Oxidative metabolism is one of the major biotransformation reactions that regulates the exposure of xenobiotics and their metabolites in the circulatory system and local tissues and organs, and influences their efficacy and toxicity. Although cytochrome (CY)P450s play critical roles in the oxidative reaction, extensive CYP450-independent oxidative metabolism also occurs in some xenobiotics, such as aldehyde oxidase, xanthine oxidoreductase, flavin-containing monooxygenase, monoamine oxidase, alcohol dehydrogenase, or aldehyde dehydrogenase-dependent oxidative metabolism. Drugs form a large portion of xenobiotics and are the primary target of this review. The common reaction mechanisms and roles of non-CYP450 enzymes in metabolism, factors affecting the expression and activity of non-CYP450 enzymes in terms of inhibition, induction, regulation, and species differences in pharmaceutical research and development have been summarized. These non-CYP450 enzymes are detoxifying enzymes, although sometimes they mediate severe toxicity. Synthetic or natural chemicals serve as inhibitors for these non-CYP450 enzymes. However, pharmacokinetic-based drug interactions through these inhibitors have rarely been reported in vivo. Although multiple mechanisms participate in the basal expression and regulation of non-CYP450 enzymes, only a limited number of inducers upregulate their expression. Therefore, these enzymes are considered non-inducible or less inducible. Overall, this review focuses on the potential xenobiotic factors that contribute to variations in gene expression levels and the activities of non-CYP450 enzymes.

氧化代谢是调节外源性物质及其代谢物在循环系统和局部组织器官中的暴露并影响其疗效和毒性的主要生物转化反应之一。尽管细胞色素 (CY)P450 在氧化反应中起关键作用，但在一些外源性物质中也会发生广泛的 CYP450 非依赖性氧化代谢，例如醛氧化酶、黄嘌呤氧化还原酶、含黄素的单加氧酶、单胺氧化酶、醇脱氢酶或醛脱氢酶依赖性氧化代谢。药物构成了外源性物质的很大一部分，是本次审查的主要目标。非CYP450酶在代谢中的常见反应机制和作用，影响非CYP450酶在抑制、诱导、调节等方面表达和活性的因素，总结了药物研发中的物种差异。这些非 CYP450 酶是解毒酶，尽管有时它们会介导严重的毒性。合成或天然化学品可作为这些非 CYP450 酶的抑制剂。然而，很少报道通过这些抑制剂进行的基于药代动力学的药物相互作用在体内。尽管多种机制参与了非 CYP450 酶的基础表达和调节，但只有有限数量的诱导剂上调了它们的表达。因此，这些酶被认为是不可诱导的或不太可诱导的。总体而言，本综述重点关注导致基因表达水平和非 CYP450 酶活性变化的潜在异生因素。