Humanized liver TK-NOG mice with functional deletion of hepatic murine cytochrome P450s as a model for studying human drug metabolism
© 2022. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Scientific reports - 12(2022), 1 vom: 01. Sept., Seite 14907 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Uehara, Shotaro [VerfasserIn] |
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| Links: |
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| Themen: |
5Q7ZVV76EI |
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| Anmerkungen: |
Date Completed 08.09.2022 Date Revised 08.11.2022 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41598-022-19242-0 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM345677137 |
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| 520 | |a 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 | ||
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| 700 | 1 | |a Iida, Yuichi |e verfasserin |4 aut | |
| 700 | 1 | |a Ida-Tanaka, Miyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Goto, Motohito |e verfasserin |4 aut | |
| 700 | 1 | |a Kawai, Kenji |e verfasserin |4 aut | |
| 700 | 1 | |a Yamamoto, Masafumi |e verfasserin |4 aut | |
| 700 | 1 | |a Higuchi, Yuichiro |e verfasserin |4 aut | |
| 700 | 1 | |a Ito, Satoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Takahashi, Riichi |e verfasserin |4 aut | |
| 700 | 1 | |a Kamimura, Hidetaka |e verfasserin |4 aut | |
| 700 | 1 | |a Ito, Mamoru |e verfasserin |4 aut | |
| 700 | 1 | |a Yamazaki, Hiroshi |e verfasserin |4 aut | |
| 700 | 1 | |a Oshimura, Mitsuo |e verfasserin |4 aut | |
| 700 | 1 | |a Kazuki, Yasuhiro |e verfasserin |4 aut | |
| 700 | 1 | |a Suemizu, Hiroshi |e verfasserin |4 aut | |
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