Purpose: Resveratrol (RES) or 3, 4′, 5‐trihydroxystilbene has been shown to inhibit carcinogenesis by affecting various molecular events in the initiation, promotion and progression stages. The cancer chemopreventive activity of RES has been demonstrated in vivo in a wide variety of tumors including skin, mammary, gastrointestinal, and liver cancer models. Modulation of Phase I and Phase II enzymes has been suggested to be one of the mechanisms responsible for the cancer preventive effect of RES. We conducted a clinical study to determine the effect of pharmacological doses of RES on drug and carcinogen metabolizing enzymes.

Methods: Forty‐two healthy volunteers underwent baseline assessment of Phase I and Phase II enzymes. A cocktail of cytochrome P450 (CYP) metabolic probe drugs, including caffeine, dextromethorphan, losartan, and buspirone, were administered to assess the activity of CYP1A2, 2D6, 2C9, and 3A4, respectively. Blood and urine samples were collected for 8 hours after probe drug administration to determine parent probe drug and metabolite concentrations for measurements of CYP enzyme activities. Blood lymphocyte glutathione S‐transferase (GST) activity and GST‐π level, and serum total and direct bilirubin, a surrogate for UDP‐glucuronosyl transferase (UGT) 1A1 activity, were measured to assess Phase II enzymes. After the baseline evaluation, study participants took 1 gm of RES once daily for 4 wks. Enzyme assessment was repeated upon intervention completion.

Results: RES intervention was found to suppress the activity of CYP3A4, 2D6, and 2C9. The geometric mean change of the activity index of CPY3A4, 2D6, and 2C9 was 33% (p = 0.01), 70% (p = 0.01), and 171% (p < 0.0001), respectively. CYP1A2 activity was induced; the geometric mean change of the activity index was 16% (p = 0.005). The overall GST and UGT1A1 activity index were minimally affected by the intervention while an induction of GST‐π level (84%, p = 0.002) and UGT1A1 activity index (20%, p = 0.0089) was observed in individuals with baseline enzyme level/activity in the lowest tertile.

Conclusion: We conclude that high doses of RES administration may modulate enzyme systems involved in carcinogen activation and detoxification, which may be one mechanism by which RES inhibits carcinogenesis. However, high doses of RES administration may lead to clinically relevant metabolic drug interactions. Further clinical studies are needed to determine whether lower doses of RES could be used to achieve cancer preventive activities. (Supported by N01CN35158 from the National Cancer Institute, Division of Cancer Prevention)

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A57.