| Project/Area Number |
12470491
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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 |
Biological pharmacy
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
KAMATAKI Tetsuya HOKKAIDO Univ., Grad.School of Pharmaceu.Sci, Prof., 大学院・薬学研究科, 教授 (00009177)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAZAKI Hiroshi HOKKAIDO Univ., Grad.School of Pharmaceu.Sci, Asso.Prof., 大学院・薬学研究科, 助教授 (30191274)
藤田 健一 北海道大学, 大学院・薬学研究科, 助手 (60281820)
有吉 範高 北海道大学, 大学院・薬学研究科, 助教授 (00243957)
高橋 芳樹 北海道大学, 大学院・薬学研究科, 助手 (80292019)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥12,500,000 (Direct Cost: ¥12,500,000)
Fiscal Year 2002: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2001: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2000: ¥6,100,000 (Direct Cost: ¥6,100,000)
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| Keywords | P450 / CYP3A7 / fetal toxicity / development / gene regulation / transgenic mouse / p53 / C / EBPα / 胎児 / CYP3A5 / CYP3A4 / ヒト肝 / 発現調節 / 個人差 / 時期特異的発現調節 / サルモネラ菌 |
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| Research Abstract |
CYP3A7 is a major P450 isoform in the human fetal liver and is involved in the metabolism of endogenous hormones such as dehydroepiandrosterone 3-sulfate and retinoic acids. This enzyme also bioactivates some carcinogens including aflatoxin B_1. Interestingly, the expression of CYP3A7 in the liver disappears after birth. The aim of this study is to elucidate the molecular mechanism responsible for the fetus-specific expression of the human CYP3A7 gene. By using human hepatoma HepG2 cells with characteristics of fetal hepatocytes and a transgenic mouse carrying EGFP reporter gene driven by the CYP3A7 promoter, we identified a novel enhancer designated as 3A7κB that confered the fetus-specific activation of the CYP3A7 gene. In HepG2 cells, tumor suppresser protein p53 bound to the 3A7κB enhancer and stimulated the CYP3A7 gene transcription. In adult hepatocytes, however, C/EBPα, which is involved in the growth-arrest and the terminal differentiation of hepatocytes, repressed the p53-mediated activation. Thus, we conclude that the fetus-specific expression of the CYP3A7 gene is controlled by the antagonistic action between p53 and C/EBPα.
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