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Chimeric mice with humanized livers: a unique tool for in vivo and in vitro enzyme induction studies Kakuni M; Yamasaki C; Tachibana A; Yoshizane Y; Ishida Y; Tateno CInt J Mol Sci 2013[Dec]; 15 (1): 58-74We performed in vivo and in vitro studies to determine the induction of human cytochrome P450 (CYP) using chimeric mice with humanized liver (PXB-mice(R)) and human hepatocytes isolated from the PXB-mice (PXB-cells), which were derived from the same donor. For the in vivo study, PXB-mice were injected with 3-methylcholanthrene (3-MC, 2 or 20 mg/kg) or rifampicin (0.1 or 10 mg/kg) for four days. For the in vitro study, PXB-cells were incubated with 3-MC (10, 50, or 250 ng/mL) or with rifampicin (5 or 25 mug/mL). The CYP1A1 and 1A2, and CYP3A4 mRNA expression levels increased significantly in the PXB-mouse livers with 20 mg/kg of 3-MC (Cmax, 12.2 ng/mL), and 10 mg/kg rifampicin (Cmax, 6.9 microg/mL), respectively. The CYP1A1 mRNA expression level increased significantly in PXB-cells with 250 ng/mL of 3-MC, indicating lower sensitivity than in vivo. The CYP1A2 and CYP3A4 mRNA expression levels increased significantly with 50 ng/mL of 3-MC, and 5 mug/mL of rifampicin, respectively, which indicated that the sensitivities were similar between in vivo and in vitro studies. In conclusion, PXB-mice and PXB-cells provide a robust model as an intermediate between in vivo and in vitro human metabolic enzyme induction studies.|Animals[MESH]|Chimera[MESH]|Cytochrome P-450 CYP1A1/*biosynthesis/genetics[MESH]|Cytochrome P-450 CYP1A2/*biosynthesis/genetics[MESH]|Cytochrome P-450 CYP3A/*biosynthesis/genetics[MESH]|Enzyme Induction[MESH]|Half-Life[MESH]|Hepatocytes/*enzymology[MESH]|Humans[MESH]|Immunohistochemistry[MESH]|Keratin-18/metabolism[MESH]|Keratin-8/metabolism[MESH]|Liver/*enzymology[MESH]|Methylcholanthrene/pharmacokinetics[MESH]|Mice[MESH]|RNA, Messenger/metabolism[MESH]|Rifampin/pharmacokinetics[MESH] |
