Roles of selected non-P450 human oxidoreductase enzymes in protective and toxic effects of chemicals: review and compilation of reactions.

Abstract

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.