Effect oftrans-resveratrol on 7-benzyloxy-4-trifluoromethylcoumarinO-dealkylation catalyzed by human recombinant CYP3A4 and CYP3A5

Abstract

Red wine concentrate has been reported to inhibit the catalytic activity of human recombinant cytochrome P450 (CYP) 3A4. Wine contains many polyphenolic compounds, including trans-resveratrol, which is also available commercially as a nutraceutical product. In the present study, we examined the in vitro effect of trans-resveratrol on human CYP3A catalytic activity by employing recombinant CYP3A4 and CYP3A5 as model enzymes and 7-benzyloxy-4-trifluoromethylcoumarin (BFC) as a CYP3A substrate. Trans-resveratrol inhibited BFC O-dealkylation catalyzed by CYP3A4 and CYP3A5 in a concentration-dependent manner. In each case, the inhibition was noncompetitive, as determined by Lineweaver-Burk and Dixon plots of the enzyme kinetic data. The apparent Kivalues (mean ± SEM) for the inhibition by trans-resveratrol of BFC O-dealkylation catalyzed by CYP3A4 and CYP3A5 were 10.2 ± 1.1 µM and 14.7 ± 0.3 µM, respectively. Preincubation of trans-resveratrol with NADPH and CYP3A4 or CYP3A5 for 10 or 15 min prior to initiation of substrate oxidation did not enhance the inhibitory effect, suggesting that this compound was not a mechanism-based inactivator of CYP3A4 or CYP3A5 when BFC was used as the substrate. Overall, our study provides the first demonstration that trans-resveratrol inhibits, in vitro, a substrate oxidation reaction catalyzed by human recombinant CYP3A4 and CYP3A5.Key words: 7-benzyloxy-4-trifluoromethylcoumarin, cytochrome P450, CYP3A4, CYP3A5, 7-hydroxy-4-trifluoromethylcoumarin, nutraceutical, trans-resveratrol.