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CELLULAR AND MOLECULAR
to Synergistically Activate the Human CYP2C9 Promoter
Human Metabolism Section, Laboratory of Pharmacology and Chemistry (Y.C., J.A.G.), Biostatistics Branch (G.K.), and Pharmacogenetics Section (M.N.), Laboratory of Reproductive and Developmental Toxicology, Department of Health and Human Services, National Institutes of Health, National Institutes of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina
CYP2C9 is an important human drug-metabolizing enzyme that is expressed primarily in liver. Recent studies in our laboratory have shown that the nuclear receptor pregnane X receptor (PXR) is important in the transcriptional activation of the CYP2C9 promoter by drugs such as rifampicin and that the essential element is a constitutive androstane receptor (CAR)/PXR site –1839 bp upstream of the translation start site. Both CAR and PXR transcriptionally up-regulate 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 hepatic nuclear factor (HNF) 4
binding sites at –152 and –185 bp of the CYP2C9 promoter, both of which bind HNF4 in gel shift assays and transcriptionally up-regulate 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 up-regulation 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.
Address correspondence to: Dr. Joyce Goldstein, National Institutes of Environmental Health Sciences, Mail Drop A3-02, PO Box 12233, Research Triangle Park, NC 27709. E-mail: goldste1{at}niehs.nih.gov
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