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Mechanism of cytotoxicity of Lysosphinogolipids, Especially Those of Impairment of Cellular Respiration and Their "Detoxication"

Research Project

Project/Area Number 01570461
Research Category

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

Allocation TypeSingle-year Grants
Research Field Neurology
Research InstitutionUniversity of Occupational and Environmental Health

Principal Investigator

IGISU Hideki  Faculty of Medicine, University of Occupational and Environmental Health, Associate Professor, 医学部, 助教授 (60108686)

Project Period (FY) 1989 – 1990
Project Status Completed (Fiscal Year 1990)
Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1990: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1989: ¥1,400,000 (Direct Cost: ¥1,400,000)
KeywordsLysosphingolipid / Psychosine / Galactosylsphingosine / Glucosylsphingosine / Sphingosine / Lipidosis / Cell respiration / Albumin
Research Abstract

Although enzymatic defects have been established in most sphingolipidoses, it has not been defined how the enzumatic defect is related to the pathophysiology of the disorder. Possible involvement of endogenous "toxins" have been suspected. In Krabbe disease there is ample evidence for such a hypothesis ; psychosine (galactosylsphingosine), a toxic lipid and a natural substrate of the missing enzyme, appears to play an important role in causing the devastating pathology. Similar mechanism may be present in other diseases such as Gaucher or Tay-Sachs disease.
We found that galactosylsphingosine, glucosylsphingosine and sphingosine all inhibit cytochrome c oxidase (COX) in mitochondria. However, such inhibitory effects were not seen when COX was purified. When COX was reconstituted with a phospholipid, clear inhibitory effects were noted, suggesting that the inhibition of COX was caused by perturbation of the environment of the enzyme in inner membrane of mitochondria. On the other hand, effects of these lysosphingoslipids were all abolished by albumin. Using gel filtration or gel equilibrium analysis, albumin was found to have a high affinity against psychosine. Effects of albumin did not differ among three lysolipids examined. Thus, the large capacity of albumin to bind these lipids seems to underlie the "detoxicating" actions of albumin and these suggest possible use of albumin for the treatment of sphingolipidoses.
Since ammonia and acrylamide, which may be regarded as "endogenous toxins", can also impair energy metabolism, attention to energy metabolism and its enzymes may be rewarding in the study of endogenous neurotoxic substances.

Report

(3 results)
  • 1990 Annual Research Report   Final Research Report Summary
  • 1989 Annual Research Report
  • Research Products

    (16 results)

All Other

All Publications (16 results)

  • [Publications] 伊規須 英輝: "サイコシン:脳が作る「毒」ーその作用機序ー" 産業医科大学雑誌. 11. 487-493 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 伊規須 英輝,他: "巨大軸索ニュ-ロパチ-ーアクリルアミド中毒との比較ー" 福岡医学雑誌. 81. 163-169 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Igisu,H. et al: "Binding of galactosylsphingosine(psychosine)by albumin" Lipids. 25. 65-68 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Matsuoka,M.,Igisu,H. et al: "Effects of acrylamide and N'Nーmethyleneーbisーacrylamide on creatine kinase activity" Brain Res.507. 351-353 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Matsuoka,M.,Igisu,H. et al: "Effects of ammonia on brain energy metabolites ーーDoseーdependent alternations" J.Neurochem.55. 354-355 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Igisu, H.: "Psychosine : "Toxin" produced in the brain-its mechanism of action." Journal of University of Occupational and Environmental Health. 11. 487-493 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Igisu, H., et al.: "Giant axonal neuropathy--comparison with acrylamide intoxication" Fukuoka Acta Medica. 81. 163-169 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Igisu, H., et al.: "Binding of galactosylsphingosine (psychosine) by albumin." Lipids. 25. 65-68 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Matsuoka, M., Igisu, H., et al.: "Effects of acrylamide and N, N'-methylene-bis-acrylamide on creatine kinase activity." Brain Research. 507. 351-353 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Matsuoka, M., Igisu, H., et al.: "Effects of ammonia on brain energy metabolite--Dose-dependent alterations." Journal of Neurochemistry. 55. 354-355 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 伊規須 英輝 他: "巨大軸索ニュ-ロパチ- ーアクリルアミド中毒との比較ー" 福岡医学雑誌. 81. 163-169 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Igisu,H.et al: "Binding of galactosylsphingosine(Psychosine)by albumin" Lipids. 25. 65-68 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Matsuoka,M.,Igisu,H.et al: "Effects of acrylamide and N'Nーmethyleneーbisーacrylamide on creatine kinase activity" Brain Res.507. 351-353 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Matsuoka,M.,Igisu,H.et al: "Effects of ammonia on brain energy metabolites ーーDoseーdependent alternations" J.Neurochem.55. 354-355 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] 伊規須英輝: "サイコシン:脳が作る「毒」ーその作用機序ー" 産業医科大学雑誌. 11. 487-493 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Igisu,H.,et al.: "Binding of galactosylsphingosine(psychosine)by albumin" Lipids. 25. 65-68 (1990)

    • Related Report
      1989 Annual Research Report

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Published: 1989-04-01   Modified: 2016-04-21  

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