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Unique Transcription Start Sites and Distinct Promoter Regions Differentiate the Pregnane X Receptor (PXR) Isoforms PXR 1 and PXR 2

Department of Environmental and Molecular Toxicology (L.M.T., A.D.W.) and Department of Plant Pathology (T.L.S.), North Carolina State University, Raleigh, North Carolina

The pregnane X receptor (PXR) is known as the xenosensing receptor responsible for coordinated regulation of metabolic genes in response to diverse xenobiotic challenges. In particular, the ability of the PXR to regulate CYP3A4, the enzyme capable of metabolizing more than 60% of all pharmaceuticals, defines its metabolic importance. Currently the list of PXR ligands and target genes is extensive, yet investigations into the regulation and expression of PXRs are few. After an initial review of available sequence data, we discovered discrepancies in the 5' untranslated region (UTR) and transcriptional start site (TSS) characterizations of the human PXR gene and subsequently endeavored to define TSSs and proximal promoters for isoforms PXR 1 and PXR 2. Reverse transcriptase-polymerase chain reaction and primer extension experiments performed on RNA from human liver identified two TSSs for each receptor isoform. These results extended the 5'UTR sequence of each isoform and defined new proximal promoters for both. Candidate response elements for liver-enriched transcription factors and other receptors were found in both proximal promoters. Quantitative PCR from human liver illustrated a highly variable expression profile for total PXRs; yet PXR 2 expression represented a consistent 2 to 5% of total PXR expression, despite the observed variability. Transfection experiments demonstrated that PXR 1 and PXR 2 had comparable abilities to transcriptionally activate the CYP3A4 promoter. Collectively, comparable function, consistent expression, and independent regulation suggest that PXR 2 is capable of contributing to the cumulative function of PXRs and should be included in the larger investigations of PXR expression and regulation.