Transcriptional regulation of the CYP3A7 gene specifically expressed in the human fetal liver.

CYP3A7 基因在人胎儿肝脏中特异性表达的转录调控。

• 批准号: 12470491
• 负责人: KAMATAKI Tetsuya
• 金额: $ 8万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470491/
• 关键词: 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

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.

CYP3A7是人胎儿肝脏中P450的主要亚型，参与内源性激素如3-硫酸脱氢表雄酮和视黄酸的代谢。这种酶还能生物激活一些致癌物，包括黄曲霉毒素B_1。有趣的是，肝脏中CYP3A7的表达在出生后消失。本研究的目的是阐明人类CYP3A7基因胎儿特异性表达的分子机制。通过使用具有胎儿肝细胞特征的人肝癌HepG2细胞和携带由CYP3A7启动子驱动的EGFP报告基因的转基因小鼠，我们发现了一种新的增强子3A7κB，该增强子赋予胎儿特异性的CYP3A7基因激活。在HepG2细胞中，肿瘤抑制蛋白p53与3A7κB增强子结合，刺激CYP3A7基因转录。然而，在成人肝细胞中，参与肝细胞生长停滞和终末分化的C/EBPα抑制了p53介导的激活。因此，我们得出结论，胎儿特异性CYP3A7基因的表达受p53和C/EBPα之间的拮抗作用控制。

项目成果

Ariyoshi N., et al.: "A single nucleotide polymorphism of CYP2B6 found in Japanese enhances catalytic activity by autoactivation"Biochem. Biophys. Res. Commun. 281. 1256-1260 (2001)

Ariyoshi N. 等人：“在日本发现的 CYP2B6 单核苷酸多态性通过自激活增强催化活性”Biochem。

Toide, K. et al.: "Aryl hydrocarbon hydroxylase represents CCYP1B1, and not CYP1A1, in human freshly isolated white cells : Trimodal distribution of Japanese population"Cancer Epidemiol. Biomarkers Prev.. (In press).

Toide, K. 等人：“在人类新鲜分离的白细胞中，芳基烃羟化酶代表 CCYP1B1，而不是 CYP1A1：日本人群的三峰分布”癌症流行病学。

Ariyoshi N. et al.: "Comparison of the Levels of Enzymes Involved in Drug Metabolism between Transgenic or Gene-knockout and the Parental Mice"Toxicologic Pathology. 29. 161-172 (2001)

Ariyoshi N.等人：“转基因或基因敲除小鼠与亲本小鼠之间参与药物代谢的酶水平的比较”毒理学病理学。

Ozeki, T. et al.: "Hepatocyte nuclear factor (HNF)-4α/γ, HNF-1α and vHNF-1 regulate the cellspecific expression of the human dihydrodiol dehydrogenase (DD) 4 /AKR1C4 gene"Archives Biochem. Biophys.. 405. 185-190 (2002)

Ozeki, T. 等人：“肝细胞核因子 (HNF)-4α/γ、HNF-1α 和 vHNF-1 调节人二氢二醇脱氢酶 (DD) 4 /AKR1C4 基因的细胞特异性表达”Archives Biochem.。 405. 185-190 (2002)

Matsumura, K. et al.: "Identification of a novel polymorphic enhancer of the human CYP3A4 gene"Mol.Pharmacol.. 65. 326-334 (2004)

Matsumura，K.等人：“人CYP3A4基因的新型多态性增强子的鉴定”Mol.Pharmacol.. 65. 326-334 (2004)