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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Effect of trans-resveratrol on 7-benzyloxy-4-trifluoromethylcoumarin O-dealkylation catalyzed by human recombinant CYP3A4 and CYP3A5.
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Effect of trans-resveratrol on 7-benzyloxy-4-trifluoromethylcoumarin O-dealkylation catalyzed by human recombinant CYP3A4 and CYP3A5.

机译：反式白藜芦醇对人重组CYP3A4和CYP3A5催化的7-苄氧基-4-三氟甲基香豆素O-脱烷基的影响。

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摘要

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 Ki values (mean +/- SEM) for the inhibition by trans-resveratrol of BFC O-dealkylation catalyzed by CYP3A4 and CYP3A5 were 10.2+/-1.1 microM and 14.7+/-0.3 microM, 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.
机译：据报道，浓缩红酒可抑制人重组细胞色素P450（CYP）3A4的催化活性。葡萄酒中含有许多多酚类化合物，包括反式白藜芦醇，也可以作为营养产品在市场上买到。在本研究中，我们通过使用重组CYP3A4和CYP3A5作为模型酶和7-苄氧基-4-三氟甲基香豆素（BFC）作为CYP3A底物，研究了反式白藜芦醇对人CYP3A催化活性的体外作用。反式白藜芦醇以浓度依赖的方式抑制CYP3A4和CYP3A5催化的BFC O-脱烷基。在每种情况下，抑制作用都是非竞争性的，这由酶动力学数据的Lineweaver-Burk和Dixon图确定。反式白藜芦醇对CYP3A4和CYP3A5催化的BFC O-脱烷基化抑制的表观Ki值（平均值+/- SEM）分别为10.2 +/- 1.1 microM和14.7 +/- 0.3 microM。在底物氧化开始前，将反式白藜芦醇与NADPH和CYP3A4或CYP3A5预温育10或15分钟不会增强抑制作用，这表明当将BFC用作CYP3A4或CYP3A5时，该化合物不是基于机理的灭活剂。基质。总体而言，我们的研究首次证明了反白藜芦醇在体外抑制人重组CYP3A4和CYP3A5催化的底物氧化反应。

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