| Title: |
Humanized liver TK-NOG mice with functional deletion of hepatic murine cytochrome P450s as a model for studying human drug metabolism. |
| Authors: |
Uehara, Shotaro1 (AUTHOR), Iida, Yuichi2,3 (AUTHOR), Ida-Tanaka, Miyuki1 (AUTHOR), Goto, Motohito4 (AUTHOR), Kawai, Kenji5 (AUTHOR), Yamamoto, Masafumi6 (AUTHOR), Higuchi, Yuichiro1 (AUTHOR), Ito, Satoshi7 (AUTHOR), Takahashi, Riichi4 (AUTHOR), Kamimura, Hidetaka7,8 (AUTHOR), Ito, Mamoru1 (AUTHOR), Yamazaki, Hiroshi9 (AUTHOR), Oshimura, Mitsuo2 (AUTHOR), Kazuki, Yasuhiro2,10 (AUTHOR), Suemizu, Hiroshi1 (AUTHOR) suemizu@ciea.or.jp |
| Source: |
Scientific Reports. 9/1/2022, Vol. 12 Issue 1, p1-12. 12p. |
| Subject Terms: |
*MICROSOMES, *DRUG metabolism, *LIVER microsomes, *CYTOCHROME P-450, *MICE, *LIVER |
| Abstract: |
Chimeric 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. [ABSTRACT FROM AUTHOR] |
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