TY - JOUR T1 - Species Specificity and Selection of Models for Drug Oxidations Mediated by Polymorphic Human Enzymes JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 123 LP - 129 DO - 10.1124/dmd.121.000742 VL - 51 IS - 1 AU - Hiroshi Yamazaki AU - Makiko Shimizu Y1 - 2023/01/01 UR - http://dmd.aspetjournals.org/content/51/1/123.abstract N2 - 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.SIGNIFICANCE STATEMENT Drug oxidations in animals and humans mediated by P450s and FMOs are important for understanding the pharmacological properties of drugs, such as the species-dependent teratogenicity of the reactive metabolites of thalidomide and the metabolism of food-derived odorous trimethylamine to non-odorous (but proatherogenic) trimethylamine N-oxide. Recognized differences exist in terms of drug metabolism between rodents, non-human primates, and humans, and such differences are important when determining individual liver enzyme contributions with substrates in in vitro and in vivo systems. ER -