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首页> 外文期刊>Biochemistry >Mechanism of Drug-Drug Interactions Mediated by Human Cytochrome P450 CYP3A4 Monomer
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Mechanism of Drug-Drug Interactions Mediated by Human Cytochrome P450 CYP3A4 Monomer

机译：人细胞色素P450 CYP3A4单体介导的药物相互作用的机理

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Using Nanodiscs, we quantitate, the heterotropic interaction between two different drugs mediated by monomeric CYP3A4 incorporated into a nativelike membrane environment. The mechanism of this interaction is deciphered by global analysis I of multiple-turnover: experiments performed under identical conditions using the pure substrates progesterone (PGS) and carbamazepine (CBZ) and their Mixtures. Activation of CBZ epoxidation and simultaneous inhibition of PGS hydroxylation are measured and quantitated through differences in their respective affinities for both a remote allosteric site and the productive catalytic site near the heme iron. Preferred binding of PGS at the allosteric site and a stronger preference for CBZ binding at the productive site give rise to a nontrivial drug drug interaction. Molecular dynamics simulations indicate functionally important conformational changes caused by PGS binding at the allosteric site and by two CBZ molecules positioned inside the substrate binding pocket. Structural changes involving Phe-213, Phe-219, and Phe-241 are thought to be responsible for the observed synergetic effects and positive allosteric interactions between these two substrates. Such a mechanism is likely of general relevante to the mutual heterotropic effects caused by biologically active compound that exhibit different patterns of interaction with the distinct allosteric and productive sites of CYP3A4, as well as other xenobiotic metabolizing cytochromes P450 that are also involved in drug drug interactions. Importantly, this work demonstrates that a monomeric CYP3A4 can display the full spectrum of activation and cooperative effects that are observed in hepatic membranes.
机译：使用纳米光盘，我们定量了两种不同药物之间的异质性相互作用，这些药物是通过掺入天然膜环境的单体CYP3A4介导的。这种相互作用的机制由多周转的全局分析I来解释：使用纯底物孕酮（PGS）和卡马西平（CBZ）及其混合物在相同条件下进行的实验。通过对远程变构位点和血红素铁附近的生产性催化位点各自的亲和力差异，对CBZ环氧化激活和PGS羟基化同时抑制进行了测量和定量。 PGS在变构位点的优选结合以及在生产位点更优先选择CBZ结合会引起非平凡的药物相互作用。分子动力学模拟表明，功能上重要的构象变化是由变构位点上的PGS结合以及位于底物结合口袋内的两个CBZ分子引起的。涉及Phe-213，Phe-219和Phe-241的结构变化被认为是这两种底物之间观察到的协同效应和正构构相互作用的原因。这种机制可能与由生物活性化合物引起的相互异向性效应有关，所述生物活性化合物与CYP3A4的不同变构位点和生产位点以及与药物代谢物相互作用也涉及的其他异种代谢细胞色素P450表现出不同的相互作用方式。重要的是，这项工作证明单体CYP3A4可以显示在肝膜中观察到的完整的活化和协同作用谱。

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