Abstract
Humanized-liver mice are attractive experimental models for drug metabolism and toxicological studies. Although chimeric mouse livers express multiple drug-metabolizing enzymes, including cytochrome P450 (P450), UDP-glucuronosyltransferase, and aldehyde oxidase, their drug-metabolizing activities have not been comprehensively analyzed. In this study, we conducted in vitro metabolic assays to characterize hepatic drug-metabolizing enzyme activity in humanized-liver mice. Human and humanized-liver mice exhibited similar hepatic microsomal coumarin 7-hydroxylation and flurbiprofen 4'-hydroxylation activities. In contrast, the regioselectivity of propafenone hydroxylation catalyzed by P450 2D enzymes differed between humans and mice, with chimeric mouse liver microsomes preferentially catalyzing propafenone 4'-hydroxylation similar to mouse liver microsomes. Unique human olanzapine N10-glucuronidation activity was detected in chimeric mouse liver microsomes. In addition, SGX523 is metabolized by chimeric mouse liver cytosol to the less soluble 2-quinolinone metabolite that is likely involved in the clinically observed obstructive nephropathy. Interestingly, in the kidneys of humanized-liver mice receiving repeated orally administered SGX523, we observed amorphous material accumulation in the renal tubules and inflammatory cell infiltration. Over all, the hepatic drug-metabolizing enzyme activities are similar in humans and humanized-liver mice. Understanding the hepatic drug-metabolizing potential of humanized-liver mice can enhance their effective use in drug development.
