Species Specificity and Selection of Models for Drug Oxidations Mediated by Polymorphic Human Enzymes

Abstract

Many drug oxygenations are mainly mediated by polymorphic cytochromes P450 (P450s) and also by flavin-containing monooxygenases (FMOs). More than 50 years of research on P450/FMO-mediated drug oxygenations have clarified their catalytic roles. The natural product coumarin causes hepatotoxicity in rats via the reactive coumarin 3,4-epoxide, a reaction catalyzed by P450 1A2; however, coumarin undergoes rapid 7-hydroxylation by polymorphic P450 2A6 in humans. The primary oxidation product of the teratogen thalidomide in rats is deactivated 5′-hydroxythalidomide plus sulfate and glucuronide conjugates; however, similar 5′-hydroxythalidomide and 5-hydroxythalidomide are formed in rabbits in vivo. Thalidomide causes human P450 3A enzyme induction in liver (and placenta) and is also activated in vitro and in vivo by P450 3A through the primary human metabolite 5-hydroxythalidomide (leading to conjugation with glutathione/nonspecific proteins). Species differences exist in terms of drug metabolism in rodents and humans, and such differences can be very important when determining the contributions of individual enzymes. The approaches used for investigating the roles of human P450 and FMO enzymes in understanding drug oxidations and clinical therapy have not yet reached maturity and still require further development.

Variants of Flavin-Containing Monooxygenase 3 Found in Subjects in an Updated Database of Genome Resources

“…Drug oxidation reactions in humans are mainly catalyzed by cytochrome P450 (P450, EC 1.14.14.1) and flavin-containing monooxygenase (FMO) enzymes (Rendic et al, 2022;Yamazaki and Shimizu, 2023). Genetic variations in these drug-metabolizing enzymes may result in altered pharmacokinetics and unexpected therapeutic responses (Guengerich, 2023).…”

Special Section on Perspectives on Drug Metabolism and Disposition, Part I—Editorial

“…The "Perspectives on Drug Metabolism and Disposition" special section features articles contributed by the current associate editors of Drug Metabolism and Disposition (DMD) to the 50 th Anniversary Celebration Collection (Ding, 2023). The Collection already includes a number of articles (Ding, 2023;Gillam and Kramlinger, 2023;Guengerich, 2023;Isin, 2023;McColl et al, 2023;Morgan et al, 2023;Roberts et al, 2023;Yamazaki and Shimizu, 2023), with many more to come.…”