Development of human specific hepatotoxicity evaluation method using humanized liver mouse and elucidation of species differences in the pathogenesis of toxicity

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K07102
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: Central Institute for Experimental Animals
• Principal Investigator: SUEMIZU HIROSHI 公益財団法人実験動物中央研究所, 実験動物研究部, 部長 (40332209)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: ヒト肝キメラマウス / 肝毒性

Outline of Final Research Achievements

In this study, we established an evaluation method for human-specific hepatotoxicity using chimeric mouse with humanized liver, in which the mouse hepatocytes are replaced by human hepatocytes. The plasma levels of apoA mRNA, alanine transaminase (ALT) protein, and human cytokeratin were measured using d-galactosamine induced liver injury in humanized liver of chimeric mouse. The major components of deviant markers detected using species-specific TaqMan assay and ALT ELISA were from mice hepatocytes. Moreover, the amount of human cytokeratin detected using M65 EpiDeath ELISA was very small. These results suggest that the toxicity of d-galactosamine in humanized liver of a chimeric mouse appears mainly in mouse hepatocytes.

Free Research Field

実験動物学

Academic Significance and Societal Importance of the Research Achievements

新薬開発の初期段階で実験動物において有効性と安全性が十分に確認された開発薬のみが臨床試験へと進められるにもかかわらず、臨床試験の段階で肝毒性が発症し開発中止となる薬剤が未だになくならない。この問題の克服にはヒトの薬物代謝を再現した動物実験モデルとヒトの肝毒性を高い確度で予見する評価システムの両方が必要である。ヒト化肝臓マウスはヒトの肝細胞を持つことから、ヒト特異的な肝毒性を再現すると考えられており、その毒性評価法の確立は前臨床段階でのヒトにおける副作用予測の精度向上と有害事象の低減に貢献することが期待される。