The Interface between Cell Signaling Pathways and Pregnane X Receptor

Abstract

Highly expressed in the enterohepatic system, pregnane X receptor (PXR, NR1I2) is a well-characterized nuclear receptor (NR) that regulates the expression of genes in the liver and intestines that encode key drug metabolizing enzymes and drug transporter proteins in mammals. The net effect of PXR activation is to increase metabolism and clear drugs and xenobiotics from the body, producing a protective effect and mediating clinically significant drug interaction in patients on combination therapy. The complete understanding of PXR biology is thus important for the development of safe and effective therapeutic strategies. Furthermore, PXR activation is now known to specifically transrepress the inflammatory- and nutrient-signaling pathways of gene expression, thereby providing a mechanism for linking these signaling pathways together with enzymatic drug biotransformation pathways in the liver and intestines. Recent research efforts highlight numerous post-translational modifications (PTMs) which significantly influence the biological function of PXR. However, this thrust of research is still in its infancy. In the context of gene-environment interactions, we present a review of the recent literature that implicates PXR PTMs in regulating its clinically relevant biology. We also provide a discussion of how these PTMs likely interface with each other to respond to extracellular cues to appropriately modify PXR activity.

Indole-3-propionic Acid Attenuates HI-Related Blood–Brain Barrier Injury in Neonatal Rats by Modulating the PXR Signaling Pathway

“…After all, the liver and small intestine are PXR-enriched sites. 20,30,49 In summary, IPA has played a BBB protective role in the neonatal rat model of HI brain injury. IPA can attenuate inflammation by inhibiting NF-κB signaling.…”

“…PXR, a ligand-activated transcription factor, is a member of the NR1I subfamily of the nuclear receptor superfamily. The effects of PXR were initially studied in the liver and the small intestine, which showed enrichment of PXR. ,, The mechanism of interaction between PXR and NF-κB has been reported to explain the potentially anti-inflammatory effects of PXR. However, these studies mainly focus on intestinal inflammation.…”

“…We speculate that it may be related to the expression level of PXR in cerebrovascular endothelial cells. After all, the liver and small intestine are PXR-enriched sites. ,, …”

Effect of polymorphisms in drug metabolism and transportation on plasma concentration of atorvastatin and its metabolites in patients with chronic kidney disease

“…The pregnane X receptor (PXR, NR1I2), a prototypical member of the nuclear receptor superfamily, can be activated by a range of steroids or exogenous drugs to regulate the transcription of target genes, and plays an important role in the regulation of the environmental homeostasis and pathophysiological processes (Rogers et al, 2021). Atorvastatin acts as a ligand for PXR and activates transcription of target genes, including CYP3A4, CYP3A5, SLC O 1B1 and ABCB1 (Marino et al, 2011;Hoffart et al, 2012), thereby affecting the metabolic process of the drug.…”

Design and Optimization of 1H-1,2,3-Triazole-4-carboxamides as Novel, Potent, and Selective Inverse Agonists and Antagonists of PXR

“…PXR was originally identified as a master transcription factor regulating the expression of key genes that encode members of the phase I and phase II metabolic enzymes and drug transporters. − PXR is the main regulator of the CYP3A4 gene, which encodes cytochrome P450 3A4, the most abundant hepatic and intestinal phase I enzyme, which is responsible for metabolizing more than 50% of clinically used drugs, along with many other xenobiotics and endobiotics, in humans . In the absence of ligands, PXR is located in the cytoplasm and forms a complex with cytoplasmic constitutive active/androstane receptor retention protein (CCRP) and the chaperone protein heat-shock protein (Hsp)­90 .…”