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

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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.