Health Care Professional Information

Scientific Name
3,5,4'-trihydroxystilbene
Clinical Summary

Resveratrol is a polyphenolic compound found in many botanical products. Red wine is a natural source of resveratrol as it is rich in grape skin and seeds. However, resveratrol is usually consumed as a dietary supplement for its purported antioxidant and anti-inflammatory properties. It is also marketed as an anti-aging supplement based on the findings that it prolongs the life span of yeast cells (1) (2). This effect has not yet been demonstrated in humans.

Resveratrol is thought to have cardioprotective effects. Earlier studies found that it reduces the oxidation of low density lipoproteins (LDL) and inhibits aggregation of platelets and may offer protection against atherogenesis (3) (4). Consumption of wine or a resveratrol-rich grape supplement is associated with reduction in risk of cardiovascular disease (5) (6) and may help promote health of the circulatory system (7) (8) (9).

Resveratrol can increase insulin sensitivity in diabetic patients (10) (11). However, clinical studies on the effect of resveratrol in controlling metabolic syndromes in obese subjects yielded mix results (12) (13). In vitro and animal studies show that resveratrol inhibits proliferation of cancer cells via different mechanisms (14) (15) (16) (17) (18) (19). It may also protect against chemotherapy-induced cardiotoxicity (19) (20). Further clinical studies are needed to confirm these effects in humans.

External application of a resveratrol containing gel reduced the symptoms of acne (21).

While resveratrol is generally safe, high doses can cause gastrointestinal side effects, such as diarrhea. Resveratrol inhibits CYP450 enzymes (22) (23) and may increase the risk of adverse effects of certain drugs.

Food Sources
  • Grape (skin and seeds)
  • Peanuts
  • Mulberries
  • Spruce
  • Eucalyptus
  • Polygonum cuspidatum or Japanese knotweed
Purported Uses
  • Atherosclerosis
  • Cancer prevention
  • Coronary heart disease
  • Inflammation
  • Anti-aging
Mechanism of Action

Resveratrol acts as an antioxidant and inhibits the oxidation of low density lipoproteins (LDL) (21), the aggregation of platelets, and eicosanoid synthesis (4). It also induces nitric oxide (NO) production (24) (25) and increases arterial blood flow (8). These actions may contribute to resveratrol's purported cardiovascular health benefits.
Resveratrol acts as an anti-inflammatory agent by inhibiting cyclooxygenase (COX) activity (26). It has been shown to decrease C-reactive protein, tumor necrosis factor, and to increase anti-inflammatory interleukin-10 and intercellular adhesion molecule-1 in humans (5).
Resveratrol decreases oxidative stress and improves insulin sensitivity by increasing protein kinase activities (10) . It decreases circulating insulin-like growth factor-1 (IGF-I) and IGF-binding protein-3 (IGFBP-3) levels (27) which may account for its anti-diabetic effects in humans.
Preliminary data suggest that resveratrol increases the life span of yeast cells by activating sirtuins (1) (2). Recent study shows it inhibits human Sirt3 and stimulates Sirt5, in addition to Sirt1 (28).
In vitro and animal studies show that resveratrol has anticancer activities. It inhibits proliferation of cancer cells via apoptosis and by exerting anti-estrogenic effects (14) (15) (16) (17). However, contradictory data from other studies showed that it acts as a phytoestrogen and could activate genes that are normally regulated by estrogen (18) or androgen (19).
Trans-resveratrol appears to decrease methylation of the tumor suppressor gene RASSF-1alpha in women at increased breast cancer risk (29). In addition, reductions in breast cancer cell migration and invasion were observed after treatment with resveratrol (30) (31). Resveratrol growth factor heregulin-beta1 (HRG-beta1) -mediated Matrix metallopeptidase 9 (MMP-9) expressions in human breast cancer cells (30).
Resveratrol may help reduce prostate tumorigenesis through a reduction in the prostatic levels of mTOR complex 1 (mTORC1) activity and increased expression of SIRT1 and (32). Another study demonstrated that resveratrol modulates steroid hormone-dependent pathways to inhibit prostate cancer cell growth. However, resveratrol also increases angiogenesis and inhibition of apoptosis in vivo (19).
In an animal model, resveratrol down-regulated p21 and up-regulated cyclin E leading to S-phase accumulation and apoptosis in neuroblastoma cells (14). Resveratrol also inhibited the enzymes CYP1A1, CYP1A2, and CYP1B1 in tumor cells. This may be one of the mechanisms by which it exerts anti-tumor effects as some of these enzymes are known to be involved in the activation of procarcinogens and toxins (22) (23).
The protective effect of resveratrol against doxorubicin-induced cardiotoxicity is due to up-regulation of SIRT1-mediated p53 deacetylation. (20). It also protects against cisplatin-induced cardiotoxicity through the suppression of oxidative stress (19).

Pharmacokinetics

Resveratrol can be consumed as a purified dietary supplement or as a constituent in red wine. The pharmacokinetic profiles may vary depending on the intake. Food and high-fat meals can decrease and delay its absorption (33) (34). Upon oral administration, resveratrol is rapidly absorbed in the gastrointestinal tract and undergoes glucuronidation and sulfation in the liver microsomes mainly to resveratrol-3-O-sulfate, resveratrol-4'-O-glucuronide, and resveratrol-3-O-glucuronide (27). Metabolic conjugation is affected by microbiota. (35). Peak plasma levels can be detected 1.5 hr after oral intake (36). Resveratrol is rapidly excreted; more than 50% is eliminated in urine in 24 hrs (37).
The aglycone forms of resveratrol are better absorbed than the glycosides (37). Micronizing resveratrol may help improve its absorption (38).

Contraindications

Because resveratrol exhibits estrogen-like properties and activates transcription by both the estrogen and androgen receptors that lead to stimulation of cancer cell proliferation, patients with hormone-sensitive cancers should use caution (18).

Adverse Reactions

At high doses (2.5 and 5 g daily), resveratrol can cause mild to moderate gastrointestinal symptoms (27), and diarrhea (33).

Herb-Drug Interactions
  • Antiplatelet drugs: Because resveratrol inhibits platelet aggregation, concurrent use of other antiplatelet drugs may increase the risk of bleeding.
  • Cytochrome P450 substrates: Resveratrol inhibits CYP3A4, CYP2D6, CYP2C9, and induces CYP1A2, thereby affecting the levels of drugs that are metabolized by these enzymes (39).
  • Carbamazepine: Polygonum cuspidatum, a herbal supplement rich in resveratrol, can increase carbamazepine blood level due to the inhibition of CYP3A and multidrug resistance-associated protein 2 (MRP 2) (40).
Literature Summary and Critique

Poulsen MM, Vestergaard PF, Clasen BF, et al. High-Dose Resveratrol Supplementation in Obese Men: An Investigator-Initiated, Randomized, Placebo-Controlled Clinical Trial of Substrate Metabolism, Insulin Sensitivity, and Body Composition. Diabetes. 2012 Nov 28. [Epub ahead of print]
In this study, 24 obese, healthy men were randomized to receive 500 mg trans-resveratrol or placebo, thrice daily, for 4 weeks. Glucose turnover and insulin sensitivity were assessed before and after the treatment. There was no significant decrease in insulin sensitivity, the primary outcome measure, in either group. There was also no change in the endogenous glucose production and the turnover and oxidation rates of glucose. Further resveratrol did not affect blood pressure; resting energy expenditure; oxidation rates of lipid; ectopic or visceral fat content; or inflammatory and metabolic biomarkers.
Reseveratrol may not be effective against metabolic disorders.

Dosage (Inside MSKCC Only)
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References
  1. Hall SS. Longevity research. In vino vitalis? Compounds activate life-extending genes. Science. Aug 29 2003;301(5637):1165.
  2. Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. Sep 11 2003;425(6954):191-196.
  3. Fauconneau B, Waffo-Teguo P, Huguet F, et al. Comparative study of radical scavenger and antioxidant properties of phenolic compounds from Vitis vinifera cell cultures using in vitro tests. Life Sci. 1997;61(21):2103-2110.
  4. Pace-Asciak CR, Hahn S, Diamandis EP, et al. 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. Mar 31 1995;235(2):207-219.
  5. Tome-Carneiro J, Gonzalvez M, Larrosa M, et al. One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. The American journal of cardiology. Aug 1 2012;110(3):356-363.
  6. Zamora-Ros R, Urpi-Sarda M, Lamuela-Raventos RM, et al. High urinary levels of resveratrol metabolites are associated with a reduction in the prevalence of cardiovascular risk factors in high-risk patients. Pharmacological research : the official journal of the Italian Pharmacological Society. Jun 2012;65(6):615-620.
  7. Kennedy DO, Wightman EL, Reay JL, et al. Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation. The American journal of clinical nutrition. Jun 2010;91(6):1590-1597.
  8. Wong RH, Howe PR, Buckley JD, et al. Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutrition, metabolism, and cardiovascular diseases : NMCD. Nov 2011;21(11):851-856.
  9. Magyar K, Halmosi R, Palfi A, et al. Cardioprotection by resveratrol: A human clinical trial in patients with stable coronary artery disease. Clinical hemorheology and microcirculation. 2012;50(3):179-187.
  10. Brasnyo P, Molnar GA, Mohas M, et al. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. The British journal of nutrition. Aug 2011;106(3):383-389.
  11. Crandall JP, Oram V, Trandafirescu G, et al. Pilot study of resveratrol in older adults with impaired glucose tolerance. The journals of gerontology Series A, Biological sciences and medical sciences. Dec 2012;67(12):1307-1312.
  12. Timmers S, Konings E, Bilet L, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell metabolism. Nov 2 2011;14(5):612-622.
  13. Poulsen MM, Vestergaard PF, Clasen BF, et al. High-Dose Resveratrol Supplementation in Obese Men: An Investigator-Initiated, Randomized, Placebo-Controlled Clinical Trial of Substrate Metabolism, Insulin Sensitivity, and Body Composition. Diabetes. Nov 28 2012.
  14. Chen Y, Tseng SH, Lai HS, et al. Resveratrol-induced cellular apoptosis and cell cycle arrest in neuroblastoma cells and antitumor effects on neuroblastoma in mice. Surgery. Jul 2004;136(1):57-66.
  15. ElAttar TM, Virji AS. Modulating effect of resveratrol and quercetin on oral cancer cell growth and proliferation. Anticancer Drugs. Feb 1999;10(2):187-193.
  16. 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. Jun 1999;179(3):297-304.
  17. Surh YJ, Hurh YJ, Kang JY, et al. Resveratrol, an antioxidant present in red wine, induces apoptosis in human promyelocytic leukemia (HL-60) cells. Cancer Lett. Jun 1 1999;140(1-2):1-10.
  18. Gehm BD, McAndrews JM, Chien PY, et al. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci U S A. Dec 9 1997;94(25):14138-14143.
  19. Wang TT, Hudson TS, Wang TC, et al. Differential effects of resveratrol on androgen-responsive LNCaP human prostate cancer cells in vitro and in vivo. Carcinogenesis. Oct 2008;29(10):2001-2010.
  20. Zhang C, Feng Y, Qu S, et al. Resveratrol attenuates doxorubicin-induced cardiomyocyte apoptosis in mice through SIRT1-mediated deacetylation of p53. Cardiovascular research. Jun 1 2011;90(3):538-545.
  21. Fabbrocini G, Staibano S, De Rosa G, et al. Resveratrol-containing gel for the treatment of acne vulgaris: a single-blind, vehicle-controlled, pilot study. American journal of clinical dermatology. Apr 1 2011;12(2):133-141.
  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. Oct 2004;25(10):2005-2013.
  23. Liu J, Wang Q, Wu DC, et al. Differential regulation of CYP1A1 and CYP1B1 expression in resveratrol-treated human medulloblastoma cells. Neurosci Lett. Jun 17 2004;363(3):257-261.
  24. Gresele P, Pignatelli P, Guglielmini G, et al. Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production. J Nutr. Sep 2008;138(9):1602-1608.
  25. Huang PH, Chen YH, Tsai HY, et al. Intake of red wine increases the number and functional capacity of circulating endothelial progenitor cells by enhancing nitric oxide bioavailability. Arteriosclerosis, thrombosis, and vascular biology. Apr 2010;30(4):869-877.
  26. Jang M, Cai L, Udeani GO, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. Jan 10 1997;275(5297):218-220.
  27. Brown VA, Patel KR, Viskaduraki M, et al. Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis. Cancer research. Nov 15 2010;70(22):9003-9011.
  28. Gertz M, Nguyen GT, Fischer F, et al. A molecular mechanism for direct sirtuin activation by resveratrol. PloS one. 2012;7(11):e49761.
  29. Zhu W, Qin W, Zhang K, et al. Trans-resveratrol alters mammary promoter hypermethylation in women at increased risk for breast cancer. Nutrition and cancer. Apr 2012;64(3):393-400.
  30. Tang FY, Chiang EP, Sun YC. Resveratrol inhibits heregulin-beta1-mediated matrix metalloproteinase-9 expression and cell invasion in human breast cancer cells. J Nutr Biochem. May 2008;19(5):287-294.
  31. Tang FY, Su YC, Chen NC, et al. Resveratrol inhibits migration and invasion of human breast-cancer cells. Mol Nutr Food Res. Jun 2008;52(6):683-691.
  32. Li G, Rivas P, Bedolla R, et al. Dietary resveratrol prevents development of high-grade prostatic intraepithelial neoplastic lesions: involvement of SIRT1/S6K axis. Cancer prevention research. Jan 2013;6(1):27-39.
  33. la Porte C, Voduc N, Zhang G, et al. Steady-State pharmacokinetics and tolerability of trans-resveratrol 2000 mg twice daily with food, quercetin and alcohol (ethanol) in healthy human subjects. Clinical pharmacokinetics. Jul 2010;49(7):449-454.
  34. Vaz-da-Silva M, Loureiro AI, Falcao A, et al. Effect of food on the pharmacokinetic profile of trans-resveratrol. International journal of clinical pharmacology and therapeutics. Nov 2008;46(11):564-570.
  35. Rotches-Ribalta M, Andres-Lacueva C, Estruch R, et al. Pharmacokinetics of resveratrol metabolic profile in healthy humans after moderate consumption of red wine and grape extract tablets. Pharmacological research : the official journal of the Italian Pharmacological Society. Nov 2012;66(5):375-382.
  36. 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. Jun 2007;16(6):1246-1252.
  37. Meng X, Maliakal P, Lu H, et al. 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. Feb 25 2004;52(4):935-942.
  38. Howells LM, Berry DP, Elliott PJ, et al. Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases—safety, pharmacokinetics, and pharmacodynamics. Cancer prevention research. Sep 2011;4(9):1419-1425.
  39. Chow HH, Garland LL, Hsu CH, et al. Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. Cancer prevention research. Sep 2010;3(9):1168-1175.
  40. Chi YC, Lin SP, Hou YC. A new herb-drug interaction of Polygonum cuspidatum, a resveratrol-rich nutraceutical, with carbamazepine in rats. Toxicology and applied pharmacology. Sep 15 2012;263(3):315-322.
  41. Patel KR, Brown VA, Jones DJ, et al. Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer research. Oct 1 2010;70(19):7392-7399.

Consumer Information

How It Works

Bottom Line: In laboratory studies, resveratrol was found to reduce inflammation and to have antitumor properties, but human studies have not been conducted.

A naturally occurring compound in the skin of red grapes and other botanicals, resveratrol has been shown to reduce inflammation. It also has antioxidant properties and may help to protect against atherosclerosis (thickening of arterial walls) and heart disease. Animal studies have shown that resveratrol has the ability to prevent certain cancer cells from dividing. Human studies on its anticancer effect are lacking.

Purported Uses
  • Atherosclerosis
    Laboratory studies have shown that resveratrol helps in preventing atherosclerosis.
  • Coronary heart disease
    There is limited scientific evidence to support this use.
  • Cancer prevention
    Several laboratory studies have demonstrated the ability of resveratrol in preventing growth of cancer cells. However, it is not clear if similar effects will be seen in humans.
  • Inflammation
    This use is supported by data from laboratory studies.
  • Anti-aging
    This effect has only been demonstrated in lab studies.
Research Evidence

Metabolic Disorders:
In this study, 24 obese, healthy men were given 500 mg trans-resveratrol  or placebo, thrice daily, for 4 weeks. Glucose turnover and insulin sensitivity were assessed before and after the treatment. There was no significant decrease in insulin sensitivity in either group. There was also no change in the endogenous glucose production and the turnover and oxidation rates of glucose. Resveratrol also did not affect blood pressure, fat content, or inflammatory and metabolic biomarkers.
 

Do Not Take If
  • You are taking antiplatelet drugs (resveratrol may increase the risk of bleeding).
  • If you are taking drugs that are substrates of cytochrome P450 (Resveratrol may increase the risk of side effects of some drugs and make others less effective).
Side Effects

Patients with hormone-sensitive cancers should use caution when taking resveratrol because it may cause certain cancer cells to multiply.

E-mail your questions and comments to aboutherbs@mskcc.org.