Niwa Toshiro, Murayama Norie, Yamazaki Hiroshi
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8583, Japan.
Curr Drug Metab. 2008 Jun;9(5):453-62. doi: 10.2174/138920008784746364.
Cytochrome P450s (P450 or CYPs) comprise a superfamily of enzymes that catalyze the oxidation of a wide variety of xenobiotic chemicals. Although most of P450 inhibitors decrease the metabolic activities mediated by the corresponding P450 forms, unexpected phenomena, which are called as activation or heterotropic cooperativity, have been often observed. We summarize Michaelis-Menten constants (K(m)), maximal velocities (V(max)), V(max)/K(m) (intrinsic clearance) values, and/or metabolic activities for 22 activators and 24 substrates (30 reactions) mainly mediated by CYP3A4 among human P450 forms. Although an allosteric mechanism has been invoked to explain the cooperativity, the activation patterns or phenomena are dependent on substrates and selected enzyme sources in vitro. Interestingly, recent studies have been shown that human P450 forms other than CYP3A4, such as CYP1A2, CYP2C8, CYP2C9, CYP2D6, and CYP3A7, are also activated by some compounds, whereas there are few reports on CYP3A5. Several models describing interaction among substrates, effectors, and enzymes have been proposed, however, the detailed mechanism for the activation is still generally unknown even though some crystal structures have been shown. A few cases of the cooperativity of CYP3A in experimental animals have been presented, whereas the clinical significance of P450 cooperativity is still unclear. The collective findings provide fundamental and useful information for the activation of P450s by chemicals despite some contradictive kinetic parameters for the same reactions reported. To understand causal factor(s) and mechanism(s) for such different reports summarized here is still one of the hot research topics to be solved in current activation reactions.
细胞色素P450（P450或CYPs）是一类酶的超家族，可催化多种外源性化学物质的氧化反应。尽管大多数P450抑制剂会降低相应P450形式介导的代谢活性，但经常会观察到一些意外现象，即所谓的激活或异源协同作用。我们总结了主要由人P450形式中的CYP3A4介导的22种激活剂和24种底物（30个反应）的米氏常数（K(m)）、最大反应速度（V(max)）、V(max)/K(m)（内在清除率）值和/或代谢活性。尽管已提出变构机制来解释协同作用，但激活模式或现象在体外取决于底物和所选的酶来源。有趣的是，最近的研究表明，除CYP3A4外的其他人P450形式，如CYP1A2、CYP2C8、CYP2C9、CYP2D6和CYP3A7，也会被某些化合物激活，而关于CYP3A5的报道很少。已经提出了几种描述底物、效应物和酶之间相互作用的模型，然而，尽管已经展示了一些晶体结构，但激活的详细机制通常仍然未知。实验动物中已出现了一些CYP3A协同作用的案例，而P450协同作用的临床意义仍不清楚。尽管对于相同反应报道了一些相互矛盾的动力学参数，但这些总体研究结果为化学物质激活P450提供了基础且有用的信息。理解此处总结的此类不同报道的因果因素和机制仍然是当前激活反应中有待解决的热门研究课题之一。
