Xenobiotic Pregnane X Receptor (PXR) Regulates Innate Immunity via Activation of NLRP3 Inflammasome in Vascular Endothelial Cells
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Pregnane X receptor
Retinoid X receptors (RXRs) form heterodimers with pregnane X receptor (PXR) and constitutive androstane receptor (CAR), two prototypical xenobiotic receptors, and mediate metabolism of xenobiotics (foreign compounds) and endobiotics (endogenous compounds). Establishment of gene knockout and transgenic mouse models of RXRs, PXR, and CAR greatly enhanced the study of the biology of nuclear receptors, leading to considerable research progress in understanding the molecular mechanism underlying the nuclear receptor-mediated pathways in xenobiotic and endobiotic metabolism. These animal models are widely used in screening nuclear receptor ligands, identifying nuclear receptor target genes, and defining physiological and pharmacological pathways mediated by these xenobiotic nuclear receptors. In addition, "humanized" PXR and CAR mouse models, which avoid species specificity, provide valuable tools for investigating human xenobiotic response. Moreover, generations of multiple gene knockout mouse models further allow us to identify unique and redundant pathways mediated by each xenosensor. In this article, we review the progress made by using animal models of RXRs, PXR, and CAR in understanding the biological functions of these nuclear receptors in physiology, pharmacology, and pathology.
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It is becoming increasingly evident that constitutive, induced, and regulated expression of genes important to the drug disposition process such as drug transporters, phase I and II metabolic enzymes are largely under the transcriptional control of certain nuclear receptor (NR) family members. In the past decade, important new insights regarding the role and relevance of ligand-activated nuclear receptors such as such as the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in terms of their activation by endogenous biochemicals, natural products, as well as synthetic compounds have led to a much better understanding of the xenobiotic-mediated induction process and the clinical relevance of such NRs to drug therapy in general. However, in addition to CAR and PXR, many orphan and adopted orphan NRs have recently been identified as key regulators of drug disposition genes. Indeed, nuclear receptors including farnesoid X receptor, peroxisome proliferator-activated receptor, and hepatocyte nuclear factors (1α, 3 and 4α) exhibit overlapping ligand specificities and regulate multiple gene targets, resulting in tissue- and organ-specific expression of drug disposition genes. In this review, the biology, pathophysiology, and the potential clinical relevance of such NRs to drug disposition and response are discussed. Keywords: nuclear receptors, gene transcription, phase I metabolism, phase II metabolism, transporters
Pregnane X receptor
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Introduction: 'Orphan' nuclear receptors belong to the nuclear receptor (NR) superfamily of transcriptional factors. Binding of ligands to these receptors results in the recruitment of the co-activators, thereby regulating the expression of cognate target genes. Areas covered: This review discusses the transcriptional regulation of P450 genes by two major xenobiotic nuclear receptors, pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Additional PXR and CAR target genes include those encoded for UDP-glucuronosyltransferases, glutathione S-transferases, sulfotransferases and drug transporters. The authors discuss the involvement of PXR and CAR in endobiotic metabolism. They also review the polymorphisms of PXR and CAR. Expert opinion: PXR and CAR are both xenobiotic and endobiotic receptors. A remarkably diverse set of chemicals can activate PXR and CAR. There is significant cross-talk among xenobiotic receptors. Future studies are needed to focus on the polymorphisms of the nuclear receptors and the complex regulatory networks among nuclear receptors. Considerations should be given while designing PXR- or CAR-targeting pharmaceutics to avoid adverse drug effects. In the meantime, due to the diverse functions of PXR and CAR, agonists or antagonists for these receptors may have therapeutic potentials in managing certain diseases and enhancing therapeutic indexes.
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Induction of drug metabolism was described more than 40 years ago. Progress in understanding the molecular mechanism of induction of drug-metabolizing enzymes was made recently when the important roles of the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), two members of the nuclear receptor superfamily of transcription factors, were discovered to act as sensors for lipophilic xenobiotics, including drugs. CAR and PXR bind as heterodimeric complexes with the retinoid X receptor to response elements in the regulatory regions of the induced genes. PXR is directly activated by xenobiotic ligands, whereas CAR is involved in a more complex and less well understood mechanism of signal transduction triggered by drugs. Most recently, analysis of these xenobiotic-sensing nuclear receptors and their nonmammalian precursors such as the chicken xenobiotic receptor suggests an important role of PXR and CAR also in endogenous pathways, such as cholesterol and bile acid biosynthesis and metabolism. In this review, recent findings regarding xenosensors and their target genes are summarized and are put into an evolutionary perspective in regard to how a living organism has derived a system that is able to deal with potentially toxic compounds it has not encountered before.
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Pregnane X receptor
Constitutive androstane receptor
Farnesoid X receptor
Liver X receptor
Liver receptor homolog-1
Retinoid X receptor
Small heterodimer partner
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Pregnane X receptor
Retinoid X receptor
Constitutive androstane receptor
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Recent advances in the molecular biology of nuclear receptors have revealed that the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are able to act as sensors for lipophilic xenobiotics, including therapeutic drugs. These receptors in turn regulate enzymes and transporters involved in drug metabolism and disposition in an adaptive fashion. An unexpected finding was that the PXR was able to recognize bile acids; transgenic animals lacking this receptor are at increased risk of bile acid-induced liver injury. These findings provide new insights into hepatic drug metabolism as well as mechanisms regulating cholesterol and bile acid homeostasis.
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The pregnane X receptor (PXR) is a member of the nuclear receptor family of ligand-regulated transcription factors. Like many former orphan nuclear receptors, it contains both DNA and ligand binding domains and binds to response elements in the regulatory regions of target genes as a heterodimer with RXRα. Unlike the vast majority of nuclear receptors, however, PXR responds to a wide variety of chemically distinct xenobiotics and endobiotics, regulating the expression of genes central to both drug and bile acid metabolism. We review the structural basis of PXRs promiscuity in ligand binding, its recruitment of transcriptional coregulators, its potential formation of higher-order nuclear receptor complexes, and its control of target gene expression. Structural flexibility appears to be central to the receptors ability to conform to ligands that differ both in size and shape. We also discuss the clinical implications of PXRs role in the drugdrug interactions, cancer, and cholestatic liver disease.
Pregnane X receptor
Constitutive androstane receptor
Small heterodimer partner
Xenobiotic
Orphan receptor
Liver receptor homolog-1
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Structural and functional studies have provided numerous insights over the past years on how members of the nuclear hormone receptor superfamily tightly regulate the expression of drug-metabolizing enzymes and transporters. Besides the role of the farnesoid X receptor (FXR) in the transcriptional control of bile acid transport and metabolism, this review provides an overview on how this metabolic sensor prevents the accumulation of toxic byproducts derived from endogenous metabolites, as well as of exogenous chemicals, in coordination with the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Decrypting this network should provide cues to better understand how these metabolic nuclear receptors participate in physiologic and pathologic processes with potential validation as therapeutic targets in human disabilities and cancers.
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Farnesoid X receptor
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Pregnane X receptor
Constitutive androstane receptor
Small heterodimer partner
Farnesoid X receptor
Liver receptor homolog-1
Estrogen-related receptor gamma
Crosstalk
PELP-1
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