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Received for publication March 30, 2005.
Revised May 24, 2005.
Accepted for publication May 24, 2005.
to Synergistically Activate the Human CYP2C9 Promoter
CYP2C9 is an important human drug-metabolizing enzyme which is expressed primarily in liver. Recent studies in our laboratory have shown that the nuclear receptor PXR is important in the transcriptional activation of the CYP2C9 promoter by drugs such as rifampicin, and that the essential element is a CAR/PXR site -1839 bp upstream of the translation start site. Both CAR and PXR transcriptionally upregulate the CYP2C9 promoter via these elements. In the present study, we ask whether additional sites in the proximal promoter also play a role in this induction. We identify two proximal HNF4
binding sites at -152 bp and -185 bp of the CYP2C9 promoter, both of which bind HNF4 in gel-shift assays and transcriptionally upregulate this promoter in response to HNF4 in HepG2 cells. HNF4 synergizes with CAR and with PXR in HepG2 cells treated with rifampicin. The synergy only occurs when the CAR/PXR binding site at -1839 bp is present. Mutation of the two HNF4 binding sites differentially prevented upregulation of CYP2C9 promoter by both CAR as well as HNF4, synergy between the two receptors, and essentially abolished induction by rifampicin in HepG2 cells transfected with PXR. These studies strongly support the hypothesis that there is cross-talk between distal CAR/PXR sites and HNF4 binding sites in the CYP2C9 promoter and that the HNF4 sites are required for maximal induction of the CYP2C9 promoter.
Key words:
CAR, CYP2C9, HNF4, PXR, promoter regulation, rifampicin
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