Mechanism of cytotoxicity of Lysosphinogolipids, Especially Those of Impairment of Cellular Respiration and Their "Detoxication"
| Project/Area Number |
01570461
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Neurology
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| Research Institution | University of Occupational and Environmental Health |
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Principal Investigator |
IGISU Hideki Faculty of Medicine, University of Occupational and Environmental Health, Associate Professor, 医学部, 助教授 (60108686)
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| Project Period (FY) |
1989 – 1990
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| Project Status |
Completed (Fiscal Year 1990)
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| 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)
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| Keywords | Lysosphingolipid / Psychosine / Galactosylsphingosine / Glucosylsphingosine / Sphingosine / Lipidosis / Cell respiration / Albumin |
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| 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.
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Report
(3 results)
Research Products
(16 results)
