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1993 Fiscal Year Final Research Report Summary

Cytosokic Acetyl CoA Hydrolase and Induction by Clofibrate

Research Project

Project/Area Number 03670123
Research Category

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

Allocation TypeSingle-year Grants
Research Field General medical chemistry
Research InstitutionOsaka University

Principal Investigator

ISOHASHI Fumihide  Osaka Univ. Med. Sch. Assoc. Prof., 医学部, 講師 (20115992)

Project Period (FY) 1991 – 1993
KeywordsAcetyl-CoA / Acetyl-CoA Hydrolase / Clofibrate / Peroxisomal / Hypolipidemic drug / Clofibrate Receptor / Receptor / Steroid Receptor Family
Research Abstract

The hypolipidemic drug ethyl chlorophenoxyisobutyrate (clofibrate) is known to induce peroxisome proliferation and to ve carcinogenic after long term administration to rats and mice. We examined the effects of treatment with this drug for periods of up to 18 months on cytosolic ATP-stimulated and ADP-inhibited acetyl-CoA hydrolase in rat liver. In male donryu albino rats on a diet containing 0.5% clofibrate, the enzyme activity increased to about 2- and 3-fold the initial level permilligram liver protein and cytosolic protein, respectively, and 2-fold per milligram DNA in 3 days, and then remained at this level for up to 18 months. The increased activity in rats receiving clofivrate for 3 months returned to control level within a week when clofibrate was sithdrown. The change in enzyme activity paralleled the change in the amount of enzyme protein determined by immunoblotting with anyibody against purified acetyl-CoA hydrolasa from rat liver cytosol. No liver tumors were detected macro … More scopically after administration of clofibrate for 18 months. However, our results suggest that cytosolic acetyl-CoA hydrelase could be an extraperoxisomal marker enzyme induced by this type of drug.
An extramitochondrial acetyl-CoA hydrolase [EC 3.1.2.1] in the rat liver, which is atimulated by ATP and inhibited by ADP, is known to ve extremely cold-labile. During subcellular fractionations at low temperatures (2-4*C), most of the enxyme activity was lost ; however, most could be recovered by rewarming at 37*C in the presence of a high concentration of potassium phosphate. This enabled us to measure the activities of cold-treated samples. The majority of the ATP-stimulated and ADP-imhibited acctyl-Coa hydrolase activity in rat livers was detected in the cytosolic fraction and small amounts were detected in the peroxixomal fraction. The activity of peroxisomal ATP-stimulated acetyl-CoA hydrolasa was not noticeably increased after clofibrate-treatment. However, the cytosolic activity greatly increased after clofibrate treatment. The activity in the isolated peroxisomal fraction per g of liver was about 5% of that in the cytosolic fraction of liver from the control and about 2% in that from clofibrate-treated rats. Vesides having similar nucleotide (ATP and ADP) sensitivity and cold lability, the enzyme protein in the peroxisomal fraction migrated to the same position as the cytosolic acetyl-CoA hydroiase based on Western blot analysis with antibody against purified acetyl-CoA gydrolase from rat liver cytosol. These results suggest that the peroxisomal enzyme and cytosolic enzyme may be the same extity. Less

  • Research Products

    (16 results)

All Other

All Publications (16 results)

  • [Publications] Kazuki Okamoto: "Rat Hepatic ATP-Stimulated Translocation Promoter That Increases The Nuclear Binding of Activated Glucocorticoid Receptor Complex." Neuroendocrine Research Methods. 2. 635-672 (1991)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yoko Nakanishi: "Effects of Chronic Administration of the Peroxisome Proliferator.Clofibrate,on Cytosolic Acetyl-CoA Hydrolase in Rat Liver." Biochemical Pharmacology. 45. 1403-1407 (1993)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kazuki Okamoto: "Molecular Cloning of Rat Liver Glucocorticoid-Receptor Translocation Promoter:" Biochem.Biophys.Res.Commun.193. 848-854 (1993)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Fumihide Isohashi: "ATP-Stimulated Translocation Promoter that Enhances the Nuclear Binding of Activated Glucocorticoid Receptor Complex:Biochemical Properties and Its Function." Receptor. 3. 113-124 (1993)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Gang Liu: "Purification and Characterization of a Macromolecular Translocation Inhibitor III of Activated Glucocorticoid Receptor Complex Binding to Nuclei from Rat Liver:" Eur.J.Biochem.218. 679-687 (1993)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yoko Nakanishi: "Subcellular Distribution of ATP-Stimulated and ADP-Inhibited Acetyl-CoA Hydrolase in Livers from Control and Clofibrate-Treated Rats;Comparison of the---" J.Biochem.115(in press). (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 礒橋文秀: "新生化学実験講座 9 ホルモンII 非ペプチドホルモン[日本生化学会(村松正實編集)編]" 東京化学同人, 536 (1993)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 上田清隆、岡本一起、礒橋文秀: "生物薬科学実験講座 第9巻 ホルモン・生理活性物質" 株式会社廣川書店 印刷中, (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Okamoto. K., Isohashi. F., and Sakamoto. Y.: "Rat Hepatic ATP-Stimulated Translocation Promoter that Enhances the Nuclear Binding of Activated Glucocorticoid Receptor Complex." Neuroendcrine Research Methods.2. 653-672 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakanishi. Y., Okamoto. K., and Isohashi. F.: "Effects of Chronic Adminisrration of the Peroxisome Proliferator. Clofibrate, on Cytosolic Acethl-CoA Hydrolase in Rat" Biochemical Pharmacology. 45. 1403-1407 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Isohashi, F.and Okamoto, K.: "ATP-Stimulated Translocation Promoter that enhances the Nuclear Binding of Activated Glucocorticoid Receptor Complex : BiochemicalProperties and Its Function." Receptor. 3. 113-124 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Okamoto, K., Hirano H., and Isohashi F.: "Molecular cloning of Rat Liver Glucocorticoid-Receptor Translocation Promoter :" Bichem.Biopys. Res. Commun.193. 848-854 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Liu G., Okamoto K., and Isohashi F.: "Purificatio and Characterization of a Macromolecular Translocation Inhibitor III of Activated Glucocorticoid Receptor Complex Binding to Nuclei form Rat Liver :" Eur. J.Biochem.218. 679-687 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakanishi Y., Okamoto K., and Isohashi F.: "Subcellular Distribution of ATP-Stimulated and ADP-Inhibited Acetyl-CoA Hydrolase in Livers fron Control and Clofibrate-Teated Rats ; Comparison of the Cytosokic and Peroxisomal Enzyme." J.Biochem.115(2). 174-179 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Okamoto K., Liu G., Yu W.G., and Isohashi F.: "Immunochemical Characterixation of the ATP Stimulated Glucocorticoid Receptor Translocation Promoter from Various Organs of Rat." J.Biochem.115(in press). (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Liu G., Okamoto K., Yu W.G., Ochiai H., and Isohashi F.: "Effect of Macromolecular Translocation Inhibitor III on Activated Gkucocorticoid-Receptor-Complex Binding to Specific DNA." (in press). (1994)

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

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Published: 1995-03-27  

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