Affinage

NR1I2

Nuclear receptor subfamily 1 group I member 2 · UniProt O75469

Length
434 aa
Mass
49.8 kDa
Annotated
2026-04-29
100 papers in source corpus 23 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NR1I2 (PXR/SXR) is a ligand-activated nuclear receptor that serves as a master regulator of xenobiotic and endobiotic detoxification, coordinating the transcriptional induction of phase I/II drug-metabolizing enzymes and efflux transporters in liver and intestine. Upon binding a structurally diverse array of ligands—including steroids, bile acids, vitamin K2, retinoids, and xenobiotics—NR1I2 heterodimerizes with RXR and binds DR-4 and related response elements in target gene promoters to activate CYP3A4, CYP2B6, MDR1/ABCB1, and CYP27A1, with coactivator SRC-1 recruitment required for full transactivation and HNF4α acting as an essential cooperating factor at CYP3A4 (PMID:9784494, PMID:10935643, PMID:11248086, PMID:11329060, PMID:12514743, PMID:17088262). NR1I2 activity is further tuned by post-translational modifications including acetylation, SUMOylation, phosphorylation, and ubiquitination, wherein an acetylation-dependent SUMO switch mediated by the HDAC3/SMRT complex converts NR1I2 from a transcriptional activator to a repressor (PMID:26883953). Beyond drug metabolism, NR1I2 modulates hepatic glucose homeostasis by repressing the HNF4α–GLUT2 axis, influences cholesterol efflux through an intestine-specific CYP27A1/LXRα pathway, and affects innate immune responses by promoting foamy macrophage formation during mycobacterial infection (PMID:35646519, PMID:17088262, PMID:27233963).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1998 High

    The cloning of SXR/PXR established the existence of a nuclear receptor that could respond to structurally diverse xenobiotics and steroids and explained how CYP3A genes are coordinately induced in liver and intestine.

    Evidence Receptor cloning, transient transfection reporter assays with heterodimer binding, tissue expression profiling

    PMID:9784494

    Open questions at the time
    • Crystal structure of the ligand-binding domain was not yet available
    • In vivo necessity not yet demonstrated genetically
  2. 2000 High

    Genetic loss-of-function (PXR knockout) and gain-of-function (humanized SXR transgenic) mouse models proved that NR1I2 is necessary and sufficient for CYP3A induction in vivo, and that the receptor's species origin dictates species-specific drug induction profiles.

    Evidence PXR-null mice, constitutively activated human SXR transgenic mice, pharmacokinetic and gene expression analysis

    PMID:10935643 PMID:11090943

    Open questions at the time
    • Mechanism of species-specific ligand selectivity at the structural level was unclear
    • Full spectrum of endogenous ligands unknown
  3. 2001 High

    Discovery that NR1I2 functions as an endogenous bile acid sensor and that it regulates drug efflux transporter MDR1/ABCB1 broadened its role from a xenobiotic receptor to a coordinator of both phase I metabolism and phase III efflux, and established corepressor displacement as a mechanism gating target gene activation.

    Evidence Bile acid activation assays, lithocholic acid hepatotoxicity rescue in PXR-null/transgenic mice, corepressor displacement assays for MDR1 activation

    PMID:11114890 PMID:11248086 PMID:11329060

    Open questions at the time
    • Relative contribution of PXR vs. FXR in bile acid homeostasis not fully delineated
    • Corepressor identity at MDR1 not fully characterized
  4. 2003 High

    Identification of HNF4α as an essential cooperating transcription factor at the CYP3A4 enhancer and of vitamin K2 as a physiological NR1I2 ligand that mediates bone homeostasis expanded the regulatory framework and functional scope beyond detoxification.

    Evidence CYP3A4 promoter element mapping with HNF4α ChIP, Hnf4α conditional knockout mice, vitamin K2 ligand-binding assays with PXR-null osteocyte validation

    PMID:12514743 PMID:12920130

    Open questions at the time
    • Whether HNF4α is required at all NR1I2 target genes was unknown
    • Bone-specific NR1I2 target gene program not characterized genome-wide
  5. 2006 High

    Demonstration that NR1I2 recruits SRC-1 to CYP27A1 chromatin in intestinal cells linked PXR to cholesterol efflux via a tissue-specific PXR→CYP27A1→LXRα axis, and retinoid activation revealed that RXR can serve as an active signaling partner in the heterodimer.

    Evidence ChIP for SRC-1 at CYP27A1, reporter assays with PXR binding-site mutation, retinoid-mediated reporter activation and CYP3A4 enzyme assays

    PMID:16632523 PMID:17088262

    Open questions at the time
    • In vivo contribution of this intestinal cholesterol pathway not tested by genetic ablation
    • Structural basis for permissive vs. silent RXR partnering with PXR unresolved
  6. 2010 High

    Genome-wide ChIP-Seq of hepatic PXR binding defined DR-4 as the dominant binding motif, discovered a novel DR-(5n+4) motif, and showed PXR occupancy correlates with active histone marks, providing the first cistromic map of this receptor.

    Evidence ChIP-Seq and ChIP-on-chip for histone marks in mouse liver, PXR-null mouse comparison, agonist treatment

    PMID:20693526

    Open questions at the time
    • Human liver cistrome not yet mapped
    • Mechanism of chromatin remodeling by PXR not addressed
  7. 2011 High

    Metformin was shown to suppress PXR-mediated CYP3A4 expression by disrupting the PXR–SRC-1 coactivator interaction without competing at the ligand-binding pocket, establishing a ligand-independent mechanism of PXR inhibition.

    Evidence Two-hybrid coactivator assay, qRT-PCR in human hepatocytes, PXR-null mouse validation

    PMID:21920351

    Open questions at the time
    • Direct binding site of metformin on PXR not mapped
    • Clinical relevance for drug–drug interactions via PXR suppression not established in controlled trials
  8. 2016 High

    Characterization of PXR post-translational modifications revealed an acetylation–SUMOylation switch controlled by the HDAC3/SMRT complex that converts PXR from activator to active repressor, and mycobacterial lipid activation of PXR was found to promote intracellular M. tuberculosis survival by blocking phagolysosomal fusion.

    Evidence PTM identification, TSA pharmacologic inhibition, co-IP of HDAC3/SMRT, hPXR-transgenic mouse M. tuberculosis infection model, macrophage infection assays

    PMID:26883953 PMID:27233963

    Open questions at the time
    • Specific lysine residues governing the SUMO-acetyl switch were not all mapped
    • Whether PXR-mediated immune evasion extends to other intracellular pathogens is unknown
    • In vivo relevance of PXR SUMOylation to drug metabolism phenotype untested
  9. 2021 High

    PXR activation was shown to impair hepatic glucose homeostasis by down-regulating HNF4α and GLUT2, establishing a PXR–HNF4α negative regulatory loop with metabolic consequences beyond xenobiotic handling.

    Evidence PXR overexpression/silencing, HNF4α ChIP, liver-specific Hnf4α knockout mice with PXR agonist treatment, glucose tolerance tests

    PMID:35646519

    Open questions at the time
    • Molecular mechanism by which PXR down-regulates HNF4α expression not fully defined
    • Long-term metabolic consequences of chronic PXR activation in humans not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • A comprehensive human liver and intestine cistrome for NR1I2, the structural basis for its uniquely promiscuous ligand recognition, and the quantitative contribution of each PTM to NR1I2 activity in physiological contexts remain to be established.
  • Human tissue-specific NR1I2 cistrome not mapped
  • No integrated structural–dynamics model explaining the breadth of ligand recognition
  • Relative in vivo importance of acetylation, SUMOylation, phosphorylation, and ubiquitination is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0008289 lipid binding 4 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 5
Pathway
R-HSA-74160 Gene expression (Transcription) 7 R-HSA-1430728 Metabolism 5 R-HSA-162582 Signal Transduction 3 R-HSA-9748784 Drug ADME 3
Partners
HDAC3HNF4AHSP90AA1NCOA1NCOR2NR1I3RXRATP53
Complex memberships
HDAC3/SMRT corepressor complexPXR/RXR heterodimer

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 SXR (NR1I2) is a novel nuclear receptor that activates transcription in response to a diversity of natural and synthetic compounds by forming a heterodimer with RXR, which binds to response elements present in steroid-inducible cytochrome P-450 genes; it is expressed in tissues where CYP catabolic enzymes are expressed. Receptor cloning, transient transfection reporter assays, heterodimer binding assays, tissue expression analysis Genes & development High 9784494
2000 Targeted disruption of the mouse PXR (NR1I2 ortholog) gene abolishes induction of CYP3A by prototypic inducers (dexamethasone, PCN), and transgenic expression of activated SXR constitutively upregulates CYP3A and confers xenobiotic protection; species origin of the receptor determines species-specific CYP3A inducibility. PXR knockout mice, transgenic humanized mice, pharmacokinetic and gene expression studies Nature High 10935643
2001 SXR/PXR (NR1I2) serves as a functional bile acid receptor; activation is necessary and sufficient to induce CYP3A enzymes and confer resistance to hepatotoxic lithocholic acid (LCA); established using knockout and transgenic animal combinations. Cell-based activation assays, knockout mice, transgenic mice, toxicity rescue experiments Proceedings of the National Academy of Sciences of the United States of America High 11248086
2001 SXR (NR1I2) regulates drug efflux by activating MDR1 (P-glycoprotein/ABCB1) expression in addition to CYP3A4; paclitaxel activates SXR and enhances P-glycoprotein-mediated drug clearance, while docetaxel does not activate SXR due to its inability to displace transcriptional corepressors; ET-743 suppresses MDR1 transcription by acting as an SXR inhibitor. Reporter gene assays, corepressor displacement assays, pharmacokinetic studies Nature medicine High 11329060
2000 SXR/PXR (NR1I2) can regulate CYP2B via adaptive recognition of the phenobarbital response element (PBRE) in cultured cells and transgenic mice; conversely, CAR activates CYP3A through SXR/PXR response elements, revealing reciprocal cross-regulation between these xenobiotic receptors. Transfection reporter assays in cultured cells, transgenic mouse gene expression studies Genes & development High 11114890
2003 HNF4α is critically required for PXR- and CAR-mediated transcriptional activation of CYP3A4; a specific cis-acting element in the CYP3A4 enhancer confers HNF4α binding enabling PXR/CAR-mediated gene activation; conditional deletion of Hnf4α in mice reduces basal and inducible CYP3A expression. Reporter assays identifying HNF4α binding element, conditional knockout mice, ChIP Nature medicine High 12514743
2003 Vitamin K2 binds to and activates SXR (NR1I2) and induces expression of the SXR target gene CYP3A4; vitamin K2 induces osteoblast markers through SXR in osteosarcoma cells, an effect absent in cells from PXR-null mice, establishing SXR as a mediator of bone homeostasis. Ligand-binding assays, reporter gene assays, qRT-PCR, primary osteocytes from PXR knockout mice The Journal of biological chemistry High 12920130
2010 Genome-wide ChIP-Seq of hepatic PXR binding in mouse liver revealed that the most frequent PXR DNA-binding motif is an AGTTCA-like direct repeat with a 4 bp spacer (DR-4) and a novel DR-(5n+4) pattern; PXR binding overlaps with histone-H3K4-di-methylation (active gene mark) but not with repressive marks; PXR agonist increases PXR binding at drug-metabolizing enzyme and transporter gene loci, and mRNA induction is absent in PXR-null mice. ChIP-Seq, ChIP-on-chip for histone marks and DNA methylation, PXR-null mouse comparison Nucleic acids research High 20693526
2006 PXR (NR1I2) induces CYP27A1 in intestinal (but not liver) cells via a functional PXR binding site in the CYP27A1 gene; rifampicin-activated PXR recruits steroid receptor coactivator 1 (SRC-1) to CYP27A1 chromatin, demonstrated by ChIP; this creates an intestine-specific PXR/CYP27A1/LXRα pathway regulating cholesterol efflux. Reporter gene assays with PXR binding site mutation, ChIP assay, CYP27A1 mRNA/protein quantification Journal of lipid research High 17088262
2016 PXR (NR1I2) undergoes acetylation on lysine residues; increased acetylation stimulates SUMOylation of PXR to support active transcriptional suppression (SUMO-acetyl switch); pharmacologic inhibition of de-acetylation with TSA alters subcellular localization of PXR and suppresses its transactivation capacity; PXR associates with the HDAC3/SMRT complex that controls its acetylation/SUMOylation status. Cell-based assays with primary hepatocytes, PTM identification, TSA pharmacologic inhibition, co-immunoprecipitation of HDAC3/SMRT complex, subcellular localization imaging Biochimica et biophysica acta High 26883953
2011 Metformin suppresses PXR (NR1I2)-mediated CYP3A4 expression in human hepatocytes and in vivo in wild-type but not Pxr-null mice; the mechanism involves disruption of PXR's interaction with the coactivator steroid receptor coactivator-1 (SRC1), independent of the PXR ligand binding pocket and independently of AMPK or SHP. Reporter gene assays, qRT-PCR in human hepatocytes and Pxr-null mice, two-hybrid coactivator interaction assay Biochemical pharmacology High 21920351
2009 Activation of SXR (NR1I2) inhibits proliferation of breast cancer cells (MCF-7, ZR-75-1) through G1/S arrest and apoptosis; the mechanism requires SXR-dependent induction of iNOS and NO production, which stabilizes p53 and upregulates p21, PUMA, and BAX; siRNA knockdown of SXR abolished iNOS induction. siRNA knockdown, cell proliferation assays, qRT-PCR, western blotting, iNOS inhibition experiments BMC cancer Medium 19123943
2004 Highly chlorinated PCBs antagonize human SXR (NR1I2) while activating rodent PXR, inhibiting target gene induction in humans; this differential effect is species-specific and suggests that PCB exposure can blunt the human xenobiotic detoxification response. Reporter gene activation assays, ligand-binding competition assays, species-comparative cell-based assays Environmental health perspectives Medium 14754570
2000 PXR (NR1I2) binds as a heterodimer with RXR to xenobiotic response elements in CYP3A gene promoters and is selectively expressed in liver and intestine, the same tissues in which CYP3A gene expression is induced; species-specific activation by rifampicin vs. PCN correlates with species-specific CYP3A induction. Cloning, electrophoretic mobility shift assays (EMSA), reporter gene assays, pharmacokinetic studies Toxicology High 11090943
2021 PXR (NR1I2) activation impairs hepatic glucose metabolism by inhibiting the HNF4α–GLUT2 pathway; PXR overexpression downregulates HNF4α and GLUT2, reducing glucose uptake; silencing PXR or overexpressing HNF4α reverses this effect; liver-specific Hnf4α deletion combined with PCN-activated PXR impairs glucose tolerance and hepatic glucose uptake in mice. PXR overexpression/silencing, HNF4α overexpression/silencing, promoter activity assays, ChIP for HNF4α recruitment, liver-specific Hnf4α knockout mice Acta pharmaceutica Sinica. B High 35646519
2016 PXR transcript variant 1 (PXR1) interacts with p53, whereas transcript variant 3 (PXR3) does not; PXR1 and PXR4 mRNA are downregulated by methylation in cancerous tissue; PXR transcript variants have differential transcriptional activity and differential effects on cellular proliferation. Protein-protein interaction assays, methylation analysis, ectopic overexpression, transcriptional activity assays Acta pharmaceutica Sinica. B Medium 27709012
2013 PXR (NR1I2) is modified by acetylation on lysine residues, phosphorylation, SUMOylation, and ubiquitination as post-translational modifications; these PTMs modulate PXR activity, sub-cellular localization, protein-binding partners, and stability in hepatic regulation of CYP genes. Review synthesizing PTM identification via mass spectrometry, mutagenesis, and biochemical assays from multiple studies Current drug metabolism Medium 24329114
2022 Panaxytriol upregulates CYP3A4 by promoting PXR dissociation from HSP90α and enhancing PXR binding to RXRα; at high concentrations, CAR also participates via a similar HSP90α-to-RXRα switch; CAR antagonizes PXR binding to RXRα and attenuates panaxytriol-induced CYP3A4 upregulation. Co-immunoprecipitation, western blot, qPCR, immunofluorescence nuclear translocation, hCAR silencing in HepG2 cells Phytomedicine : international journal of phytotherapy and phytopharmacology Medium 35417848
2006 Retinoids activate the RXR/SXR (NR1I2)-mediated pathway and induce endogenous CYP3A4 enzyme activity in human hepatoma Huh7 cells; acid-form retinoids (9-cis-RA, 13-cis-RA, all-trans-RA) activate this pathway with potency comparable to or greater than rifampin; RXR may serve as a silent or active partner of SXR depending on the ligand. Transient transfection reporter assays in CV-1 and Huh7 cells using ER-6 response elements, CYP3A4 enzyme activity assays Toxicological sciences : an official journal of the Society of Toxicology Medium 16632523
2016 Human PXR (NR1I2) promotes Mycobacterium tuberculosis survival inside macrophages by enhancing foamy macrophage formation and abrogating phagolysosomal fusion, inflammation, and apoptosis; mycobacterial cell wall lipids (mycolic acids) interact with the PXR ligand binding domain; expression of human PXR in transgenic mice promotes M. tuberculosis survival in vivo. Human monocyte-derived macrophage infection assays, ligand-binding domain interaction studies, hPXR-transgenic mice in vivo infection model Journal of immunology (Baltimore, Md. : 1950) Medium 27233963
2015 RXRα/PXR (NR1I2)/CAR signaling pathways mediate nonylphenol-induced apoptosis and neurotoxicity in mouse hippocampal neurons; siRNA knockdown of Pxr reduced nonylphenol-induced caspase-3 activation and LDH release; nonylphenol induced nuclear translocation of PXR in neurons. siRNA knockdown, immunofluorescence, caspase-3 and LDH assays in primary hippocampal neuronal cultures The Journal of steroid biochemistry and molecular biology Medium 26643981
2010 Vinblastine induces CYP3A4 via an NR1I2 (PXR)-dependent mechanism; cell-based reporter gene assays showed weak activation of human and mouse full-length NR1I2 but no effect on NR1I3 (CAR); CYP3A4 protein induction was confirmed by western blot in treated cells, and midazolam clearance increased in cancer patients treated with vinblastine. Clinical pharmacokinetic study, western blot, reporter gene assays in HepG2 and NIH3T3 cells The Annals of pharmacotherapy Medium 20959500
2016 Acetylated deoxycholic acid (DCA 3,12-diacetate) and cholic acid (CA 3,7,12-triacetate) are potent ligands of PXR (NR1I2); DCA 3,12-diacetate induces PXR target genes CYP3A4, CYP2B6, and ABCB1/MDR1, established by TR-FRET binding assay and reporter gene assays. Reporter gene assays in HepG2 cells, TR-FRET ligand-binding assay with recombinant PXR, RT-PCR of target genes in HepaRG cells Toxicology letters Medium 27871908

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes & development 783 9784494
2001 The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nature medicine 705 11329060
2001 An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Proceedings of the National Academy of Sciences of the United States of America 616 11248086
2000 Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 542 10935643
2000 Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes & development 391 11114890
2003 The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nature medicine 372 12514743
2006 CAR and PXR: the xenobiotic-sensing receptors. Steroids 327 17284330
2010 Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR. Advanced drug delivery reviews 304 20727377
2003 Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor SXR. The Journal of biological chemistry 297 12920130
2009 Nuclear receptors CAR and PXR: Molecular, functional, and biomedical aspects. Molecular aspects of medicine 241 19427329
2005 CAR and PXR: xenosensors of endocrine disrupters? Chemico-biological interactions 211 16054614
2012 Role of CAR and PXR in xenobiotic sensing and metabolism. Expert opinion on drug metabolism & toxicology 190 22554043
2011 Nuclear receptor PXR, transcriptional circuits and metabolic relevance. Biochimica et biophysica acta 185 21295138
2003 Drug-activated nuclear receptors CAR and PXR. Annals of medicine 138 12822739
2017 PXR: More Than Just a Master Xenobiotic Receptor. Molecular pharmacology 137 29113993
2009 The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism. Nuclear receptor signaling 135 19240808
2008 PXR: a xenobiotic receptor of diverse function implicated in pharmacogenetics. Pharmacogenomics 131 19018724
2011 FXR and PXR: potential therapeutic targets in cholestasis. The Journal of steroid biochemistry and molecular biology 130 21801835
2000 Use of the nuclear receptor PXR to predict drug interactions. Toxicology 125 11090943
2013 Nuclear receptors PXR and CAR: implications for drug metabolism regulation, pharmacogenomics and beyond. Expert opinion on drug metabolism & toxicology 124 23327618
2012 Targeting xenobiotic receptors PXR and CAR for metabolic diseases. Trends in pharmacological sciences 121 22889594
2008 The roles of nuclear receptors CAR and PXR in hepatic energy metabolism. Drug metabolism and pharmacokinetics 115 18305370
2004 Highly chlorinated PCBs inhibit the human xenobiotic response mediated by the steroid and xenobiotic receptor (SXR). Environmental health perspectives 102 14754570
2003 Functional and structural comparison of PXR and CAR. Biochimica et biophysica acta 100 12573482
2005 Expression of PXR, CYP3A and MDR1 genes in liver of zebrafish. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 99 15914091
2009 Tissue factor and PAR2 signaling in the tumor microenvironment. Arteriosclerosis, thrombosis, and vascular biology 98 19661489
2005 Genetic variants of PXR (NR1I2) and CAR (NR1I3) and their implications in drug metabolism and pharmacogenetics. Current drug metabolism 98 16101575
2006 PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine. Journal of lipid research 97 17088262
2014 Targeting xenobiotic receptors PXR and CAR in human diseases. Drug discovery today 94 25463033
2010 Pregnane X Receptor (PXR) expression in colorectal cancer cells restricts irinotecan chemosensitivity through enhanced SN-38 glucuronidation. Molecular cancer 92 20196838
2013 Post-translational and post-transcriptional modifications of pregnane X receptor (PXR) in regulation of the cytochrome P450 superfamily. Current drug metabolism 89 24329114
2016 Regulation of hepatic energy metabolism by the nuclear receptor PXR. Biochimica et biophysica acta 78 27041449
2013 Role of PPAR, LXR, and PXR in epidermal homeostasis and inflammation. Biochimica et biophysica acta 78 24315978
2011 Metformin suppresses pregnane X receptor (PXR)-regulated transactivation of CYP3A4 gene. Biochemical pharmacology 77 21920351
2008 New insights on the xenobiotic-sensing nuclear receptors in liver diseases--CAR and PXR--. Current drug metabolism 77 18781913
2008 A gut feeling of the PXR, PPAR and NF-kappaB connection. Journal of internal medicine 74 18479261
2010 ChIPing the cistrome of PXR in mouse liver. Nucleic acids research 71 20693526
2002 The nuclear receptor PXR: a master regulator of "homeland" defense. Critical reviews in eukaryotic gene expression 67 12433065
2021 The xenobiotic receptors PXR and CAR in liver physiology, an update. Biochimica et biophysica acta. Molecular basis of disease 64 33600998
2020 Regulation of CAR and PXR Expression in Health and Disease. Cells 60 33142929
2018 PAR2 promotes M1 macrophage polarization and inflammation via FOXO1 pathway. Journal of cellular biochemistry 59 30552714
2016 Small-molecule modulators of PXR and CAR. Biochimica et biophysica acta 59 26921498
1998 BXR, an embryonic orphan nuclear receptor activated by a novel class of endogenous benzoate metabolites. Genes & development 59 9573044
2022 The role of pregnane X receptor (PXR) in substance metabolism. Frontiers in endocrinology 55 36111293
2007 PXR and LXR in hepatic steatosis: a new dog and an old dog with new tricks. Molecular pharmaceutics 54 18072748
2016 PXR variants: the impact on drug metabolism and therapeutic responses. Acta pharmaceutica Sinica. B 52 27709012
2016 Targeting Liver Fibrosis with a Cell-penetrating Protease-activated Receptor-2 (PAR2) Pepducin. The Journal of biological chemistry 51 27613872
2020 Drug Mimicry: Promiscuous Receptors PXR and AhR, and Microbial Metabolite Interactions in the Intestine. Trends in pharmacological sciences 50 33097284
2014 Cathepsin S signals via PAR2 and generates a novel tethered ligand receptor agonist. PloS one 50 24964046
2018 A current structural perspective on PXR and CAR in drug metabolism. Expert opinion on drug metabolism & toxicology 49 29757018
2016 A brief history of the discovery of PXR and CAR as xenobiotic receptors. Acta pharmaceutica Sinica. B 49 27709013
2014 Proteinase-activated receptor 2 (PAR2) decreases apoptosis in colonic epithelial cells. The Journal of biological chemistry 49 25331954
2009 Activation of the steroid and xenobiotic receptor, SXR, induces apoptosis in breast cancer cells. BMC cancer 49 19123943
2018 Plasma kallikrein modulates immune cell trafficking during neuroinflammation via PAR2 and bradykinin release. Proceedings of the National Academy of Sciences of the United States of America 44 30559188
2021 The Nuclear Receptor PXR in Chronic Liver Disease. Cells 41 35011625
2015 RXRα, PXR and CAR xenobiotic receptors mediate the apoptotic and neurotoxic actions of nonylphenol in mouse hippocampal cells. The Journal of steroid biochemistry and molecular biology 40 26643981
2014 Role for β-arrestin in mediating paradoxical β2AR and PAR2 signaling in asthma. Current opinion in pharmacology 40 24907413
2013 Pregnane X receptor (PXR) at the crossroads of human metabolism and disease. Current drug metabolism 40 23237007
2023 AhR, PXR and CAR: From Xenobiotic Receptors to Metabolic Sensors. Cells 39 38067179
2016 Acetylated deoxycholic (DCA) and cholic (CA) acids are potent ligands of pregnane X (PXR) receptor. Toxicology letters 39 27871908
2022 Nuclear Receptor PXR in Drug-Induced Hypercholesterolemia. Cells 34 35159123
2021 PXR activation impairs hepatic glucose metabolism partly via inhibiting the HNF4α-GLUT2 pathway. Acta pharmaceutica Sinica. B 34 35646519
2020 PAR2 induces ovarian cancer cell motility by merging three signalling pathways to transactivate EGFR. British journal of pharmacology 34 33226635
2014 Pregnane X receptor (PXR)--a contributor to the diabetes epidemic? Drug metabolism and drug interactions 33 24166671
2010 Protease-activated receptor-2 (PAR(2)) in human periodontitis. Journal of dental research 33 20530726
2010 Effects of pregnane X receptor (NR1I2) and CYP2B6 genetic polymorphisms on the induction of bupropion hydroxylation by rifampin. Drug metabolism and disposition: the biological fate of chemicals 32 20876786
2002 Ion transport induced by proteinase-activated receptors (PAR2) in colon and airways. Cell biochemistry and biophysics 32 12139406
2019 Patchouli alcohol activates PXR and suppresses the NF-κB-mediated intestinal inflammatory. Journal of ethnopharmacology 31 31614203
2016 Novel functions of PXR in cardiometabolic disease. Biochimica et biophysica acta 29 26924429
2022 Insights into the critical role of the PXR in preventing carcinogenesis and chemotherapeutic drug resistance. International journal of biological sciences 27 35002522
2015 Environmental contaminants activate human and polar bear (Ursus maritimus) pregnane X receptors (PXR, NR1I2) differently. Toxicology and applied pharmacology 27 25680588
2007 Identification of NR1I2 genetic variation using resequencing. European journal of clinical pharmacology 27 17404718
2022 Renal tubular PAR2 promotes interstitial fibrosis by increasing inflammatory responses and EMT process. Archives of pharmacal research 26 35334088
2017 The Role of PAR2 in TGF-β1-Induced ERK Activation and Cell Motility. International journal of molecular sciences 26 29261154
2021 Pregnane X Receptor (PXR) Polymorphisms and Cancer Treatment. Biomolecules 25 34439808
2020 Punicalagin Ameliorates Lupus Nephritis via Inhibition of PAR2. International journal of molecular sciences 25 32674502
2020 Regulation of High-Altitude Hypoxia on the Transcription of CYP450 and UGT1A1 Mediated by PXR and CAR. Frontiers in pharmacology 25 33041817
2020 Pregnane X receptor (PXR) protects against cisplatin-induced acute kidney injury in mice. Biochimica et biophysica acta. Molecular basis of disease 25 33127475
2016 A SUMO-acetyl switch in PXR biology. Biochimica et biophysica acta 25 26883953
2011 Potent agonists of the protease activated receptor 2 (PAR2). Journal of medicinal chemistry 25 21294569
2004 Proteinase-activated Receptor 2 (PAR2): a challenging new target for treatment of vascular diseases. Current pharmaceutical design 25 15320742
2002 Eleven novel single nucleotide polymorphisms in the NR1I2 (PXR) gene, four of which induce non-synonymous amino acid alterations. Drug metabolism and pharmacokinetics 25 15618712
2022 Distinct Roles of the Sister Nuclear Receptors PXR and CAR in Liver Cancer Development. Drug metabolism and disposition: the biological fate of chemicals 24 35184041
2019 Association of PXR and CAR Polymorphisms and Antituberculosis Drug-Induced Hepatotoxicity. Scientific reports 24 30778091
2019 New Aspects of Vitamin K Research with Synthetic Ligands: Transcriptional Activity via SXR and Neural Differentiation Activity. International journal of molecular sciences 24 31226734
2016 Human Xenobiotic Nuclear Receptor PXR Augments Mycobacterium tuberculosis Survival. Journal of immunology (Baltimore, Md. : 1950) 24 27233963
2008 PAR1 and PAR2 integrate shade and hormone transcriptional networks. Plant signaling & behavior 24 19704482
2023 Crohn's disease proteolytic microbiota enhances inflammation through PAR2 pathway in gnotobiotic mice. Gut microbes 23 37131291
2016 Protease activated receptor 2 (PAR2) modulators: a patent review (2010-2015). Expert opinion on therapeutic patents 23 26936077
2013 PXR cross-talks with internal and external signals in physiological and pathophysiological responses. Drug metabolism reviews 23 23701014
2005 Beyond CAR and PXR. Current drug metabolism 23 16101576
2004 Induction of PXR-mediated metabolism by beta-carotene. Biochimica et biophysica acta 23 15949683
2012 Cytochrome P450 regulation by α-tocopherol in Pxr-null and PXR-humanized mice. Drug metabolism and disposition: the biological fate of chemicals 22 23160821
2013 The TERE1 protein interacts with mitochondrial TBL2: regulation of trans-membrane potential, ROS/RNS and SXR target genes. Journal of cellular biochemistry 21 23564352
2010 Induction of CYP3A4 by vinblastine: Role of the nuclear receptor NR1I2. The Annals of pharmacotherapy 21 20959500
2007 A pharmacogenetic study of pregnane X receptor (NR1I2) in Han Chinese. Current drug metabolism 21 18220558
2006 Retinoids activate the RXR/SXR-mediated pathway and induce the endogenous CYP3A4 activity in Huh7 human hepatoma cells. Toxicological sciences : an official journal of the Society of Toxicology 21 16632523
2016 PAR2 regulates regeneration, transdifferentiation, and death. Cell death & disease 20 27809303
2022 Panaxytriol upregulates CYP3A4 expression based on the interaction of PXR, CAR, HSP90α, and RXRα. Phytomedicine : international journal of phytotherapy and phytopharmacology 19 35417848
2005 Protease-activated receptor-2 (PAR2) in cardiovascular system. Vascular pharmacology 19 16183333