Cytochrome P450s in chimeric mice with humanized liver.

Shotaro Uehara, Hiroshi Suemizu, Hiroshi Yamazaki

Advances in pharmacology (San Diego, Calif.) 2022

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Chimeric mice with humanized livers (humanized liver mice) are attractive experimental animal models for drug metabolism and pharmacokinetic studies. The "humanized liver" is a mature and functional liver with zonal position-specific expressions of human cytochrome P450 (P450) enzymes and a global gene expression pattern consistent with that of the mature human liver. Most P450-dependent drug oxidation activities were comparable between microsomes from livers of human and humanized liver mice based on similar expression levels of human P450 enzymes; however, some differences were observed between the two species, including considerable variations in activities of bufuralol 1'-hydroxylation and propafenone 4'-hydroxylation. Human disproportionate and/or unique metabolites of P450 substrate drugs were produced in humanized liver mice. Plasma concentration profiles of typical P450 substrate drugs in humans could be extrapolated from the corresponding data in humanized liver mice using simplified physiologically based pharmacokinetic modeling. Drug-drug interaction-mediated hepatic human CYP3A/2C induction by rifampicin (a human pregnane X receptor agonist) was observed in humanized liver mice. The major role of human CYP2C9 in in vivo diclofenac 4'-hydroxylation were determined using human CYP2C9-inactivated chimeric mice using a mechanism-based inhibitor, tienilic acid. Overall, based on the functional characteristics of hepatic human P450 enzymes, humanized liver mice are valuable experimental animals for studying metabolite profiling, pharmacokinetics, and drug interactions. Copyright © 2022 Elsevier Inc. All rights reserved.

Citation

Shotaro Uehara, Hiroshi Suemizu, Hiroshi Yamazaki. Cytochrome P450s in chimeric mice with humanized liver. Advances in pharmacology (San Diego, Calif.). 2022;95:307-328