Establishment of a predictive test system for idiosyncratic drug-induced liver injury and study for evaluation of onset biomarkers
| Project/Area Number |
16H02616
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Nagoya University |
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Principal Investigator |
Yokoi Tsuyoshi 名古屋大学, 医学系研究科, 教授 (70135226)
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| Co-Investigator(Kenkyū-buntansha) |
織田 進吾 名古屋大学, 医学系研究科, 特任助教 (10725534)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥35,100,000 (Direct Cost: ¥27,000,000、Indirect Cost: ¥8,100,000)
Fiscal Year 2018: ¥10,530,000 (Direct Cost: ¥8,100,000、Indirect Cost: ¥2,430,000)
Fiscal Year 2017: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
Fiscal Year 2016: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
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| Keywords | 薬物性肝障害 / 肝障害予測 / 医薬品開発 / マイクロRNA / 特異体質性肝障害 / バイオマーカー / 動物モデル / 肝類洞内皮細胞 / microRNA / 薬物性腎障害 / 毒性発現機序解析 / 毒性発現予測試験系 / グルタチオン / ラモトリギン / エナラプリル / in vitro cell-based スクリーニング / 酸化ストレス / 毒性発現機序 / 血中マイクロRNA / 薬剤反応性 / 薬学 / 細胞・組織 |
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| Outline of Final Research Achievements |
The final purpose of drug-induced liver injury (DILI) prediction study is to establish a DILI prediction test system that is classified as idiosyncratic DILI, which has no significant dose-dependent onset and very large individual differences. During the three-year research period, we established a model animal for liver injury with methimazole, carbamazepine, enalapril, and faciglifam, and reported the mechanism of its onset. MicroRNA (miRNA) as a biomarker in early plasma was investigated by NGS using a rat liver injury model, and as a result, a plasma miRNA capable of discriminating pathologenesis of hepatocytotoxicity, cholestasis and fatty liver was suggested. In addition, we reported that the information from in vivo animal model was applied to an in vitro cell-based test system.
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| Academic Significance and Societal Importance of the Research Achievements |
新薬が市場から撤退する理由の約30％は薬物性肝障害の発症であり、患者や製薬会社のみならず社会にとっても大きな損失である。本研究では、研究代表者らが最近個々の臨床での肝障害発症被疑薬で報告している反応性代謝物の生成反応と免疫や炎症因子の関与を考慮した非臨床肝障害予測試験系を更に発展させ、新規化合物の細胞レベルおよび実験動物レベルでの実践的で統括的な肝障害予測試験系を提案・評価することを目的とした。その結果、多くの代表的な臨床肝障害被疑薬の動物モデルと発症機序を明らかにできたことより、創薬における非臨床研究に寄与できると考えられる。
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Report
(4 results)
Research Products
(31 results)
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[Journal Article] Serum microRNA profiles in patients with chronic hepatitis B, chronic hepatitis C, primary biliary cirrhosis, autoimmune hepatitis, nonalcoholic steratohepatitis, or drug-induced liver injury.2017
Author(s)
Yu Yamaura, Naoyuki Tatsumi, Shingo Takagi, Shinsaku Tokumitsu, Tatsuki Fukami, Kazuto Tajiri, Masami Minemura, Tsuyoshi Yokoi and Miki Nkajima.
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Journal Title
Clinical Biochemistry
Volume: 50
Issue: 18
Pages: 1034-1039
DOI
Related Report
Peer Reviewed
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[Presentation] Application of microRNAs derived from liver sinusoidal endothelial cells to circulating biomarkers that discern pathogenesis of liver injuries.2019
Author(s)
Shingo Oda, Masaki Takeuchi, Sho Akai, Yuji Shirai, and Tsuyoshi Yokoi.
Organizer
58th Annual Meeting of Society of Toxicology, March 10-14, 2019, Baltimore Convention Center, Baltimore, Maryland, USA.
Related Report
Int'l Joint Research
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[Presentation] Characterization of microRNAome in rat liver sinusoidal endothelial cells and hepatocytes and their potential application to plasma biomarkers that discern pathogenesis of liver injuries2017
Author(s)
Shingo Oda, Masataka Takeuchi, Yuji Shirai, Sho Akai, Koichi Tsuneyama, Tsuyoshi Yokoi.
Organizer
56th Annual Meeting of Society of Toxicology, March 12-16, 2017, Baltimore Convention Center, Baltimore, Maryland, USA.
Related Report
Int'l Joint Research
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[Presentation] Individual variability of carbamazepine-induced liver injury in mice.2017
Author(s)
Yasuaki Uematsu, Sho Akai, Shingo Oda, Toru Yamada, Tsuyoshi Yokoi.
Organizer
56th Annual Meeting of Society of Toxicology, March 12-16, 2017, Baltimore Convention Center, Baltimore, Maryland, USA.
Related Report
Int'l Joint Research
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