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Pharmacokinetics and Hepatotoxicity due to the oxidative stress

Research Project

Project/Area Number 06672155
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Physical pharmacy
Research InstitutionChiba University

Principal Investigator

HORIE Toshiharu  Chiba University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (90120154)

Project Period (FY) 1994 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1995: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1994: ¥1,400,000 (Direct Cost: ¥1,400,000)
Keywordsoxidative stress / lipid peroxidation / hepatotoxicity / hepatocyte / chemiluminescence / acetaminophen / glutathione / naproxen
Research Abstract

In order to verify the contribution of the active oxygens to the drug-induced hepatotoxicity, it is very important to detect the active oxygens generated during the drug metabolism. Chemiluminescence produced from the active oxygens, glutathione, fluorescent substances, high molecular weight protein aggregates and thiobarbituric acid reactive substances were used to study the drug-induced oxidative stress in perfused rat liver, isolated rat hepatocyte and mitochondria. 1. The ultra weak chemiluminescence was detected in the homogenates of rat liver perfused with acetaminophen solution.
The high molecular weight protein aggregates were foromed in the liver perfused with a cetaminophen and the reduced glutathione decreased in the liver. The oxidized glutathione increased slightly in the rat liver perfused with naproxen solution. 2. The ultra weak chemiluminescence was detected in the isolated hepatocytes with acetaminophen. Naproxen also produced the chemiluminescence in the hepatocyte suspension and increased the ratio of oxidized glutathione to the total glutathione. Ethacrynic acid induced lipid peroxidation in the hepatocytes due to the oxidative metabolism. 3. The ultra weak chemiluminescence was detected in the mitochondria with doxorubicin and the origins of the chemiluminescence were found to be singlet oxygen and excited carbonyls. Phosphatidylcholine hydroperoxide was detected in the heart homogenates of doxorubicin administered mouse using the chemiluminescence-HPLCsystem.

Report

(3 results)
  • 1995 Annual Research Report   Final Research Report Summary
  • 1994 Annual Research Report
  • Research Products

    (13 results)

All Other

All Publications (13 results)

  • [Publications] M.Kitada: "Chemiluminescence associated with doxorubicin-induced lipid peroxidation in rat heart mitochondria" Biochem.Pharmacol.48. 93-99 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] H.Yokoyama: "Lipid peroxidation and chemiluminescence during naproxen metabolism in rat liver microsomes" Hum.& Experi.Toxicol.13. 831-838 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 堀江利治: "薬による肝毒性発現機構:酸化的ストレスを中心として" J.Toxicol Sci.20. 13-18 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] F.Fukuda: "Fluorescent substances and high molecular weight protein aggregates formed in rat heart mitochondria upon doxorubicin-induced lipid peroxidation" J.Pharm.Pharmacol.47. 246-249 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] H.Yokoyama: "Oxidative stress in isolated rat hepatocytes during naproxen metabolism" Biochem.Pharmacol.49. 991-996 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Mitsuo Kitada, Toshiharu Horie and Shoji Awazu: "Chemiluminescence associated with doxorubicininduced lipid peroxidation in rat heart mitochondria" Biochem. Pharmacol.48(1). 93-99 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hiroyuki Yokoyama, Toshiharu Horie and Shoji Awazu: "Lipid peroxidation and chemiluminescence during naproxen metabolism in rat liver microsomes" Hum. & Exper. Toxicol. 13(12). 831-838 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Toshiharu Horie: "The mechanism of drug-induced hepatotoxicity" J.Toxicol. Sci.20(1). 13-18 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Fumiyasu Fukuda, Mitsuo Kitada, Toshiharu Hurie and Shoji Awazu: "Fluorescent substances and high molecular weight protein aggergates formed in rat heart mitochondria upon doxorubicin-induced lipid peroxidation" J.Pharm. Pharmacol.47(3). 246-249 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hiroyuki Yokoyama, Toshiharu Horie and Shoji Awazu: "Oxidative stress in isolated rat hepatocytes during naproxen metabolism" Biochem. Pharmacol.49(7). 991-996 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] F.Fukuda: "Fluorescent substances and high molecular weight protein aggregates fcrmed in rat heart mitochondria upon doxorubicin‐induced lipid peroxidation" J. Pharm. Pharmacol.47. 246-249 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 堀江利治: "薬による肝毒性発現機構:酸化的ストレスを中心として" J.Toxicol.Sci.20. 13-18 (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] H.Yokoyama: "Oxidative stress in the isolated rat hepatocytes during naproxen metabolism" Biochem.Pharmacol.(in press). (1995)

    • Related Report
      1994 Annual Research Report

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Published: 1994-04-01   Modified: 2016-04-21  

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