Construction of a method for analyzing the toxic mechanism and new toxic markers by metabolome analysis

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K10682
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 58040:Forensics medicine-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Funakoshi Takeshi 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (40444715)
• Co-Investigator(Kenkyū-buntansha): 上村 公一 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30244586) ; 秋 利彦 東京医科歯科大学, 大学院医歯学総合研究科, 准教授 (60304474)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: メタボローム解析

Outline of Final Research Achievements

Death from poisoning caused by various drugs such as drugs and antipsychotics is treated as abnormal death, and the cause of death has been determined legally, but the detailed mechanism of action has been clarified among many drugs. There aren't many things. In recent years, cases of drugs with unknown toxicity and mechanism, such as synthetic cannabinoids have been increasing, and the toxicity of these drug poisons is rapidly evaluated and the mechanism of toxicity is clarified from a forensic perspective. There is an urgent need to develop a method to do this.
The purpose of this study is to analyze cell toxicity caused by drug toxins by using wide-target metabolomics and non-target metabolomics methods. We elucidated the mechanism of cytotoxicity using the antiepileptic drugs carbamazepine and oxcarbazepine and aristolochic acid, which is a plant alkaloid contained, as a model.

Free Research Field

中毒学

Academic Significance and Societal Importance of the Research Achievements

薬物毒性モデルとして使用したNRK52E細胞においては、抗てんかん薬オクスカルバゼピン曝露により腎近位尿細管細胞はPlk1活性化阻害による異常紡錘体の形成・G2/M期細胞周期停止が誘導され、結果Mitotic catastropheによるアポトーシス誘導、細胞毒性が惹起されることが明らかになった。またメタボローム解析から脂質生合成・代謝経路の変動が確認されたことから、近位尿細管細胞におけるMitotic catastrophe、細胞毒性にこれら脂質代謝経路の関与が示唆され、今後より詳細なメタボローム解析により、さらなる細胞毒性マーカー代謝物の検討を進めていきたいと考えている。