title: Current status of prediction of drug disposition and toxicity in humans using chimeric mice with humanized liver.
abstract: 1. Human-chimeric mice with humanized liver have been constructed by transplantation of human hepatocytes into several types of mice having genetic modifications that injure endogenous liver cells. Here, we focus on liver urokinase-type plasminogen activator-transgenic severe combined immunodeficiency (uPA/SCID) mice, which are the most widely used human-chimeric mice. Studies so far indicate that drug metabolism, drug transport, pharmacological effects and toxicological action in these mice are broadly similar to those in humans. 2. Expression of various drug-metabolizing enzymes is known to be different between humans and rodents. However, the expression pattern of cytochrome P450, aldehyde oxidase and phase II enzymes in the liver of human-chimeric mice resembles that in humans, not that in the host mice. 3. Metabolism of various drugs, including S-warfarin, zaleplon, ibuprofen, naproxen, coumarin, troglitazone and midazolam, in human-chimeric mice is mediated by human drug-metabolizing enzymes, not by host mouse enzymes, and thus resembles that in humans. 4. Pharmacological and toxicological effects of various drugs in human-chimeric mice are also similar to those in humans. 5. The current consensus is that chimeric mice with humanized liver are useful to predict drug metabolism catalyzed by cytochrome P450, aldehyde oxidase and phase II enzymes in humans in vivo and in vitro. Some remaining issues are discussed in this review.
authors: Department of Environmental Science, Nihon Pharmaceutical University , Saitama , Japan and.
authors: Shigeyuki
authors: S
authors: Kitamura
authors: Kazumi
authors: K
authors: Sugihara
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology; D042931:Aldehyde Oxidase / Q000378:metabolism; D000818:Animals; D002678:Chimera; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D006505:Hepatitis / Q000821:virology; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics; D014859:Warfarin / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000081:Acetamides; D004364:Pharmaceutical Preparations; D011743:Pyrimidines; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D042931:Aldehyde Oxidase; D014568:Urokinase-Type Plasminogen Activator; C085665:zaleplon