CCAAT/enhancer-binding protein alpha (C/EBPalpha) and hepatocyte nuclear factor 4alpha (HNF4alpha) synergistically cooperate with constitutive androstane receptor to transactivate the human cytochrome P450 2B6 (CYP2B6) gene: application to the development of a metabolically competent human hepatic cell model.

The Journal of Biological Chemistry
Marta BenetRamiro Jover

Abstract

The transcription of tissue-specific and inducible genes is usually subject to the dynamic control of multiple activators. Dedifferentiated hepatic cell lines lose the expression of tissue-specific activators and many characteristic hepatic genes, such as drug-metabolizing cytochrome P450. Here we demonstrate that by combining adenoviral vectors for CCAAT/enhancer-binding protein alpha (C/EBPalpha), hepatocyte nuclear factor 4alpha (HNF4alpha), and constitutive androstane receptor, the CYP2B6 expression and inducibility by CITCO are restored in human hepatoma HepG2 cells at levels similar to those in cultured human hepatocytes. Moreover, several other phase I and II genes are simultaneously activated, which suggests that this is an effective approach to endow dedifferentiated human hepatoma cells with a particular metabolic competence and response to inducers. In order to gain insight into the molecular mechanism, we examined the cooperation of these three transcription factors on the CYP2B6 5'-flanking region. We show new CYP2B6-responsive sequences for C/EBPalpha and HNF4alpha and a novel synergistic regulatory mechanism whereby C/EBPalpha, HNF4alpha, and constitutive androstane receptor bind and cooperate through proximal an...Continue Reading

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Citations

Dec 17, 2014·Acta Pharmacologica Sinica·Jiong YanWen Xie
Apr 15, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Takeshi HoriMasahiko Negishi
May 22, 2016·Toxicological Sciences : an Official Journal of the Society of Toxicology·Laia TolosaRamiro Jover
May 16, 2015·Archives of Toxicology·Kaoru KobayashiMasahiko Negishi
Jun 27, 2019·Toxicological Sciences : an Official Journal of the Society of Toxicology·Andy RampersaudDavid J Waxman
Aug 27, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Barbara PetzuchAlbert Braeuning

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