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To ascertain MAPK whether such interactions might be a potential problem for resveratrol, the effect of once daily dosing on the activity of drug and carcinogen metabolizing enzymes, phase I cytochrome P450s plus the conjugating enzymes glutathione S-transferase (GST) and UDP-glucuronosyl transferase (UGT) 1A1, was investigated in healthy volunteers.20 Subjects received resveratrol (1 g daily) for 4 weeks and when pre and post intervention activities were compared resveratrol was found to significantly inhibit the phenotypic indices of plasma CYP3A4, 2D6 and 2C9, while inducing 1A2. In addition, in subjects with low baseline values, intervention was associated with an induction of GST-�� protein expression and UGT1A1 activity. Inhibition of CYP3A4 and 2C9 in particular, which metabolize a broad range of drugs, could lead to elevated plasma concentrations and increased likelihood of toxicity. The authors therefore acknowledged that although the enzyme modulation observed could be one of the mechanisms through which resveratrol inhibits carcinogenesis, doses of less than 1 g should be evaluated in future trials to minimize adverse drug interactions.20 A further demonstration EPZ5676 mouse of the capability of resveratrol to alter physiological parameters in humans was shown in a randomized double-blind placebo-controlled crossover study.29 Single oral doses of resveratrol (250 or 500 mg) were associated with a dose-dependent pattern of higher cerebral blood flow in the prefrontal cortex during task performance, find more as indexed by total concentrations of hemoglobin. This is the first indication that resveratrol can alter cerebral blood flow variables in humans and supports additional research on its effects on brain function. It is extremely encouraging for the future clinical development of resveratrol that doses of up to 5 g/day, taken for a month, are safe and reasonably well-tolerated. However, it seems likely that the occurrence of dose-related mild to moderate side effects, coupled with the ability of resveratrol to alter the activity of drug metabolizing enzymes, will limit the dosage employed in future studies to
