, Haulikova 6, 10 000, Zagreb, Croatia.
College of Pharmacy and Health Sciences, Lipscomb University, Nashville, TN, 37204, USA.
Arch Toxicol. 2022 Aug;96(8):2145-2246. doi: 10.1007/s00204-022-03304-3. Epub 2022 Jun 1.
This is an overview of the metabolic reactions of drugs, natural products, physiological compounds, and other (general) chemicals catalyzed by flavin monooxygenase (FMO), monoamine oxidase (MAO), NAD(P)H quinone oxidoreductase (NQO), and molybdenum hydroxylase enzymes (aldehyde oxidase (AOX) and xanthine oxidoreductase (XOR)), including roles as substrates, inducers, and inhibitors of the enzymes. The metabolism and bioactivation of selected examples of each group (i.e., drugs, "general chemicals," natural products, and physiological compounds) are discussed. We identified a higher fraction of bioactivation reactions for FMO enzymes compared to other enzymes, predominately involving drugs and general chemicals. With MAO enzymes, physiological compounds predominate as substrates, and some products lead to unwanted side effects or illness. AOX and XOR enzymes are molybdenum hydroxylases that catalyze the oxidation of various heteroaromatic rings and aldehydes and the reduction of a number of different functional groups. While neither of these two enzymes contributes substantially to the metabolism of currently marketed drugs, AOX has become a frequently encountered route of metabolism among drug discovery programs in the past 10-15 years. XOR has even less of a role in the metabolism of clinical drugs and preclinical drug candidates than AOX, likely due to narrower substrate specificity.
这是一个概述的药物代谢反应，天然产物，生理化合物，和其他（一般）化学品的黄素单加氧酶（FMO），单胺氧化酶（MAO），NAD（P）H醌氧化还原酶（NQO），和钼羟化酶（醛氧化酶（AOX）和黄嘌呤氧化还原酶（XOR）），包括作为底物，酶的诱导剂和抑制剂的作用。讨论了每个组（即药物，“一般化学品”，天然产物和生理化合物）的选定示例的代谢和生物活化。我们发现与其他酶相比，FMO 酶的生物活化反应比例更高，主要涉及药物和一般化学品。MAO 酶以生理化合物为主要底物，一些产物会导致不良副作用或疾病。AOX 和 XOR 酶是钼羟化酶，可催化各种杂芳环和醛的氧化以及许多不同官能团的还原。虽然这两种酶都不会对目前市售药物的代谢产生重大影响，但在过去 10-15 年中，AOX 已成为药物发现计划中经常遇到的代谢途径。与 AOX 相比，XOR 在临床药物和临床前药物候选物的代谢中作用更小，可能是由于底物特异性较窄。
