非P450酶介导的药物氧化代谢研究进展

Research advances in non-P450-mediated drug oxidative metabolism

常见的催化药物氧化代谢的非P450酶包括黄素单氧化酶(FMO)、单胺氧化酶(MAO)、醛氧化酶(AO)、黄嘌呤氧化酶(XO)、乙醇脱氢酶(ADH)和乙醛脱氢酶(ALDH)。近年来,它们在药物氧化代谢中的作用越来越受到重视。但是,由于在药物发现和先导化合物优化过程中通常使用P450酶相关的体外模型进行代谢研究,非P450酶在药物氧化代谢中的贡献往往被低估。本文综述了以上非P450酶的催化反应类型、常见底物、基因多态性以及药物相互作用,并总结了非P450酶介导药物氧化代谢的体外研究模型及影响因素。与P450酶类似,非P450酶可以直接催化药物发生氧化代谢,产生具有治疗活性的代谢物或者毒性代谢物。这类酶也可以进一步氧化经P450酶催化产生的毒性代谢物,发挥解毒作用。与P450酶相比,大部分非P450酶(如FMO和MAO)不容易被诱导。

The major non-P450 enzymes involved in the oxidative metabolism of drugs are： the flavin- containing monooxygenase （FMO）, the monoamine oxidase （MAO）, the aldehyde oxidase （AO）, the xanthine oxidase （XO）, the alcohol dehydrogenase （ADH） and the aldehyde dehydrogenase （ALDH）. In recent years, the role of non-P450 enzymes in drug oxidative metabolism has garnered increasing attention. However, the contribution of non-P450 enzymes to the drug oxidative metabolism is possibly underestimated in many cases, as most metabolism studies in drug discovery and lead optimization are conducted using in vitro test systems related to P450 enzymes. In this article, these non-P450 enzymes in terms of catalyzed reaction types, common substrates, gene polymorphism and drug interaction are reviewed, and the in vitro models and factors for non-P450-mediated oxidative metabolism are summarized. Similar to P450 enzymes, non-P450 enzymes can directly catalyze the oxidation of drugs, yielding therapeutically active metabolites or toxic metabolites. These enzymes can also oxidize the toxic metabolites, generated from P450-catalyzed reaction, to nontoxic metabolites. In general, most non-P450 enzymes （such as FMO and MAO） appear to be much less inducible than P450 enzymes.