1993 Fiscal Year Final Research Report Summary
Study on the mechanism of drug-evoked peroxisomal enzyme induction
| Project/Area Number |
04671372
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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 |
Biological pharmacy
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| Research Institution | Tokyo College of Pharmacy |
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Principal Investigator |
WATANABE Takafumi Tokyo College of Pharmacy, Department of Clinical biochemistry, Associate professor, 薬学部, 助教授 (70096692)
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| Co-Investigator(Kenkyū-buntansha) |
YAMADA Junji Tokyo College of Pharmacy, Department of Clinical biochemistry, Assistant profes, 薬学部, 助手 (60200721)
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| Project Period (FY) |
1992 – 1993
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| Keywords | Peroxisome / Hypolipidemic drug / Protein phosphorylation / Induction mechanism / Phospholipase C / Protein kinase C / Tyrosine kinase / Rat |
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| Research Abstract |
A mechanism of drug-evoked peroxisomal enzyme induction in liver was studied with respect to species difference and cellular signal transduction system.
(1)Dehydroepiandrosteron (DHEA) was orally dosed to rat, mouse, hamster and guine a pig, and hepatic peroxisomal fatty acid oxidation activity was determined. The activity was increased markedly in rat and mouse, showing endogenous hormone DHEA is a typical peroxisomal enzyme inducer, like clofibrate, etc.
(2)An induction of peroxisomal fatty acid oxidation by peroxisome proliferators in rat hepatocytes was markedly suppressed by calmodulin or protein kinase C inhibitor. Analysis of mRNA levels of peroxisomal bifunctional enzyme showed that these inhibitors blocked the induction at transcription level. Furthermore, inhibitors of phospho-lipase C and tyrosine kinase also showed suppressive activity on peroxisomal enzyme induction.
(3) Peroxisome proliferators induced sustained increase in cellular calcium level.
(4)Associated with an increaase in cellular calcium level, increase in phosphorylation of 50-55kDa protein in cytosol and 11-13kDa protein in nuclear fraction in peroxisome proliferator-treated rat hepatocytes.
(5)These results suggest that enzyme induction triggerd by peroxisome proliferator by interaction with nuclear receptor, but the extent was regulated by cellular signal transduction.
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