2022 Fiscal Year Final Research Report
Elucidation of the mechanism for drug-induced liver injury based on metabolite profiling
| Project/Area Number |
20K15101
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 27040:Biofunction and bioprocess engineering-related
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | 薬物性肝障害 / メタボローム解析 / 薬物アッセイシステム / ヒト肝腫瘍由来細胞株HepG2細胞 / 質量分析 / グルタチオン / ペントースリン酸経路 |
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| Outline of Final Research Achievements |
We developed an advanced drug evaluation system for drug-induced liver injury (DILI) using HepG2 cells, a human liver tumor-derived cell line. Metabolome analysis of HepG2 cells exposed to each 10 drugs was performed using this drug evaluation system. The results showed that drug and some drug metabolites were detected in HepG2 cells, and some drug metabolizing enzymes and transferase enzymes involved in conjugation reactions were significantly increased compared to the control group. In addition, 443 metabolites were detected using metabolomic and lipidomic analysis. Among these, a significant decrease in reduced-glutathione (GSH), which is associated with oxidative stress, were observed. These results suggest that this system is capable of capturing molecular initiation events based on precise toxicity pathways using HepG2 cells.
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| Free Research Field |
メタボロミクス
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| Academic Significance and Societal Importance of the Research Achievements |
本研究で開発した薬物アッセイシステムは，高解像度のフェノタイピング解析が実施可能なメタボローム解析を基盤技術として用いているため，鋭敏かつ正確でノンバイアスのDILI評価手法である．当該アッセイシステムは，従来の方法論では見出すことのできなかった薬物性肝障害発症に至るまでの作用機序，および有害性発現経路を推定できる可能性があり，ひいては医薬品開発の効率化に貢献できると考えられる．
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