Received for publication June 15, 2005.
Revised October 14, 2005.
Accepted for publication October 14, 2005.

Transcriptional regulation of the PXR gene: Identification and characterization of a functional PPAR-binding site within the proximal promoter of the PXR gene

Abstract

The Pregnane-X-receptor (PXR, NR1I2) is widely regarded as a central factor in the body's response to changes in the fluxome, the overall metabolite profile in the body. PXR expression is regulated by a number of chemicals at the transcriptional level; the majority of these chemicals are ligands for PXR and substrates for PXR target genes. However, transcriptional activators of PXR such as clofibrate do not appear to be PXR ligands, or substrates for its target genes. Understanding the molecular mechanisms underlying both these expected, and more importantly unexpected, transcriptional activations is central to fully understanding the roles of PXR in the human body. We have carried out an in silico analysis of the human PXR proximal promoter, identifying putative protein:DNA interaction sites within the 2Kb 5' to the putative transcription start site. These sites included several for liver-enriched transcription factors such as the HNFs and C/EBP, and COUP-TF, commensurate with the high expression of PXR in liver. Further, we identified putative binding sites for a number of ligand activated transcription factors, suggesting these factors may regulate PXR gene expression. Further analysis of this regulatory region has shown that transcriptional activation of PXR by PPAR is via a binding site located approximately 1.3kb upstream of the putative transcription start site, with ablation of this site preventing PPAR-mediated activation of PXR gene expression. We present a model of how regulation of PXR gene expression by ligand-activated transcription factors may play a central role in the body's response to xenobiotic exposure

Key words: adverse drug reactions, induction, PXR, RXR, SXR

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