Resveratrol Modulates Drug- and Carcinogen-Metabolizing Enzymes in a Healthy Volunteer Study

Abstract

Resveratrol has been shown to exhibit cancer-preventive activities in preclinical studies. We conducted a clinical study to determine the effect of pharmacologic doses of resveratrol on drug-and carcinogen-metabolizing enzymes. Forty-two healthy volunteers underwent baseline assessment of cytochrome P450 (CYP) and phase II detoxification enzymes. CYP1A2, CYP2D6, CYP2C9, and CYP3A4 enzyme activities were measured by the metabolism of caffeine, dextromethorphan, losartan, and buspirone, respectively. 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 g of resveratrol once daily for 4 weeks. Enzyme assessment was repeated upon intervention completion. Resveratrol intervention was found to inhibit the phenotypic indices of CYP3A4, CYP2D6, and CYP2C9 and to induce the phenotypic index of 1A2. Overall, GST and UGT1A1 activities were minimally affected by the intervention, although an induction of GST-π level and UGT1A1 activity was observed in individuals with low baseline enzyme level/activity. We conclude that resveratrol can modulate enzyme systems involved in carcinogen activation and detoxification, which may be one mechanism by which resveratrol inhibits carcinogenesis. However, pharmacologic doses of resveratrol could potentially lead to increased adverse drug reactions or altered drug efficacy due to inhibition or induction of certain CYPs. Further clinical development of resveratrol for cancer prevention should consider evaluation of lower doses of resveratrol to minimize adverse metabolic drug interactions. Cancer Prev Res; 3(9); 1168-75. ©2010 AACR.

Resveratrol and health – A comprehensive review of human clinical trials

“…C max more than doubled in the 25 and 150 mg group between the first and thirteenth dose, although this was not observed with the 50 and 100 mg groups. Regardless, C max of the 150 mg group was 63.8 mg/L following 13 days of administration, far lower than the C max for 5 g dosage used by Boocock [29,31], but similar to C max Boocock achieved following a single 0.5 g dosage. The CV for C max was large, similar to that reported by Boocock et al, ranging from 40 to 113%.…”

“…Coefficient of variation (CV) for C max for the dosages used ranged from 48.9 to 73.1%, indicating substantial variation in metabolism between subjects. Similarly, Chow et al found plasma resveratrol concentration to range from 8.3 to 404.4 mg/L 1 h following 1 g resveratrol supplementation [31]. C max can be increased through multiple days of supplementation [32].…”

Resveratrol Induces p53-independent, X-linked Inhibitor of Apoptosis Protein (XIAP)-mediated Bax Protein Oligomerization on Mitochondria to Initiate Cytochrome c Release and Caspase Activation

“…It is generally believed that for chemoprevention or cancer therapy doses of resveratrol used to induce apoptotic cell death may not easily be achieved under physiological conditions through regular diets. However, various lines of evidence indicate that in vitro doses that have been shown to induce apoptotic cell death could be achieved in cancer cells through higher intake of resveratrol (87)(88)(89)(90)(91). For example, resveratrol at daily doses of up to 5 g for 29 days is not toxic to humans, and daily doses of 0.5 or 1 g produce levels of resveratrol in tumor cells that are sufficient to elicit anticancer effects such as induction of apoptosis in cancer cells (88).…”

Susceptibility of Lung Cancer with Polymorphisms of CYP1A1, GSTM1, GSTM3, GSTT1 and GSTP1 Genotypes in the Population of Inner Mongolia Region

“…The genetic constitution seems to play the key role in this context with an increased number of xenobiotic metabolizing enzymes, such as GSTs and CYPs, have been shown to be polymorphic (Chow et al, 2010;Malik et al, 2010).…”