2004 Fiscal Year Final Research Report Summary
Elucidation of defensive mechanism against xenobiotics in cytokine knock out and pathologic model mice
| Project/Area Number |
15390041
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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) |
NUMAZAWA Satoshi Showa Univ, Sch Pharmaceut Sci., Associate Professor, 薬学部, 助教授 (80180686)
TANAKA Sachiko Showa Univ., Sch Pharmaceutt Sci., Assistant Professor, 薬学部, 講師 (00197419)
ASHINO Takashi Showa Univ., Sch. Pharmaceut Sci., Assistant Professor, 薬学部, 助手 (00338534)
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| Project Period (FY) |
2003 – 2004
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| Keywords | Cytochrome P450 / Cytokine / Lipopolysaccharide / HTLV-I Tg mouse / Heine oxygenase-1 / Cocaine / CYP2B / Constitutive androstane receptor |
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| Research Abstract |
Down-regulation of cytochrome P450 (P450) gene and induction of heme oxygenase-1 (HO-1) gene under oxidative stress and pathological conditions have been shown to be indicative as protective responses. It has been shown that these gene expressions are regulated by inflammatory cytokines such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor a (TNFα). In this research, we aimed to elucidate relationship between gene regulations of P450 and HO-1 and pathological conditions using various cytokine knock out mice and disease model mice. We clarified that IL-6 and TNFα play important role in down-regulation of CYP3A11 and CYP2C29 mRNAs during acute phase response to Bacillus Calmette-Guerin. Moreover, we found that CYP3A11 and CYP2B9 mRNA expressions were suppressed in rheumatoid arthritis model (HTLV-I Tg) mice. In hepatotoxic injury model mice evoked by cocaine, we found the indication of HO-1, and that the increased onset and exacerbation of liver injury by the drug in LPS-treated mice, due to IL-6 and TNFα. CYP2B induction requires nuclear translocation of constitutive androstane receptor (CAR). However, CYP2B induction by xenobiotics attenuates under the hepatoma. We clarified that translocation of CAR was impaired in hepatoma. These findings suggest that P450 and HO-1 expressions were affected under various pathological conditions and were regulated by various cytokines. We also exploited important roles of Nrf2 and Bachl in HO-1 induction.
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