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2005 Fiscal Year Final Research Report Summary

Role of Mitochondria as Signal Sensors in Drug-Induced Liver Injury

Research Project

Project/Area Number 16590106
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Medical pharmacy
Research InstitutionCHIBA INSTITUTE OF SCIENCE (2005)
Chiba University (2004)

Principal Investigator

MASUBUCHI Yasuhiro  Chiba Institute of Science, Fac.Pharm.Sci., Professor, 薬学部, 教授 (10209455)

Project Period (FY) 2004 – 2005
KeywordsDrug-induced liver injury / Mitochondria / Mitochondrial permeability transition / Antidiabetic agent / Troglitazone / Thiazolidinediones / Cyclosporin A / Idiosyncratic hepatotoxicity
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.

  • Research Products

    (4 results)

All 2006 2005

All Journal Article (4 results)

  • [Journal Article] Mitochondrial permeability transition as a potential determinant of hepatotoxicity of antidiabetic thiazolidinediones.2006

    • Author(s)
      Masubuchi, Yasuhiro
    • Journal Title

      Toxicology 222・3

      Pages: 233-239

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Mitochondrial permeability transition as a potential determinant of hepatotoxicity of antidiabetic thiazolidinediones.2006

    • Author(s)
      Masubuchi, Yasuhiro et al.
    • Journal Title

      Toxicology 222(3)

      Pages: 233-239

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice.2005

    • Author(s)
      Masubuchi, Yasuhiro
    • Journal Title

      Journal of Hepatology 42・1

      Pages: 110-116

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice.2005

    • Author(s)
      Masubuchi, Yasuhiro et al.
    • Journal Title

      Journal of Hepatology 42(1)

      Pages: 110-116

    • Description
      「研究成果報告書概要(欧文)」より

URL: 

Published: 2007-12-13  

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