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Received for publication July 15, 2004.
Revised October 27, 2004.
Accepted for publication October 28, 2004.
Recent data has made it increasingly clear that the gene expression profile of a cell system, and its alteration in response to external stimuli, is highly dependent on both the higher order chromatin structure of the genome, and the interaction of gene products in interpreting stimuli. To further explore this phenomenon we have examined the role of both of these factors in controlling xenobiotic-mediated gene expression changes in primary and transformed human hepatocytes (Huh7). Using quantitative PCR, expression levels of several transcription factors implicated in the liver specific regulation of the CYP3A gene family were examined in human adult and foetal liver RNA samples. These expression profiles were then compared to those obtained from both primary and transformed human hepatocytes, showing that in general, cultured cells exhibit a distinct profile compared to either the foetal or adult samples. Transcriptome profiles before and after exposure to the CYP3A transcriptional activators rifampicin, dexamethasone, pregnane-16
-carbonitrile and phenobarbital were subsequently examined. Whereas exposure to these compounds elicited a dose-dependent increase in CYP3A transcription in primary hepatocytes, no alteration in expression levels was observed for the hepatoma cell line Huh7. Alteration in the expression levels of PXR and COUP-TFI expression and the disruption of higher order chromatin within Huh7 cells altered CYP3A expression and/or activation by xenobiotics towards that observed in primary hepatocytes. This data provides potential roles for these two processes in regulating CYP3A expression in vivo.
Key words:
CYP3A, human CYP enzymes, SXR, transcriptional regulation
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