Intersection of the Roles of Cytochrome P450 Enzymes with Xenobiotic and Endogenous Substrates: Relevance to Toxicity and Drug Interactions.
Intersection of the Roles of Cytochrome P450 Enzymes with Xenobiotic and Endogenous Substrates: Relevance to Toxicity and Drug Interactions.
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DOI：
10.1021/acs.chemrestox.6b00226
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发表时间：
2017-01-17
影响因子：
4.1
通讯作者：
Guengerich FP
中科院分区：
文献类型：
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作者：
Guengerich FP
今天，人们对细胞色素P450（P450）酶及其催化特异性了解很多，但每种酶催化的反应范围仍然令人惊讶。历史上，P450被认为参与外源性物质或内源性化学物质的代谢，在前一种情况下发挥一般的保护作用，在后一种情况下发挥确定的生理作用。然而，分界线有时是模糊的。在药物设计中很难做到完全特异性，一些参与类固醇和维生素代谢的P450可能会脱靶。在许多情况下，已经开发了作用于这些P450中的一些作为主要靶标的药物，例如，类固醇芳香酶抑制剂。参与内源性底物代谢的几种P450比以前认为的特异性更低，并氧化几种相关结构。一些主要氧化内源性化学物质的P450已被证明可以氧化异生物质化学物质，即使在生物活化模式下。
Today much is known about cytochrome P450 (P450) enzymes and their catalytic specificity, but the range of reactions catalyzed by each still continues to surprise. Historically P450s had been considered to be involved in either the metabolism of xenobiotics or endogenous chemicals, in the former case playing a generally protective role and in the latter case a defined physiological role. However, the line of demarcation is sometimes blurred. It is difficult to be completely specific in drug design, and some P450s involved in the metabolism of steroids and vitamins can be off-targets. In a number of cases, drugs have been developed that act on some of those P450s as primary targets, e.g., steroid aromatase inhibitors. Several of the P450s involved in the metabolism of endogenous substrates are less specific than once thought and oxidize several related structures. Some of the P450s that primarily oxidize endogenous chemicals have been shown to oxidize xenobiotic chemicals, even in a bioactivation mode.