Humanization of Excretory Pathway in Chimeric Mice with Humanized Liver

• Published in: Toxicological sciences Vol. 97; no. 2; pp. 533 - 538
• Main Authors: Okumura, Hirotoshi, Katoh, Miki, Sawada, Toshiro, Nakajima, Miki, Soeno, Yoshinori, Yabuuchi, Hikaru, Ikeda, Toshihiko, Tateno, Chise, Yoshizato, Katsutoshi, Yokoi, Tsuyoshi
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.06.2007
• Subjects: Animals; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - toxicity; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; biliary excretion; Cefmetazole - pharmacokinetics; Cefmetazole - toxicity; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - pathology; CMZ; Feces - chemistry; Hepatocytes - physiology; Humans; Liver - cytology; Liver - physiology; Mice; Mice, Inbred ICR; Mice, SCID; Mice, Transgenic - physiology; Pharmaceutical Preparations - metabolism; renal excretion; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; transporter; Urokinase-Type Plasminogen Activator - genetics; CMZ; renal excretion; biliary excretion; transporter
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfm041

The liver of a chimeric urokinase-type plasminogen activator (uPA)+/+/severe combined immunodeficient (SCID) mouse line recently established in Japan could be replaced by more than 80% with human hepatocytes. We previously reported that the chimeric mice with humanized liver could be useful as a human model in studies on drug metabolism and pharmacokinetics. In the present study, the humanization of an excretory pathway was investigated in the chimeric mice. Cefmetazole (CMZ) was used as a probe drug. The CMZ excretions in urine and feces were 81.0 and 5.9% of the dose, respectively, in chimeric mice and were 23.7 and 59.4% of the dose, respectively, in control uPA−/−/SCID mice. Because CMZ is mainly excreted in urine in humans, the excretory profile of chimeric mice was demonstrated to be similar to that of humans. In the chimeric mice, the hepatic mRNA expression of human drug transporters could be quantified. On the other hand, the hepatic mRNA expression of mouse drug transporters in the chimeric mice was significantly lower than in the control uPA−/−/SCID mice. In conclusion, chimeric mice exhibited a humanized profile of drug excretion, suggesting that this chimeric mouse line would be a useful animal model in excretory studies.