title: Chimeric mice with humanized livers: a unique tool for in vivo and in vitro enzyme induction studies.
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.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kakuni
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yamasaki
authors.forename: Asato
authors.initials: A
authors.lastname: Tachibana
authors.forename: Yasumi
authors.initials: Y
authors.lastname: Yoshizane
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishida
authors.affiliation: PhoenixBio Co., Ltd., 3-4-1, Kagamiyama, Higashihiroshima, Hiroshima 739-0046, Japan. chise.mukaidani@phoenixbio.co.jp.
authors.forename: Chise
authors.initials: C
authors.lastname: Tateno
mesh_terms: D000818:Animals; D002678:Chimera; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis* / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction; D006207:Half-Life; D022781:Hepatocytes / Q000201:enzymology*; D006801:Humans; D007150:Immunohistochemistry; D053538:Keratin-18 / Q000378:metabolism; D053533:Keratin-8 / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008748:Methylcholanthrene / Q000493:pharmacokinetics; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D012293:Rifampin / Q000493:pharmacokinetics
chemical_list: D053538:Keratin-18; D053533:Keratin-8; D012333:RNA, Messenger; D008748:Methylcholanthrene; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D012293:Rifampin