PXR: More Than Just a Master Xenobiotic Receptor

Abstract

Pregnane X receptor (PXR) is a nuclear receptor considered to be a master xenobiotic receptor that coordinately regulates the expression of genes encoding drug-metabolizing enzymes and drug transporters to essentially detoxify and eliminate xenobiotics and endotoxins from the body. In the past several years, the function of PXR in the regulation of xenobiotic metabolism has been extensively studied, and the role of PXR as a xenobiotic sensor has been well established. It is now clear, however, that PXR plays many other roles in addition to its xenobiotic-sensing function. For instance, recent studies have discovered previously unidentified roles of PXR in inflammatory response, cell proliferation, and cell migration. PXR also contributes to the dysregulation of these processes in diseases states. These recent discoveries of the role of PXR in the physiologic and pathophysiologic conditions of other cellular processes provides the possibility of novel targets for drug discovery. This review highlights areas of PXR regulation that require further clarification and summarizes the recent progress in our understanding of the nonxenobiotic functions of PXR that can be explored for relevant therapeutic applications.

Fig. 1.

Schematic representation of the possible PXR dimers and trimer. (A) PXR forms a homodimer and binds to PXR response elements within the promoter of the target gene. Mutation to the PXR-PXR interacting surface has been shown to decrease PXR transcriptional activity. (B) PXR forms a heterodimer with RXR, its obligate binding partner, to regulate the transcription of target genes. (C) PXR can potentially form a PXR-PXR-RXR trimer because the interacting surfaces of PXR homodimer and PXR-RXR heterodimer are different. PXR-RXR dimer formation in regulating PXR activity is well established. PXR-PXR dimer formation is relatively new and requires further exploration to gain a better understanding of its function. The idea that PXR-PXR-RXR trimer can potentially form in cells and may be required for full PXR transcriptional activity is thought provoking and warrants investigation.

Fig. 2.

PXR serves a dual role in regulating cell proliferation. PXR could inhibit cell proliferation by inhibiting the G2-M phase progression of cell cycle (left panel), or enhance cell proliferation by imposing its effects in the G1-S phase transition of cell cycle. The driving factor for what role to favor remains unknown, but whatever role is favored is predominant in that model.

Fig. 3.

PXR enhances cell migration through the GADD45β-p38, HNF4α-IGFBP1, and FGF19 regulatory axes.

Fig. 4.

Schematic summary of nonxenobiotic functions of PXR. It has become clearer that PXR plays critical roles in physiologic and pathophysiologic states beyond its canonical xenobiotic-sensing function. BAK1, Bcl-2 antagonist/killer 1; BIRC2, baculoviral apoptosis inhibitory protein repeat–containing protein 2; MAD1, mitotic arrest-deficient 1; TNF-α, tumor necrosis factor-α.