Non-cytochrome P450 enzymes involved in the oxidative metabolism of xenobiotics: Focus on the regulation of gene expression and enzyme activity

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 reactionmechanisms and roles of non-CYP450 enzymes inmetabolism, 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 theymediate 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. (c) 2021 Elsevier Inc. All rights reserved.

Automated summary

This review focuses on the role of oxidative metabolism in regulating the exposure and effects of xenobiotics and their metabolites. It discusses the involvement of non-CYP450 enzymes in the metabolism of drugs and summarizes the common reaction mechanisms, factors affecting enzyme expression and activity, and species differences. The review highlights the potential impact of xenobiotic factors on the gene expression levels and activities of non-CYP450 enzymes.