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Received for publication July 6, 2004.
Revised September 13, 2004.
Accepted for publication September 14, 2004.
Recently, a chimeric mouse line in which the liver could be replaced by more than 80% with human hepatocytes was established in Japan. Because the chimeric mouse produces human albumin (hAlb), replacement by human hepatocytes could be estimated by the hAlb concentration in the blood of the chimeric mice. In this study, we investigated human major cytochrome P450 (CYP) in the livers of chimeric mice by mRNA, protein, and enzyme activity using real-time PCR, Western blot analysis, and HPLC, respectively. Chimeric mice with humanized liver generated using hepatocytes from a Japanese and Caucasian donor were used. Human CYP mRNAs were expressed in the liver of the chimeric mice, and major human CYP proteins such as CYP1A2, CYP2C9, and CYP3A4 were detected. The expression of CYP mRNA and protein was correlated with the hAlb concentration in the blood. The enzyme activities such as diclofenac 4'-hydroxylase activity, dexamethasone 6-hydroxylase activity, and coumarin 7-hydroxylase activity, activities that are specific to human CYP but not to murine Cyp, were increased in a hAlb concentration-dependent manner. The chimeric mice with nearly 90% replacement by human hepatocytes demonstrated almost the same protein contents of human CYPs and drug metabolizing enzyme activity as those of the donor. It was confirmed that genomic DNA from the livers of the chimeric mice and that from the liver of the donor exhibited the same genotype. In conclusion, the chimeric mice exhibited a similarly efficient capacity of drug metabolism as humans, suggesting that they could be a useful animal model for drug development.
Key words:
CYP expression, human CYP enzymes
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