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Involvement of cytokines in drug-induced liver injury

Research Project

Project/Area Number 14572050
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionCHIBA UNIVERSITY

Principal Investigator

MASUBUCHI Yasuhiro  Chiba University, Graduate School of Pharmaceut.Sci., Assoc.Prof., 大学院・薬学研究院, 助教授 (10209455)

Co-Investigator(Kenkyū-buntansha) ITO Kousei  Chiba University, Graduate School of Pharmaceut Sci., Res.Assoc., 大学院・薬学研究院, 助手 (30323405)
HORIE Toshiharu  Chiba University, Graduate School of Pharmaceut.Sci., Prof., 大学院・薬学研究院, 教授 (90120154)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2002: ¥2,800,000 (Direct Cost: ¥2,800,000)
KeywordsDrug-induced liver injury / Cytokines / Acetaminophen / Interleukin-6 / Heat shock proteins / Indomethacin / Endotoxin / Toll-like receptor 4 / TNF-α / インターロイキン-10 / ジクロフェナック / シトクロムP450
Research Abstract

To determine pathogenic or suppressive mediators in drug-induced liver injury, we focused on cytokines in interleukin-6 (IL-6) family. During development of liver injury after administration of acetaminophen, hepatic mRNA expressions of IL-6, IL-11 and oncostatin M were increased. The acetaminophen-induced liver injury was aggregated in IL-6 knockout (KO) mice, suggesting that IL-6 behaves as a protective modulator. Livers of the KO mice exhibited decreased expressions of heat shock proteins (HSP) HSP25,HSP32,and HSP40. It is thus suggested that IL-6 acts via up-regulation of these proteins. On the other hand, non-steroidal anti-inflammatory drug (NSAID)-induced liver dysfunction was monitored by cytochrome P450-mediated drug-metabolizing enzyme activities. An increase in portal endotoxin was observed in indomethacin-treated mice. The endotoxin resistant C3H/HeJ mice were resistant to indomethacin-induced down-regulation of P450 enzymes in the liver. These results suggests that the NSAID-induced liver dysfunction is mediated by endotoxin and inflammatory cytokines stimulated by the endotoxin. We could thus conclude that cytokines were primary mediators participated in both promotion and suppression of drug-induced liver injury.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (8 results)

All Other

All Publications (8 results)

  • [Publications] Masubuchi, Yasuhiro: "Role of interleukin-6 in hepatic heat shock protein expression and protection against acetaminophen-induced liver disease."Biochemical and Biophysical Research Communications. 304・1. 207-212 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Masubuchi, Yasuhiro: "Resistance to indomethacin-induced down-regulation of hepatic cytochrome P450 enzymes in the mice with non-functional Toll-like receptor 4."Journal of Hepatology. 39・3. 349-356 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Masubuchi, Yasuhiro et al.: "Role of interleukin-6 in hepatic heat shock protein expression and protection against acetaminophen-induced liver disease."Journal of Hepatology. 39(3). 349-356 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Masubuchi, Yasuhiro et al.: "Resistance to indomethacin-induced down-regulation of hepatic cytochrome P450 enzymes in the mice with non-functional Toll-like receptor 4."Biochemical and Biophysical Research Communications. 304(1). 207-212 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Masubuchi, Yasuhiro: "Role of interleukin-6 in hepatic heat shock protein expression and protection against acetaminophen-induced liver disease"Biochemical and Biophysical Research Communications. 304・1. 207-212 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Masubuchi, Yasuhiro: "Resistance to indomethacin-induced down-regulation of hepatic cytochrome P450 enzymes in the mice with non-functional Toll-like receptor 4"Journal of Hepatology. 39・3. 349-356 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Masubuchi, Yasuhiro: "Multiple mechanisms in indomethacin-induced impairment of hepatic cytochrome P450 enzymes in rats"Gastroenterology. 122・3. 774-783 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Masubuchi, Yasuhiro: "Role of mitochondrial permeability transition in diclofenac-induced hepatocyte injury in rats"Hepatology. 35・3. 544-551 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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