Elucidation of the mechanism of human-specific drug hepatotoxicity using a novel humanized liver mouse model of drug-induced liver injury

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K06463
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 42040:Laboratory animal science-related
• Research Institution: Central Institute for Experimental Animals
• Principal Investigator: Uehara Shotaro 公益財団法人実験動物中央研究所, 実験動物応用研究部, 研究員 (10733123)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: ヒト化肝臓マウス / チトクロムP450 / チトクロムP450酸化還元酵素 / TK-NOGマウス / 薬物代謝 / S-ワルファリン / 肝臓特異的Por欠損 / 薬物代謝の動物種差

Outline of Final Research Achievements

Conventional humanized liver mice are unable to predict the pharmacokinetics and toxicity of some drugs in humans due to drug-metabolizing enzyme activity in the residual mouse hepatocytes. In this study, we transplanted human hepatocytes into mice deficient in liver-specific Por activity and successfully established a liver-specific Por-deficient humanized liver TK-NOG mouse model. In this model, P450 enzyme activity of the remaining mouse hepatocytes is reduced due to liver-specific Por deficiency, suggesting that the drug metabolizing capacity is more similar to that of humans compared to the conventional humanized liver model. In conclusion, the liver Por-deficient humanized liver mouse model is expected to be utilized as a new platform for pharmacokinetic and safety studies.

Free Research Field

薬物動態

Academic Significance and Societal Importance of the Research Achievements

ヒト化肝臓マウスはヒト肝細胞で構築されたミニ肝臓を有しており、ヒトに類似した薬物代謝の特徴を示す。しかしながら、肝臓に残存する僅かなマウス肝細胞が原因で、稀にヒトとは異なる薬物代謝を示すことが明らかになっている。残存マウス肝P450の薬物代謝への干渉を最小化した肝臓特異的チトクロムP450酸化還元酵素欠損ヒト化肝臓マウスは、ヒトの薬物動態・安全性を精度よく予測するための重要な実験動物となる。すなわち、本動物を創薬へと応用することにより、より安全で有効性の高い医薬品の創出が期待される。