| Project/Area Number |
18K06767
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 47060:Clinical pharmacy-related
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| Research Institution | Osaka University of Pharmaceutical Sciences |
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Principal Investigator |
Kato Ryuji 大阪薬科大学, 薬学部, 准教授 (30411482)
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| 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)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
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| 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 / cytochrome P450 / 抗原提示細胞 / インフラマソーム反応 |
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| 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.
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| 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。
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