Drug Metabolism and Toxicity in Chimeric Mice with Humanized Liver

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The cytochrome P450 (P450, CYP) enzyme superfamily is associated with the metabolism of drugs, environmental pollutants and endogenous substrates with broad overlapping substrate specificities. In addition, species differences between experimental animals and humans in the roles of P450 enzymes in drug metabolism are determinant factors in the drug discovery process. The induction and inhibition of P450-dependent metabolism, especially in the case of P450 3A enzyems, can cause serious problems in clinical practice and in the attrition of drug candidates because of adverse toxicology or pharmacokinetics. Recently, chimeric mice whose livers have been replaced to a level of 80% or more with human hepatocytes were established using urokinase-type plasminogen activator transgenic/severe combined immunodeficiency (uPA/SCID) mice. In the livers of these chimeric mice, hepatic cords and sinusoid-like structures were observed. Moreover, bile canaliculi associated with human hepatocytes were also detected. The mRNA expressions derived from humans of 52 phase I and 26 phase II enzymes (including 20 P450 s) and 21 transporters were ascertained in the chimeric mice liver. Taken together, these chimeric mice exhibited the glutathione conjugate form of a possible quinine-imine metabolite and responded to treatment with rifampicin or rifabutin by induction of P450 3A enzyems. This animal model should prove to be a good in vivo tool to assess the safety of drug candidates in terms of toxicity and drug-drug interactions caused by P450 induction.