Differential inhibition of human cytochrome P450 enzymes by "-viniferin, the dimer of resveratrol: comparison with resveratrol and polyphenols from alcoholized beverages

E-Viniferin, a dimer of resveratrol, was isolated in wine at concentration between 0.5 and 5 AM. As resveratrol and polyphenols from red wine were reported to inhibit cytochrome P450 (CYP)activities, this led us to investigate the inhibitory effects of "-viniferin on human CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2E1, CYP3A4 and CYP4A activities. These effects were compared to those of resveratrol and non volatiles compounds from red wine or various CognacR beverages (enriched with oak-polyphenols). Assays were carried out on human liver microsomes and heterologously expressed CYPs. Ethoxyresorufin, coumarin, benzoxyresorufin, chlorzoxazone, testosterone and lauric acid were used as selective substrates for CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2E1, CYP3A4 and CYP4A, respectively. "-viniferin displayed a more potent inhibitory effect than resveratrol for all the CYP activities tested (Ki 0.5 to 20 AM vs. 10 to 100 AM, respectively). This effect was not due to an inhibition of the NADPH reductase. A particularly potent inhibitory effect was shown for CYP1A1, CYP1B1 and CYP2B6 which are involved in bioactivation of numerous carcinogens. "-viniferin was not a mechanism-based inhibitor of human CYPs. It displayed, like resveratrol, mixed-type inhibitions for all the CYP tested, except for CYP2E1 (non-competitive). Comparison of the inhibitory effects exerted on CYP activities by "-viniferin , resveratrol and non volatile components from red wine or various Cognac beverages showed that neither resveratrol, nor "-viniferin is the main CYP inhibitor present in red wine solids.