2005 Fiscal Year Final Research Report Summary
Role of Mitochondria as Signal Sensors in Drug-Induced Liver Injury
| Project/Area Number |
16590106
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | CHIBA INSTITUTE OF SCIENCE (2005)
Chiba University (2004) |
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Principal Investigator |
MASUBUCHI Yasuhiro Chiba Institute of Science, Fac.Pharm.Sci., Professor, 薬学部, 教授 (10209455)
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| Project Period (FY) |
2004 – 2005
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| Keywords | Drug-induced liver injury / Mitochondria / Mitochondrial permeability transition / Antidiabetic agent / Troglitazone / Thiazolidinediones / Cyclosporin A / Idiosyncratic hepatotoxicity |
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| Research Abstract |
Recent studies have suggested a pathogenetic role of mitochondrial permeability transition (MPT) in the mitochondria-mediated hepatocyte injury by chemical agents. MPT is characterized by a progressive permeabilization of the inner mitochondrial membrane dependent on the excessive amount of intramitochondrial Ca^<2+> and results in mitochondrial swelling, decrease in mitochondrial ΔΨ and release of accumulated Ca^<2+> Troglitazone, a thiazolidinedione class of antidiabetic agent, causes serious idiosyncratic hepatotoxicity. Troglitazone is metabolized to a reactive metabolite that covalently binds to cellular macromolecules, whereas its role in the hepatotoxicity is controversial. Because troglitazone has been found to cause cytotoxicity to hepatocytes along with mitochondrial dysfunction, we investigated the effects of troglitazone and other thiazolidinediones on mitochondrial function by using liver mitochondria fraction isolated from male CD-1 mice. Incubation of energized mitochondria with succinate in the presence of Ca^<2+> and troglitazone induced mitochondrial swelling, and the swelling was partially inhibited by cyclosporin A. Troglitazone also induced decreases in mitochondrial membrane potential and mitochondrial Ca^<2+> accumulation. These results demonstrate that troglitazone induces MPT. Similar results were obtained for ciglitazone, whereas rosiglitazone and pioglitazone, which are less hepatotoxic than troglitazone, had little effect on these mitochondria functions. In conclusion, the troglitazone-induced opening of MPT pore, which is not induced by rosiglitazone or pioglitazone, may contribute to the hepatotoxicity induced specifically by troglitazone.
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