The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism

Abstract

The steroid and xenobiotic receptor (SXR) (also known as pregnane X receptor or PXR) is a nuclear hormone receptor activated by a diverse array of endogenous hormones, dietary steroids, pharmaceutical agents, and xenobiotic compounds. SXR has an enlarged, flexible, hydrophobic ligand binding domain (LBD) which is remarkably divergent across mammalian species and SXR exhibits considerable differences in its pharmacology among mammals. The broad response profile of SXR has led to the development of "the steroid and xenobiotic sensor hypothesis". SXR has been established as a xenobiotic sensor that coordinately regulates xenobiotic clearance in the liver and intestine via induction of genes involved in drug and xenobiotic metabolism. In the past few years, research has revealed new and mostly unsuspected roles for SXR in modulating inflammation, bone homeostasis, vitamin D metabolism, lipid homeostasis, energy homeostasis and cancer. The identification of SXR as a xenobiotic sensor has provided an important tool for studying new mechanisms through which diet, chemical exposure, and environment ultimately impact health and disease. The discovery and pharmacological development of new PXR modulators might represent an interesting and innovative therapeutic approach to combat various diseases.

Figure 1. Structure of SXR gene, protein and mRNA isoforms.

a) The genomic structure of SXR and its three splice variants. The protein coding regions are depicted as filled boxes and the untranslated 5’ and 3’ regions are shown as white boxes. The horizontal line represents introns. b) The structure of splice variants of SXR. Variant 1 originates from exon 1a and gives rise to proteins 1l and 1s through the use of the alternative initiation codons shown by arrows. Variant 2 originates from exon 1b and it makes the longest protein. Variant 3 represents an in-frame deletion of 111bp at the 5’ end of exon 5 (shown by white box). The arrows depict translation initiation codon. c) Single nucleotide polymorphisms (SNPs) in SXR. Fifteen known non-synonymous SNPs of SXR are represented by * and arranged according to their position on the wild-type (variant 1l) SXR protein. The DNA and ligand binding domains of the protein are shown in black boxes.