Abstract: We performed in vivo and in vitro studies to determine the induction of human cytochrome P450 (CYP) using chimeric mice with humanized liver (PXB-mice®) 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 μg/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 µg/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 μg/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.
Keywords: liver; P450 induction; humanized animal model; rifampicin; 3-methylcholanthrene
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Kakuni, M.; Yamasaki, C.; Tachibana, A.; Yoshizane, Y.; Ishida, Y.; Tateno, C. Chimeric Mice with Humanized Livers: A Unique Tool for in Vivo and in Vitro Enzyme Induction Studies. Int. J. Mol. Sci. 2014, 15, 58-74.
Kakuni M, Yamasaki C, Tachibana A, Yoshizane Y, Ishida Y, Tateno C. Chimeric Mice with Humanized Livers: A Unique Tool for in Vivo and in Vitro Enzyme Induction Studies. International Journal of Molecular Sciences. 2014; 15(1):58-74.
Kakuni, Masakazu; Yamasaki, Chihiro; Tachibana, Asato; Yoshizane, Yasumi; Ishida, Yuji; Tateno, Chise. 2014. "Chimeric Mice with Humanized Livers: A Unique Tool for in Vivo and in Vitro Enzyme Induction Studies." Int. J. Mol. Sci. 15, no. 1: 58-74.