin Nutr. 2004;79(1):123-130.  (PubMed)

66.  De Curtis A, Murzilli S, Di Castelnuovo A, et al. Alcohol-free red wine prevents arterial thrombosis in dietary-induced hypercholesterolemic rats: experimental support for the 'French paradox'. J Thromb Haemost. 2005;3(2):346-350.  (PubMed)

67.  Lekakis J, Rallidis LS, Andreadou I, et al. Polyphenolic compounds from red grapes acutely improve endothelial function in patients with coronary heart disease. Eur J Cardiovasc Prev Rehabil. 2005;12(6):596-600.  (PubMed)

68.  Wang Z, Huang Y, Zou J, Cao K, Xu Y, Wu JM. Effects of red wine and wine polyphenol resveratrol on platelet aggregation in vivo and in vitro. Int J Mol Med. 2002;9(1):77-79.  (PubMed)

69.  Chen CK, Pace-Asciak CR. Vasorelaxing activity of resveratrol and quercetin in isolated rat aorta. Gen Pharmacol. 1996;27(2):363-366.  (PubMed)

70.  Szewczuk LM, Forti L, Stivala LA, Penning TM. Resveratrol is a peroxidase-mediated inactivator of COX-1 but not COX-2: a mechanistic approach to the design of COX-1 selective agents. J Biol Chem. 2004;279(21):22727-22737.  (PubMed)

71.  Tsai SH, Lin-Shiau SY, Lin JK. Suppression of nitric oxide synthase and the down-regulation of the activation of NFkappaB in macrophages by resveratrol. Br J Pharmacol. 1999;126(3):673-680.  (PubMed)

72.  Fukao H, Ijiri Y, Miura M, et al. Effect of trans-resveratrol on the thrombogenicity and atherogenicity in apolipoprotein E-deficient and low-density lipoprotein receptor-deficient mice. Blood Coagul Fibrinolysis. 2004;15(6):441-446.  (PubMed)

73.  Wang Z, Zou J, Huang Y, Cao K, Xu Y, Wu JM. Effect of resveratrol on platelet aggregation in vivo and in vitro. Chin Med J (Engl). 2002;115(3):378-380.  (PubMed)

74.  Wilson T, Knight TJ, Beitz DC, Lewis DS, Engen RL. Resveratrol promotes atherosclerosis in hypercholesterolemic rabbits. Life Sci. 1996;59(1):PL15-21.  (PubMed)

75.  Li ZG, Hong T, Shimada Y, et al. Suppression of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats by resveratrol. Carcinogenesis. 2002;23(9):1531-1536.  (PubMed)

76.  Tessitore L, Davit A, Sarotto I, Caderni G. Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21(CIP) expression. Carcinogenesis. 2000;21(8):1619-1622.  (PubMed)

77.  Banerjee S, Bueso-Ramos C, Aggarwal BB. Suppression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: role of nuclear factor-kappaB, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res. 2002;62(17):4945-4954.  (PubMed)

78.  Hecht SS, Kenney PM, Wang M, et al. Evaluation of butylated hydroxyanisole, myo-inositol, curcumin, esculetin, resveratrol and lycopene as inhibitors of benzo[a]pyrene plus 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in A/J mice. Cancer Lett. 1999;137(2):123-130.  (PubMed)

79.  Berge G, Ovrebo S, Eilertsen E, Haugen A, Mollerup S. Analysis of resveratrol as a lung cancer chemopreventive agent in A/J mice exposed to benzo[a]pyrene. Br J Cancer. 2004;91(7):1380-1383.  (PubMed)

80.  Ziegler CC, Rainwater L, Whelan J, McEntee MF. Dietary resveratrol does not affect intestinal tumorigenesis in Apc(Min/+) mice. J Nutr. 2004;134(1):5-10.  (PubMed)

81.  Schneider Y, Duranton B, Gosse F, Schleiffer R, Seiler N, Raul F. Resveratrol inhibits intestinal tumorigenesis and modulates host-defense-related gene expression in an animal model of human familial adenomatous polyposis. Nutr Cancer. 2001;39(1):102-107.  (PubMed)

82.  Sengottuvelan M, Nalini N. Dietary supplementation of resveratrol suppresses colonic tumour incidence in 1,2-dimethylhydrazine-treated rats by modulating biotransforming enzymes and aberrant crypt foci development. Br J Nutr. 2006;96(1):145-153.  (PubMed)

83.  Sengottuvelan M, Senthilkumar R, Nalini N. Modulatory influence of dietary resveratrol during different phases of 1,2-dimethylhydrazine induced mucosal lipid-peroxidation, antioxidant status and aberrant crypt foci development in rat colon carcinogenesis. Biochim Biophys Acta. 2006;1760(8):1175-1183.  (PubMed)

84.  Sengottuvelan M, Viswanathan P, Nalini N. Chemopreventive effect of trans-resveratrol--a phytoalexin against colonic aberrant crypt foci and cell proliferation in 1,2-dimethylhydrazine induced colon carcinogenesis. Carcinogenesis. 2006;27(5):1038-1046.  (PubMed)

85.  Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006;5(6):493-506.  (PubMed)

86.  Heilbronn LK, Ravussin E. Calorie restriction and aging: review of the literature and implications for studies in humans. Am J Clin Nutr. 2003;78(3):361-369.  (PubMed)

87.  Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 2000;289(5487):2126-2128.  (PubMed)

88.  Wood JG, Rogina B, Lavu S, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004;430(7000):686-689.  (PubMed)

89.  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. Curr Biol. 2006;16(3):296-300.  (PubMed)

90.  Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444(7117):337-342.  (PubMed)

91.  Barger JL, Kayo T, Vann JM, et al. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One. 2008;3(6):e2264.  (PubMed)

92.  Burns J, Yokota T, Ashihara H, Lean ME, Crozier A. Plant foods and herbal sources of resveratrol. J Agric Food Chem. 2002;50(11):3337-3340.  (PubMed)

93.  Rimando AM, Kalt W, Magee JB, Dewey J, Ballington JR. Resveratrol, pterostilbene, and piceatannol in vaccinium berries. J Agric Food Chem. 2004;52(15):4713-4719.  (PubMed)

94.  Sanders TH, McMichael RW, Jr., Hendrix KW. Occurrence of resveratrol in edible peanuts. J Agric Food Chem. 2000;48(4):1243-1246.  (PubMed)

95.  Creasey LL, Coffee M. Phytoalexin production potential of grape berries. J Am Soc Hortic Sci. 1988;113(2):230-234.

96.  Fremont L. Biological effects of resveratrol. Life Sci. 2000;66(8):663-673.  (PubMed)

97.  Goldberg DM, Karumanchiri A, Ng E, Yan J, Eleftherios P, Soleas G. Direct gas chromatographic-mass spectrometric method to assay cis-resveratrol in wines: preliminary survey of its concentration in commercial wines. J Agric Food Chem. 1995;43(5):1245-1250.

98.  Burns J, Gardner PT, Matthews D, Duthie GG, Lean ME, Crozier A. Extraction of phenolics and changes in antioxidant activity of red wines during vinification. J Agric Food Chem. 2001;49(12):5797-5808.  (PubMed)

99.  Moreno-Labanda JF, Mallavia R, Perez-Fons L, Lizama V, Saura D, Micol V. Determination of piceid and resveratrol in Spanish wines deriving from Monastrell (Vitis vinifera L.) grape variety. J Agric Food Chem. 2004;52(17):5396-5403.  (PubMed)

100.  Romero-Perez AI, Lamuela-Raventos RM, Waterhouse AL, de la Torre-Boronat MC. Levels of cis- and trans-resveratrol and their glucosides in white and rosé Vitis vinifera wines from Spain. J Agric Food Chem. 1996;44(8):2124-2128.

101.  Sobolev VS, Cole RJ. trans-resveratrol content in commercial peanuts and peanut products. J Agric Food Chem. 1999;47(4):1435-1439.  (PubMed)

102.  Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001.

103.  Boocock DJ, Faust GE, Patel KR, et al. Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomarkers Prev. 2007;16(6):1246-1252.  (PubMed)

104.  Crowell JA, Korytko PJ, Morrissey RL, Booth TD, Levine BS. Resveratrol-associated renal toxicity. Toxicol Sci. 2004;82(2):614-619.  (PubMed)

105.  Juan ME, Vinardell MP, Planas JM. The daily oral administration of high doses of trans-resveratrol to rats for 28 days is not harmful. J Nutr. 2002;132(2):257-260.  (PubMed)

106.  American Academy of Pediatrics. Committee on Substance Abuse and Committee on Children With Disabilities. Fetal alcohol syndrome and alcohol-related neurodevelopmental disorders. Pediatrics. 2000;106(2 Pt 1):358-361.  (PubMed)

107.  Bertelli AA, Giovannini L, Giannessi D, et al. Antiplatelet activity of synthetic and natural resveratrol in red wine. Int J Tissue React. 1995;17(1):1-3.  (PubMed)

108.  Piver B, Berthou F, Dreano Y, Lucas D. Inhibition of CYP3A, CYP1A and CYP2E1 activities by resveratrol and other non volatile red wine components. Toxicol Lett. 2001;125(1-3):83-91.  (PubMed)

109.  Regev-Shoshani G, Shoseyov O, Kerem Z. Influence of lipophilicity on the interactions of hydroxy stilbenes with cytochrome P450 3A4. Biochem Biophys Res Commun. 2004;323(2):668-673.  (PubMed)