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Mechanism underlying the selective removal of copper accumulating in the liver of LEC rats and development of the therapy for Wilson disease

Research Project

Project/Area Number 09470511
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 医薬分子機能学
Research InstitutionChiba University

Principal Investigator

SUZUKI Kazuo t.  Chiba University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (90109918)

Co-Investigator(Kenkyū-buntansha) OGRA Yasumitsu  Chiba University, Faculty of Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (40292677)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥9,700,000 (Direct Cost: ¥9,700,000)
Fiscal Year 1999: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1998: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1997: ¥4,900,000 (Direct Cost: ¥4,900,000)
KeywordsLEC rats / Wilson disease / copper / metallothionein / thiomolybdate / ICP-MS / liver / ATP7B / テトラチオモリブデート / HPLC / スペシエーション / テトラチオモリブデ-ト / ウイルソン病
Research Abstract

Wilson disease is caused by an abnormal accumulation of copper (Cu) in the liver owing to the inherited defect in Cu metabolism, and the Cu accumulates in the form bound to metallothionein (MT), Cu,Zn-MT. When Cu accumulates more than the biosynthetic capacity of MT, Cu-MT without Zn starts to work as a prooxidant and causes acute hepatitis. This mechanism was revealed by the speciation study of Cu in the liver, bloodstream, kidneys and urine.
Cu accumulating in the liver has to be lowered in the therapy of Wilson disease either by i) feeding diets of low Cu content, ii) lowering the absorption at the gastro-intestinal tract or iii) removing Cu from Cu, Zn-MT in the liver. In the present study, the third approach was examined. Based on the complex formation between Cu, Mo and S, tetrathiomolybdate (TTM) was used to remove Cu in the liver of LEC rats, an animal model of Wilson disease. Precise mechanisms underlying the reaction between TTM and Cu bound to MT and underlying the removal of Cu from liver have been presented. TTM is specific not only to Cu among various metals but also to Cu bound to MT.
The selective removal of Cu by TTM was demonstrated in vivo, and it was also shown that the Cu removed from the liver does not redistribute to other organs. The Cu removed from MT is effluxed into bile and bloodstream in the form of the Cu/TTM complex, and then excreted into feces but not into urine.
As side-effects, it was shown that excessive treatment with TTM causes a severe Cu deficiency, and that sulfide ions produced by hydrolysis under acidic conditions affect acutely liver function. As a result, it has been recommended to administer TTM as a single or several injections but not repeatedly to avoid the side-effects due to overdose.

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (29 results)

All Other

All Publications (29 results)

  • [Publications] Y.Ogra: "Targeting of tetrathiomolybdate on the copper accumulating in the liver of LEC rats"J. Inorg. Biochem.. 70. 49-50 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Y.Ogra: "Comparative mechanism and toxicity of tetra- and dithiomolybdates in the removal of copper"J. Inorg. Biochem.. 75. 199-204 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] K.T.Suzuki: "Identification of the zinc-binding protein specifically present in male rat liver as carbonic anhydrase III"Chem.-Biol. Interact.. 122. 185-197 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] K.T.Suzuki: "Copper increases in both plasma and red blood cells at the onset of acute hepatitis in LEC rats"Res. Commun. Mol. Pathol. Pharmacol.. 103. 189-194 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Y.Komatsu: "Excretion of copper complexed with thiomolybdate into the bile and blood in LEC rats"Chem.-Biol. Interact.. 124. 217-231 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Y.Ogra: "Metabolic fate of the insoluble copper/tetrathiomolybdate complex formed in the liver of LEC rats with excess tetrathiomolybdate"J. Inorg. Biochem.. 78. 123-128 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 鈴木和夫: "生体による銅の制御機構と銅の選択的除去法 : 先天的銅代謝異常症ウィルソン病の治療法"薬学雑誌. (印刷中). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Y. Ogra and K.T. Suzuki: "Targeting of tetrathiomolybdate on the copper accumulating in the liver of LEC rats."J. Inorg. Biochem.. 70. 49-55 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Y. Ogra, Y. Komada and K.T. Suzuki: "Comparative mechanism and toxicity of tetra- and dithiomolybdates in the removal of copper."J. Inorg. Biochem.. 75. 199-204 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] K.T. Suzuki, J. Takenaka and Y. Ogra: "Identification of the zinc-binding protein specifically present in male rat liver as carbonic anhydrase III."Chem.-Biol. Interact.. 122. 185-197 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] K.T. Suzuki, Y. Shiobara, A. Tachibana, Y. Ogra and K. Matsumoto: "Copper increases in both plasma and red blood cells at the onset of acute hepatitis in LEC rats."Res. Commun. Mol. Pathol. Pharmacol.. 103. 189-194 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Y. Komatsu, I. Sadakata, Y. Ogra and K.T. Suzuki: "Excretion of copper complexed with thiomolybdate into the bile and blood in LEC rats."Chem.-Biol. Interact.. 124. 217-231 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Y. Ogra, H. Chikusa and K.T. Suzuki: "Metabolic fate of the insoluble copper/tetrathiomolybdate complex formed in the liver of LEC rats with excess tetrathiomolybdate."J. Inorg. Biochem.. 78. 123-128 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] K.T. Suzuki and Y. Ogra: "Biological Regulation of Copper and Selective Removal of Copper : Therapy for Wilson Disease and Its Molecular Mechanism"YAKUGAKU ZASSHI. (in press). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Y. Ogra: "Comparative mechanism and toxicity of tetra- and dithiomolybdates in the removal of copper"J. Inorg. Biochem.. 75. 199-204 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] K.T. Suzuki: "Identification of the zinc-binding protein specifically present in male rat liver as carbonic anhydrase III"Chem.-Biol. Interact.. 122. 185-197 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] K.T. Suzuki: "Copper increases in both plasma and red blood cells at the onset of acute hepatitis in LEC rats"Res. Commun. Mol. Pathol. Pharmacol.. 103. 189-194 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Y. Komatsu: "Excretion of copper complexed with thiomolybdate into the bile and blood in LEC rats"Chem.-Biol. Interact.. 124. 217-231 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Y. Ogra: "Metabolic fate of the insoluble copper/tetrathiomolybdate complex formed in the liver of LEC rats with excess tetrathiomolybdate"J. Inorg. Biochem.. 78. 123-128 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 鈴木和夫: "生体による銅の制御機構と銅の選択的除去法:先天的銅代謝異常症ウィルソン病の治療法."薬学雑誌. (印刷中). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] K.T.Suzuki: "Hyphenated techniques as a tool to speciate biological metals:metallothionein and metal-binding proteins." Analusis. 26. 57-60 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Y.Ogra: "Targeting of tetrathiomolybdate to copper-metallothionein in the liver of LEC rats." J.Inorg.Biochem.70. 49-55 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 鈴木和夫: "バイオメタル-生体調節の多彩な役割と病態-山口正義編" 黒船出版, 232 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] K.T.Suzuki: "Production of ascorbate and hydroxyl radicals in the liver of LEC rats in relation to hepatitis." Res.Commun.Mol.Pathol.Pharmacol.96. 71-76 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] K.T.Suzuki: "Selective removal of copper accumulating in a form bound to metallothionein in the liver of LEC rats by tetrathiomolybdate." J.Trace Elem.Exp.Med.10. 101-109 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] K.T.Suzuki: "Mechanisms underlying the toxiic action of copper and the selective removal of Cu in the liver of LEC rats." J.Toxicol.Sci.22. 318 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] M.Rui: "Copper in plasma reflects its status and subsequent toxicity in the liver of LEC rats." Res.Commun.Mol.Pathol.Pharmacol.98. 335-346 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Y.Ogra: "Targeting of tetrathiomolybdate on the copper accumulating in the liver of LEC rats." J.Inorg.Biochem.(印刷中).

    • Related Report
      1997 Annual Research Report
  • [Publications] I.Sadakata: "Effect of cadmium on selective removal of copper by tetrathiomolybdate in the liver of LEC rats." Jpn.J.Toxicol.Environ.Health. (印刷中).

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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