Author:
Uehara Shotaro,Iida Yuichi,Ida-Tanaka Miyuki,Goto Motohito,Kawai Kenji,Yamamoto Masafumi,Higuchi Yuichiro,Ito Satoshi,Takahashi Riichi,Kamimura Hidetaka,Ito Mamoru,Yamazaki Hiroshi,Oshimura Mitsuo,Kazuki Yasuhiro,Suemizu Hiroshi
Abstract
AbstractChimeric TK-NOG mice with a humanized liver (normal Hu-liver) are a unique animal model for predicting drug metabolism in humans. However, residual mouse hepatocytes occasionally prevent the precise evaluation of human drug metabolism. Herein, we developed a novel humanized liver TK-NOG mouse with a conditional knockout of liver-specific cytochrome P450 oxidoreductase (POR cKO Hu-liver). Immunohistochemical analysis revealed only a few POR-expressing cells around the portal vein in POR cKO mouse livers. NADPH-cytochrome c reductase and cytochrome P450 (P450)-mediated drug oxidation activity in liver microsomes from POR cKO mice was negligible. After the intravenous administration of S-warfarin, high circulating and urinary levels of S-7-hydroxywarfarin (a major human metabolite) were observed in POR cKO Hu-liver mice. Notably, the circulating and urinary levels of S-4′-hydroxywarfarin (a major warfarin metabolite in mice) were much lower in POR cKO Hu-liver mice than in normal Hu-liver mice. POR cKO Hu-liver mice with minimal interference from mouse hepatic P450 oxidation activity are a valuable model for predicting human drug metabolism.
Funder
Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research
The Adaptable and Seamless Technology Transfer Program through target-driven R&D (A-STEP) from Japan Science and Technology
The Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research [BINDS]) from AMED
Grant-in-aid for Life Science Joint Research in City of KAWASAKI
Publisher
Springer Science and Business Media LLC
Cited by
4 articles.
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