Mechanisms of idiosyncratic drug induced liver injury focused on inflammasome reaction and development of the evaluation methods.

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06767
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Osaka University of Pharmaceutical Sciences
• Principal Investigator: Kato Ryuji 大阪薬科大学, 薬学部, 准教授 (30411482)
• Co-Investigator(Kenkyū-buntansha): 林 哲也 大阪薬科大学, 薬学部, 教授 (30257852) ; 井尻 好雄 大阪薬科大学, 薬学部, 准教授 (50449823)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 特異体質性薬物性肝障害 / 反応性代謝物 / インフラマソーム / DAMPs

Outline of Final Research Achievements

The reactive metabolite of acetaminophen, amiodarone, amodiaquine, carbamazepine, entacapone, gefitinib, nevirapine, tolcapone and troglitazone can cause the release of damage-associated molecular patterns (DAMPs) from hepatocytes which can activate inflammasomes. In this study, DAMPs which include DNA, RNA, heat shock protein (HSP) 40, HSP60, HSP70 and HSP90, were identified in the culture supernatant of a hepatocyte cell line. These results in the production of DAMPs that activate inflammasomes result in an immune response. Inflammasome activation may be an important step in the activation of the immune system, which in some patients, can cause immune-related adverse events. The method, which is developed in this study may provide a method to study the mechanism of idiosyncratic drug reactions and even predict which drug candidates are likely to cause such adverse reactions.

Free Research Field

臨床毒性学

Academic Significance and Societal Importance of the Research Achievements

本研究では、特異体質性薬物性肝障害が、肝細胞から放出されたdamage-associated molecular patterns（DAMPs）により抗原提示細胞のインフラマソームを活性化することで発症するという発症機序、およびそれらDAMPsの具体的な種類について明らかにすることが出来た。このような詳細な検討は現在までに行われておらず、特異体質性薬物性肝障害の治療において、抗DAMPs抗体の投与など新たな治療戦略になりうると考えられる。さらに本研究で用いたin vitro評価系は利便性が高く、今後の医薬品開発および個別化医療の分野での応用が期待されるものである。