Nuclear receptors CAR and PXR: Molecular, functional, and biomedical aspects

Masi, Alessandra di; Marinis, Elisabetta De; Ascenzi, Paolo; Marino, Maria

doi:10.1016/j.mam.2009.04.002

Cited by 253 publications

(271 citation statements)

References 327 publications

(599 reference statements)

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“…One member of the nuclear receptor superfamily, CAR, shares many structural and functional similarities with PXR (Honkakoski et al, 2003;Timsit and Negishi, 2007;di Masi et al, 2009). CAR and PXR each heterodimerize with retinoid X receptor (RXR) and have overlapping domains of genes on which they exert control.…”

Section: Discussionmentioning

confidence: 99%

Gestational and Pregnane X Receptor-Mediated Regulation of Placental ATP-Binding Cassette Drug Transporters in Mice

Gahir

Piquette-Miller²

2010

Drug Metab Dispos

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ABSTRACT:The ATP-binding cassette (ABC) drug transporters in the placenta are involved in controlling the exchange of endogenous and exogenous moieties. Pregnane X receptor (PXR) is a nuclear receptor that regulates the hepatic expression of several key ABC transporters, but it is unclear whether PXR is involved in the regulation of these transporters in the placenta. This study explores the role of PXR in the regulation of placental drug transporters. The placental mRNA expression of Mdr1a, Bcrp, and Mrp1, 2, and 3 was

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Section: Discussionmentioning

confidence: 99%

Gestational and Pregnane X Receptor-Mediated Regulation of Placental ATP-Binding Cassette Drug Transporters in Mice

Gahir

Piquette-Miller²

2010

Drug Metab Dispos

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“…Nuclear receptors (NRs) are a class of transcription factors that control gene expression and play a key role in the development, homeostasis, and metabolism of living organisms (di Masi et al, 2009). The pregnane X receptor (PXR) belongs to the NR1I family and regulates enzymes and transporters involved in xenobiotic detoxification as well as maintaining a homeostatic balance of endobiotics, including bile acids, cholesterols, and steroid hormones (Jyrkkärinne et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…The pregnane X receptor (PXR) belongs to the NR1I family and regulates enzymes and transporters involved in xenobiotic detoxification as well as maintaining a homeostatic balance of endobiotics, including bile acids, cholesterols, and steroid hormones (Jyrkkärinne et al, 2008). PXR mediates activation of gene sets pertinent to xenobiotic metabolism, such as cytochrome 450 superfamily members CYP1, CYP2B, CYP2C, and CYP3A4 in rodents and humans (Maglich et al, 2002;Plant, 2007;di Masi et al, 2009). A very broad range of substances have been identified as human (h) PXR activators in vitro, including commercial drugs, pesticides, environmental contaminants, and natural products (Timsit and Negishi, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Because of its vital role in drug metabolism, it is not surprising that human PXR has been found responsible for decreased drug efficacy and increased drug toxicity (Ma et al, 2008;di Masi et al, 2009). For example, coadministration of rifampicin, a hPXR activator used for treatment of tuberculosis (Chrencik et al, 2005) with a variety of drugs [including oral contraceptives (Ma et al, 2008), the anesthetic midazolam (Backman et al, 1996), and HIV protease inhibitors (Ivanovic et al, 2008)], resulted in decreased drug efficacy mainly due to hPXR-mediated increased expression of CYP3A4 (Ivanovic et al, 2008;Ma et al, 2008;di Masi et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Identification and Validation of Novel Human Pregnane X Receptor Activators among Prescribed Drugs via Ligand-Based Virtual Screening

Pan

Li²,

Gregory³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Human pregnane X receptor (hPXR) plays a key role in regulating metabolism and clearance of endogenous and exogenous substances. Identification of novel hPXR activators among commercial drugs may aid in avoiding drug-drug interactions during coadministration. We applied ligand-based computational approaches for virtual screening of a commonly prescribed drug database (SCUT). Bayesian classification models were generated with a training set comprising 177 compounds using Fingerprints and 117 structural descriptors. A cell-based luciferase reporter assay was used for evaluation of chemical-mediated hPXR activation in HepG2 cells. All compounds were tested at 10 M concentration with rifampicin and dimethyl sulfoxide as positive and negative controls, respectively. The Bayesian models showed specificity and overall prediction accuracy up to 0.92 and 0.69 for test set compounds. Screening the SCUT database with this model retrieved 105 hits and 17 compounds from the top 25 hits were chosen for in vitro testing. The reporter assay confirmed that nine drugs, i.e., fluticasone, nimodipine, nisoldipine, beclomethasone, finasteride, flunisolide, megestrol, secobarbital, and aminoglutethimide, were previously unidentified hPXR activators. Thus, the present study demonstrates that novel hPXR activators can be efficiently identified among U.S. Food and Drug Administrationapproved and commonly prescribed drugs, which should lead to detection and prevention of potential drug-drug interactions.

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“…Increasing evidence suggests that PXR regulates not only drug metabolism and disposition but also physiological and pathophysiological processes, such as glucose metabolism, lipid metabolism, bile acid homeostasis, cancer, diabetes, inflammatory diseases, metabolic diseases and liver diseases [12][13][14][15] . Therefore, any genetic variations in PXR that play a role detoxifying xenobiotics could potentially have widespread effects on endocrine signaling pathways and could explain interindivdual variations in response [16] .…”

Section: Reviewmentioning

confidence: 99%

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

2015

Receptors Clin Investig

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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.

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Nuclear receptors CAR and PXR: Molecular, functional, and biomedical aspects

Cited by 253 publications

References 327 publications

Gestational and Pregnane X Receptor-Mediated Regulation of Placental ATP-Binding Cassette Drug Transporters in Mice

Gestational and Pregnane X Receptor-Mediated Regulation of Placental ATP-Binding Cassette Drug Transporters in Mice

Identification and Validation of Novel Human Pregnane X Receptor Activators among Prescribed Drugs via Ligand-Based Virtual Screening

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

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