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

CYP3A7是人胎肝中一种主要的P450亚型，参与脱氢表雄酮、3-硫酸酯和维甲酸等内源性激素的代谢。这种酶还可以激活一些致癌物质，包括黄曲霉毒素B_1。有趣的是，出生后肝脏中的CYP3A7表达消失。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。利用具有胎肝细胞特征的人肝癌细胞系HepG2和由3A7启动子驱动的携带绿色荧光蛋白报告基因的转基因小鼠，我们鉴定了一种新的增强子，命名为3A7κB，该增强子具有胎儿特异性激活细胞色素P3A7基因的功能。在肝癌细胞中，肿瘤抑制蛋白P53与3A7κB增强子结合，并刺激3A7基因转录。然而，在成年肝细胞中，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，我们认为CYP3A7基因的胎儿特异性表达受P53和C/EBPα的拮抗作用所控制。

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.