2002 Fiscal Year Final Research Report Summary
Changes in cytochrome P450 and stress responsive proteins under oxidative stress
| Project/Area Number |
13672347
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Environmental pharmacy
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| Research Institution | Showa university |
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Principal Investigator |
YOSHIDA Takemi Showa Univ. Sch. Pharmaceut. Sci., Professor, 薬学部, 教授 (20138415)
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| Co-Investigator(Kenkyū-buntansha) |
ASHINO Takashi Showa Univ. Sch. Pharmaceut. Sci., Assistant, 薬学部, 助手 (00338534)
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| Project Period (FY) |
2001 – 2002
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| Keywords | cytochromeP450 / heme oxygenese-1 / cytokine / oxidative stress / MAPK / BCG / LPS / STAT |
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| Research Abstract |
The purpose of this study was to explore the roles of cytokines in the regulation of cytochrome P450(CYP) stress responsive enzyme heme oxygenase-1(HO-1).We examined the effect of each cytokine on their target cells,especially the expression of HO-1 and CYP in the liver of IL-1α/β(IL-1),TNFα and IL-6 knockout(KO) mice.We found that TNFα played an important role in HO-1 gene expresssion by LPS.Based on these findings, we also examined major signal transduction from LPS in cytokine knockout mice. LSP has been shown to lead HO-1 gene expression via activation of AP-1. Therefore,we determined the effect of LPS on signal transduction from MAPK cascade leading to HO-1 gene expression in TNFα KO mice,which produced little response to the agent. We found that TNFα plays actively in the LPS-mediated induction of HO-1 gene expression, and its signal is conducted via p38 and/or JNK.In addition, cocaine-mediated HO-1 was modulated not only TNFα but also IL-6.Moreover, we clarified the important role of cytokines was in BCG-mediated down-regulation of CYP3A
and penobarbital-mediated induction of CYP2B by using cytokine KO mice. Suggesting IL-6 is an important factor for CYP regulation. This study thus indicate that cytokine KO mice are very useful in vivo model to explain their roles in the regulation of CYP and HO-1 Comprehensive study on enzyme indication and stress response and their signal transduction in cytokine KO mice could lead to exploit the significant role of each cytokine played vivo.
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