Resveratrol, a red wine constituent, is a mechanism-based inactivator of cytochrome P450 3A4

Resveratrol, a phytoalexin found in red wine, has been shown to possess ant ioxidant and antimutagenic properties. Incubation of resveratrol with Sf9 i nsect microsomes containing baculovirus-derived human cytochrome P450 3A4 ( CYP3A4) and NADPH-cytochrome P450 reductase showed that resveratrol inactiv ated CYP3A4 in a time- and NADPH-dependent manner. Resveratrol, erythromyci n and troleandomycin inactivated CYP3A4 at a similar rate (as reflected by k(inact)) whereas the binding affinity to CYP3A4 (as reflected by K-I) was in the order of: troleandomycin > erythromycin > resveratrol, (K-I and k(in act) for CYP3A4 inactivation by resveratrol, erythromycin and troleandomyci n are 20 muM and 0.20 min(-1), 5.3 muM and 0.12 min(-1) and 0.18 muM and 0. 15 min(-1), respectively.) Fractionation studies of red wine showed that fr actions that did not contain resveratrol inactivated CYP3A4 significantly. In addition, the resveratrol content in red wine used in the study was too low to account for the degree of CYP3A4 inactivation observed after red win e treatment. Inactivation studies using a variety of red wine types showed that the CYP3A4 inactivation did not correlate to their resveratrol content . In summary, data here showed that resveratrol is an effective mechanism-b ased inactivator of CYP3A4; however, it is not one of the main red wine con stituents that are responsible for CYP3A4 inactivation by red wine. Neverth eless, inactivation of CYP3A4 by resveratrol may cause clinically relevant drug interactions with CYP3A4 substrates. (C) 2000 Elsevier Science Inc. Al l rights reserved.