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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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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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 / メタボロームプロファイリング / 薬物アッセイ / 肝障害 / 親水性代謝物 / 疎水性代謝物 / 薬物性肝障害 (DILI) / 薬物代謝物 / HepG2細胞スフェロイド |
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| Outline of Research at the Start |
薬物性肝障害(drug-induced liver injury; DILI)は，医薬品の開発中止および市場撤退の主要な原因である．そのため，医薬品開発の初期段階でDILIを惹起する可能性のある化合物を判定するための評価法が求められている．DILI発症の原因薬物はその多くが薬物由来の代謝物が関与していることが示唆されているが，DILI発症に関与する薬物代謝反応の全貌あるいは薬物代謝物の構造とDILIとの関連性は未だ明らかとなっていない．本研究では，生体内の様々な代謝酵素によって生成する薬物代謝物を包括的かつ迅速に同定し，薬物代謝物が生体に及ぼす影響を高解像度で評価可能な方法論の開発を目指す．
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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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| 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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Report
(4 results)
Research Products
(34 results)
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[Journal Article] Kastor and Polluks polypeptides encoded by a single gene locus cooperatively regulate VDAC and spermatogenesis.2022
Author(s)
Mise S#, Matsumoto A#*, Shimada K, Hosaka T, Takahashi M, Ichihara K, Shimizu H, Shiraishi C, Saito D, Suyama M, Yasuda T, Ide T, Izumi Y, Bamba T, Kimura-Someya T, Shirouzu M, Miyata H, Ikawa M, Nakayama KI*.
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Journal Title
Nat. Commun.
Volume: 13(1)
Issue: 1
Pages: 1071-1071
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Comparative evaluation of plasma metabolomic data from multiple laboratories.2022
Author(s)
Nishiumi S#*, Izumi Y#*, Hirayama A#*, Takahashi M, Nakao M, Hata K, Saigusa D, Hishinuma E, Matsukawa N, M Tokuoka S, Kita Y, Hamano F, Okahashi N, Ikeda K, Nakanishi H, Saito K, Yokota Hirai M, Yoshida M, Oda Y, Matsuda F, Bamba T.
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Journal Title
Metabolites
Volume: 12(2)
Issue: 2
Pages: 135-135
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Differential effect of canagliflozin, a sodium-glucose cotransporter (SGLT2) inhibitor, on slow and fast skeletal muscles from nondiabetic mice.2022
Author(s)
Otsuka H, Yokomizo H*, Nakamura S, Izumi Y, Takahashi M, Obara S, Nakao M, Ikeda Y, Sato N, Sakamoto R, Miyachi Y, Miyazawa T, Bamba T, Ogawa Y*.
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Journal Title
Biochem. J.
Volume: 479(3)
Issue: 3
Pages: 425-444
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Targeting leukemia-specific dependence on the de novo purine synthesis pathway.2022
Author(s)
Yamauchi T, Miyawaki K, Semba Y, Takahashi M, Izumi Y, Nogami J, Nakao F, Sugio T, Sasaki K, Pinello L, Bauer DE, Bamba T, Akashi K, Maeda T*.
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Journal Title
Leukemia
Volume: 36(2)
Issue: 2
Pages: 383-393
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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