Pregnane X receptor and natural products: beyond drug–drug interactions

Staudinger, Jeff; Ding, Xunshan; Lichti, Kristin

doi:10.1517/17425255.2.6.847

Cited by 76 publications

(45 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Highly expressed in the liver and intestinal epithelium, the PXR has been previously characterized as a master regulator of xenobiotic metabolism and clearance (Watkins et al, 2002;Staudinger et al, 2006;Shukla et al, 2011;Dou et al, 2013;Pondugula and Mani, 2013). Acting as a sensor of exogenous chemicals, the PXR's activation leads to the expression of a variety of target genes related to detoxification and efflux pathways.…”

Section: Discussionmentioning

confidence: 99%

Pregnane X Receptor Activation Attenuates Inflammation-Associated Intestinal Epithelial Barrier Dysfunction by Inhibiting Cytokine-Induced Myosin Light-Chain Kinase Expression and c-Jun N-Terminal Kinase 1/2 Activation

Garg¹,

Zhao²,

Erickson³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

The inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex etiology. IBD is thought to arise in genetically susceptible individuals in the context of aberrant interactions with the intestinal microbiota and other environmental risk factors. Recently, the pregnane X receptor (PXR) was identified as a sensor for microbial metabolites, whose activation can regulate the intestinal epithelial barrier. Mutations in NR1I2, the gene that encodes the PXR, have been linked to IBD, and in animal models, PXR deletion leads to barrier dysfunction. In the current study, we sought to assess the mechanism(s) through which the PXR regulates barrier function during inflammation. In Caco-2 intestinal epithelial cell monolayers, tumor necrosis factor-a/interferon-g exposure disrupted the barrier and triggered zonula occludens-1 relocalization, increased expression of myosin light-chain kinase (MLCK), and activation of c-Jun N-terminal kinase 1/2 (JNK1/2).Activation of the PXR [rifaximin and [[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenylidene]bis-phosphonic acid tetraethyl ester (SR12813); 10 mM] protected the barrier, an effect that was associated with attenuated MLCK expression and JNK1/2 activation. In vivo, activation of the PXR [pregnenolone 16a-carbonitrile (PCN)] attenuated barrier disruption induced by toll-like receptor 4 activation in wild-type, but not Pxr2/2, mice. Furthermore, PCN treatment protected the barrier in the dextran-sulfate sodium model of experimental colitis, an effect that was associated with reduced expression of mucosal MLCK and phosphorylated JNK1/2. Together, our data suggest that the PXR regulates the intestinal epithelial barrier during inflammation by modulating cytokineinduced MLCK expression and JNK1/2 activation. Thus, targeting the PXR may prove beneficial for the treatment of inflammationassociated barrier disruption in the context of IBD.

show abstract

Section: Discussionmentioning

confidence: 99%

Pregnane X Receptor Activation Attenuates Inflammation-Associated Intestinal Epithelial Barrier Dysfunction by Inhibiting Cytokine-Induced Myosin Light-Chain Kinase Expression and c-Jun N-Terminal Kinase 1/2 Activation

Garg¹,

Zhao²,

Erickson³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

show abstract

“…These include synthetic drugs of various therapeutic classes and diverse chemical structures, naturally occurring compounds, endogenous substances, including bile acids and vitamins, and environmental toxicants. In contrast to the volume of information on PXR activation by single chemical entities (12,16), considerably less is known about the effect of complex chemical mixtures, such as herbal medicines, on PXR activity (26). St. John's wort was the first herbal medicine shown to activate PXR (13,14).…”

Section: Pregnane X Receptormentioning

confidence: 99%

Activation of Pregnane X Receptor (PXR) and Constitutive Androstane Receptor (CAR) by Herbal Medicines

Chang

2009

AAPS J

View full text Add to dashboard Cite

Abstract. Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are transcription factors that control the expression of a broad array of genes involved not only in transcellular transport and biotransformation of many drugs, other xenochemicals, and endogenous substances, such as bile acid, bilirubin, and certain vitamins, but also in various physiological/pathophysiological processes such as lipid metabolism, glucose homeostasis, and inflammation. Ligands of PXR and CAR are chemicals of diverse structures, including naturally occurring compounds present in herbal medicines. The overall aim of this article is to provide an overview of our current understanding of the role of herbal medicines as modulators of PXR and CAR.

show abstract

“…The scope has widened to include many natural products after it was demonstrated that gugulipid, kava kava, Coleus forskolii, Hypoxis, Sutherlandia, Sweet Wormwood, Schisandra chinensis, and Glycyrrhiza are activators of PXR-mediated target gene expression [58] . PXR is also activated by vitamins E (tocopherol) and K2 [59,60] .…”

Section: Implications Of Pxr In Ddismentioning

confidence: 99%

Role of the nuclear pregnane X receptor in drug metabolism and the clinical response

2015

Receptors Clin Investig

View full text Add to dashboard Cite

The pregnane X receptor (PXR) is an orphan nuclear receptor that regulates the expression of phase I and phase II drug metabolizing enzymes and transporters involved in the absorption, distribution, metabolism, and elimination of xenobiotics. PXR is expressed predominantly in the liver and intestine and resembles cytochrome P450s (CYPs), which is a phase I drug metabolizing enzyme. It is estimated that CYP 3As and CYP2Cs metabolize > 50% of all prescription drugs. PXR upregulates gene expression of these CYPs. Therefore, PXR plays a crucial role detoxifying xenobiotics and could potentially have effects on drug-drug interactions. PXR is reportedly responsible for activating a variety of target genes through cross-talk with other nuclear receptors and coactivators at transcriptional and translation levels. Recent findings have demonstrated the regulatory role of PXR and show the potential use of a PXR antagonist during drug therapy. In addition, genetic variations in the PXR gene are associated with the pharmacological effects of several drugs, and inter-individual differences in the clinical response are likely to be understood through these PXR polymorphisms. Many approaches have been used to explain the PXR regulatory mechanisms, such as microRNA-mediated PXR post-translational regulation and diverse PXR haplotype analysis. Understanding these PXR polymorphisms may lead to improving personalized therapeutic treatments.Keywords: pregnane X receptor; drug metabolizing enzyme; polymorphism; personalized therapeutic treatment To cite this article: Jung Yeon Moon, et al. Role of the nuclear pregnane X receptor in drug metabolism and the clinical response. Receptor Clin Invest 2015; 2: e996.

show abstract

Pregnane X receptor and natural products: beyond drug–drug interactions

Cited by 76 publications

References 65 publications

Pregnane X Receptor Activation Attenuates Inflammation-Associated Intestinal Epithelial Barrier Dysfunction by Inhibiting Cytokine-Induced Myosin Light-Chain Kinase Expression and c-Jun N-Terminal Kinase 1/2 Activation

Pregnane X Receptor Activation Attenuates Inflammation-Associated Intestinal Epithelial Barrier Dysfunction by Inhibiting Cytokine-Induced Myosin Light-Chain Kinase Expression and c-Jun N-Terminal Kinase 1/2 Activation

Activation of Pregnane X Receptor (PXR) and Constitutive Androstane Receptor (CAR) by Herbal Medicines

Role of the nuclear pregnane X receptor in drug metabolism and the clinical response

Contact Info

Product

Resources

About