RT Journal Article SR Electronic T1 Development of Murine Cyp3a Knockout Chimeric Mice with Humanized Liver JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1208 OP 1217 DO 10.1124/dmd.115.063479 VO 43 IS 8 A1 Kota Kato A1 Masato Ohbuchi A1 Satoko Hamamura A1 Hiroki Ohshita A1 Yasuhiro Kazuki A1 Mitsuo Oshimura A1 Koya Sato A1 Naoyuki Nakada A1 Akio Kawamura A1 Takashi Usui A1 Hidetaka Kamimura A1 Chise Tateno YR 2015 UL http://dmd.aspetjournals.org/content/43/8/1208.abstract AB We developed murine Cyp3a knockout (KO) chimeric mice with humanized liver expressing human P450s similar to those in humans and whose livers and small intestines do not express murine Cyp3a. This approach may overcome effects of residual mouse metabolic enzymes like Cyp3a in conventional chimeric mice with humanized liver, such as PXB-mice [urokinase plasminogen activator/severe combined immunodeficiency (uPA/SCID) mice repopulated with over 70% human hepatocytes] to improve the prediction of drug metabolism and pharmacokinetics in humans. After human hepatocytes were transplanted into Cyp3a KO/uPA/SCID host mice, human albumin levels logarithmically increased until approximately 60 days after transplantation, findings similar to those in PXB-mice. Quantitative real-time–polymerase chain reaction analyses showed that hepatic human P450s, UGTs, SULTs, and transporters mRNA expression levels in Cyp3a KO chimeric mice were also similar to those in PXB-mice and confirmed the absence of Cyp3a11 mRNA expression in mouse liver and intestine. Findings for midazolam and triazolam metabolic activities in liver microsomes were comparable between Cyp3a KO chimeric mice and PXB-mice. In contrast, these activities in the intestine of Cyp3a KO chimeric mice were attenuated compared with PXB-mice. Owing to the knockout of murine Cyp3a, hepatic Cyp2b10 and 2c55 mRNA levels in Cyp3a KO/uPA/SCID mice (without hepatocyte transplants) were 8.4- and 61-fold upregulated compared with PXB-mice, respectively. However, human hepatocyte transplantation successfully restored Cyp2b10 level nearly fully and Cyp2c55 level partly (still 13-fold upregulated) compared with those in PXB-mice. Intestinal Cyp2b10 and 2c55 were also repressed by human hepatocyte transplantation in Cyp3a KO chimeric mice.