Humanized liver TK-NOG mice with functional deletion of hepatic murine cytochrome P450s as a model for studying human drug metabolism-Reference-Cited by-同舟云学术

Humanized liver TK-NOG mice with functional deletion of hepatic murine cytochrome P450s as a model for studying human drug metabolism

Published:2022-09-01 Issue:1 Volume:12 Page:
ISSN:2045-2322
Container-title:Scientific Reports
language:en
Short-container-title:Sci Rep

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

Subject

Multidisciplinary

Link

https://www.nature.com/articles/s41598-022-19242-0.pdf

Reference24 articles.

1. Dalvie, D. et al. Assessment of three human in vitro systems in the generation of major human excretory and circulating metabolites. Chem. Res. Toxicol. 22, 357–368. https://doi.org/10.1021/tx8004357 (2009).

2. Hasegawa, M. et al. The reconstituted “humanized liver” in TK-NOG mice is mature and functional. Biochem. Biophys. Res. Commun. 405, 405–410. https://doi.org/10.1016/j.bbrc.2011.01.042 (2011).

3. Uehara, S., Yoneda, N., Higuchi, Y., Yamazaki, H. & Suemizu, H. Metabolism of desloratadine by chimeric TK-NOG mice transplanted with human hepatocytes. Xenobiotica 50, 733–740. https://doi.org/10.1080/00498254.2019.1688892 (2020).

4. Uehara, S., Yoneda, N., Higuchi, Y., Yamazaki, H. & Suemizu, H. Methyl-hydroxylation and subsequent oxidation to produce carboxylic acid is the major metabolic pathway of tolbutamide in chimeric TK-NOG mice transplanted with human hepatocytes. Xenobiotica 51, 582–589. https://doi.org/10.1080/00498254.2021.1875515 (2021).