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

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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.