Resveratrol, a red wine constituent, is a mechanism-based inactivator of cytochrome P450 3A4
Resveratrol, a red wine constituent, is a mechanism-based inactivator of cytochrome P450 3A4
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DOI：
10.1016/s0024-3205(00)00888-2
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发表时间：
2000-11-10
期刊：
影响因子：
6.1
通讯作者：
Delucchi, AB
中科院分区：
文献类型：
--
作者：
Chan, WK;Delucchi, AB
白藜芦醇是一种在红酒中发现的植物抗毒素，已被证明具有抗氧化和抗突变特性。将白藜芦醇与含有杆状病毒衍生的人细胞色素 P450 3A4 (CYP3A4) 和 NADPH-细胞色素 P450 还原酶的 Sf9 昆虫微粒体一起孵育，结果表明，白藜芦醇以时间和 NADPH 依赖性方式灭活 CYP3A4。白藜芦醇、红霉素和醋竹桃霉素以相似的速率灭活 CYP3A4（如 k(inact) 所示），而与 CYP3A4 的结合亲和力（如 K-I 所示）的顺序为：醋竹桃霉素 > 红霉素 > 白藜芦醇，（K-I 和 k(inact) 对于 CYP3A4 灭活的影响 白藜芦醇、红霉素和醋竹桃霉素分别为 20 μM 和 0.20 min(-1)、5.3 μM 和 0.12 min(-1) 以及 0.18 μM 和 0.15 min(-1)。红酒的分馏研究表明，不含白藜芦醇的分馏物显着灭活了 CYP3A4。此外，研究中使用的红酒中的白藜芦醇含量太低，无法解释红酒处理后观察到的 CYP3A4 失活程度。使用多种红酒类型进行的灭活研究表明，CYP3A4 灭活与其白藜芦醇含量无关。总之，这里的数据表明白藜芦醇是一种有效的基于机制的 CYP3A4 灭活剂；然而，它并不是红酒中导致 CYP3A4 失活的主要成分之一。然而，白藜芦醇灭活 CYP3A4 可能会导致与 CYP3A4 底物发生临床相关的药物相互作用。 (C) 2000 Elsevier Science Inc. 保留所有权利。
Resveratrol, a phytoalexin found in red wine, has been shown to possess antioxidant and antimutagenic properties. Incubation of resveratrol with Sf9 insect microsomes containing baculovirus-derived human cytochrome P450 3A4 (CYP3A4) and NADPH-cytochrome P450 reductase showed that resveratrol inactivated CYP3A4 in a time- and NADPH-dependent manner. Resveratrol, erythromycin 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(inact) for CYP3A4 inactivation by resveratrol, erythromycin and troleandomycin 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 fractions 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 wine 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-based inactivator of CYP3A4; however, it is not one of the main red wine constituents that are responsible for CYP3A4 inactivation by red wine. Nevertheless, inactivation of CYP3A4 by resveratrol may cause clinically relevant drug interactions with CYP3A4 substrates. (C) 2000 Elsevier Science Inc. All rights reserved.