Pregnane X receptor

Function

PXR is a nuclear receptor whose primary function is to sense the presence of foreign toxic substances and in response up regulate the expression of proteins involved in the detoxification and clearance of these substances from the body. PXR belongs to the nuclear receptor superfamily, members of which are transcription factors characterized by a ligand-binding domain and a DNA-binding domain. PXR is a transcriptional regulator of the cytochrome P450 gene CYP3A4, binding to the response element of the CYP3A4 promoter as a heterodimer with the 9-cis retinoic acid receptor RXR. It is activated by a range of compounds that induce CYP3A4, including dexamethasone and rifampicin.

Ligands

Agonists

PXR is activated by a large number of endogenous and exogenous chemicals including steroids (e.g., progesterone, 17α-hydroxyprogesterone, 17α-hydroxypregnenolone, 5α-dihydroprogesterone, 5β-dihydroprogesterone, allopregnanolone, corticosterone, cyproterone acetate, spironolactone, dexamethasone, mifepristone), antibiotics (e.g., rifampicin, rifaximin), antimycotics, bile acids, hyperforin (a constituent of St. John's Wort), and other compounds such as meclizine, paclitaxel, cafestol, and forskolin.

Antagonists

Ketoconazole is an example of one of the relatively few-known antagonists of the PXR. SPA70 (also known as LC-1) was recently identified and characterized as a potent and selective PXR antagonist.

Mechanism

Like other type II nuclear receptors, when activated, it forms a heterodimer with the retinoid X receptor, and binds to hormone response elements on DNA which elicits expression of gene products.

One of the primary targets of PXR activation is the induction of CYP3A4, an important phase I oxidative enzyme that is responsible for the metabolism of many drugs. In addition, PXR up regulates the expression of phase II conjugating enzymes such as glutathione S-transferase and phase III transport uptake and efflux proteins such as OATP2 and MDR1.

References

References

1. [https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=8856&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum Entrez result for NR1I2].
2. (September 1998). "The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions". The Journal of Clinical Investigation.
3. (October 1998). "Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction". Proceedings of the National Academy of Sciences of the United States of America.
4. (October 2002). "The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism". Endocrine Reviews.
5. "Entrez Gene: NR1I2 nuclear receptor subfamily 1, group I, member 2".
6. (July 2007). "The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors". Molecular Endocrinology.
7. (February 2018). "Forskolin convalesces memory in high fat diet-induced dementia in wistar rats-Plausible role of pregnane x receptors". Pharmacological Reports.
8. (February 2005). "Induction of drug metabolism by forskolin: the role of the pregnane X receptor and the protein kinase a signal transduction pathway". The Journal of Pharmacology and Experimental Therapeutics.
9. (November 2013). "Reverse yeast two-hybrid system to identify mammalian nuclear receptor residues that interact with ligands and/or antagonists". Journal of Visualized Experiments.
10. (February 2013). "PXR antagonists and implication in drug metabolism". Drug Metabolism Reviews.
11. (December 2017). "High-Throughput Screening Identifies 1,4,5-Substituted 1,2,3-Triazole Analogs as Potent and Specific Antagonists of Pregnane X Receptor". Assay and Drug Development Technologies.
12. (September 2017). "SPA70 is a potent antagonist of human pregnane X receptor". Nature Communications.
13. (September 2001). "Regulation of the rat glutathione S-transferase A2 gene by glucocorticoids: involvement of both the glucocorticoid and pregnane X receptors". Molecular Pharmacology.
14. (March 2001). "The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity". Proceedings of the National Academy of Sciences of the United States of America.
15. (May 2001). "The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux". Nature Medicine.
16. (May 2001). "Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin". The Journal of Biological Chemistry.