Affinage

NR1I2

Nuclear receptor subfamily 1 group I member 2 · UniProt O75469

Length
434 aa
Mass
49.8 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NR1I2 (SXR/PXR) is a ligand-activated nuclear receptor that functions as a broad-specificity sensor of steroids, bile acids, and xenobiotics, heterodimerizing with RXR and binding response elements in target gene promoters to induce drug-metabolizing enzymes and transporters in liver and intestine (PMID:9784494, PMID:21733184). Its defining role is xenobiotic detoxification: it is the necessary and sufficient mediator of CYP3A induction by prototypic inducers, conferring protection against toxic compounds in vivo (PMID:10935643), and it coordinately controls cross-regulated CYP families through the phenobarbital response element (PMID:11114890) as well as drug efflux via MDR1/P-glycoprotein and MRP2 to integrate catabolism with clearance (PMID:11329060, PMID:21733184). PXR is endogenously activated by the secondary bile acid lithocholic acid, driving CYP3A-mediated hydroxylation that detoxifies bile acids (PMID:11248086), and its unusually large, flexible ligand-binding pocket—conferred by a unique H1-3 insert—accommodates an exceptionally diverse ligand set including vitamin K2, tocotrienols, neurosteroids, nicotine, and bacterial mycolic acids (PMID:11981033, PMID:12920130, PMID:15269186, PMID:15364541, PMID:27233963). Beyond detoxification, NR1I2 regulates energy metabolism, promoting a SREBP-independent lipogenic program via CD36 and PPARγ (PMID:18072748), impairing hepatic glucose handling by suppressing the HNF4α–GLUT2 pathway (PMID:35646519), and driving diet-induced obesity and insulin resistance through JNK activation and lipin-1 induction (PMID:23349477). It also suppresses inflammation by antagonizing NF-κB and AP-1 to downregulate chemokines such as CXCL2 (PMID:33076328, PMID:31614203), mediates vitamin K2-dependent bone homeostasis (PMID:12920130), and exhibits tissue-protective metabolic functions, as in the PXR/AKR1B7/mitochondrial axis in acute kidney injury (PMID:32404507). Its transcriptional output is tuned by coactivators (SRC1, PGC-1α) and corepressors (NCoR, SMRT) and by post-translational modification, including an acetylation–SUMOylation switch executed in complex with HDAC3/SMRT (PMID:15269186, PMID:21933665, PMID:21920351, PMID:26883953).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 High

    Established the existence and basic mechanism of NR1I2 as a xenobiotic-responsive nuclear receptor, answering whether a single receptor could couple diverse chemical sensing to CYP3A induction.

    Evidence Receptor cloning, RXR heterodimer reconstitution, transactivation and DNA-binding assays, tissue expression analysis

    PMID:9573044 PMID:9784494

    Open questions at the time
    • Endogenous physiological ligands not yet defined
    • In vivo requirement not established by genetics
    • Structural basis of ligand promiscuity unknown
  2. 2000 High

    Genetic knockout and gain-of-function transgenics proved PXR is the necessary in vivo mediator of CYP3A induction and that receptor species origin dictates inducibility, moving the receptor from in vitro candidate to physiological detoxification sensor.

    Evidence Pxr knockout and activated-SXR transgenic mice, CYP3A expression and xenobiotic toxicity assays

    PMID:10935643

    Open questions at the time
    • Endogenous activating ligands not yet identified
    • Scope of target gene network beyond CYP3A unknown
  3. 2000 High

    Showed NR1I2 cross-regulates CYP2B via the PBRE and shares response elements reciprocally with CAR, establishing a redundant xenobiotic-response safety net rather than a single-gene regulator.

    Evidence Transactivation and reporter assays, transgenic mice with CYP2B PBRE and CYP3A XREM

    PMID:11114890

    Open questions at the time
    • Quantitative contribution of each receptor in vivo not resolved
    • Determinants of element selectivity unclear
  4. 2001 High

    Identified MDR1/P-glycoprotein as a direct PXR target and revealed corepressor displacement as the discriminator between activating and non-activating ligands, linking drug catabolism with efflux clearance.

    Evidence Reporter assays, RT-PCR, corepressor displacement assays, pharmacokinetics with paclitaxel/docetaxel/ET-743

    PMID:11329060

    Open questions at the time
    • Identity of displaced corepressors not fully mapped here
    • Genome-wide transporter target set undefined
  5. 2001 High

    Demonstrated NR1I2 is a bile acid receptor and that LCA is both a ligand and a CYP3A substrate, establishing a feed-forward detoxification loop necessary and sufficient for LCA resistance.

    Evidence Pxr knockout and transgenic mice, LCA toxicity and CYP3A induction assays, cell-based transactivation

    PMID:11248086

    Open questions at the time
    • Other endogenous bile acid ligands not exhaustively profiled
    • Quantitative flux of LCA clearance not measured
  6. 2002 Medium

    Comparative profiling across NR1I subfamily attributed PXR promiscuity to a unique H1-3 insert that enlarges the ligand-binding pocket, providing a structural rationale for broad ligand sensing.

    Evidence LBD fusion-protein activation assays across species, structural modeling, sequence analysis

    PMID:11981033

    Open questions at the time
    • Pocket-expansion model is computational, not crystallographic
    • Helix unwinding mechanism not experimentally resolved
  7. 2003 High

    Identified vitamin K2 as a bona fide PXR ligand mediating osteoblast marker induction, extending NR1I2 function from detoxification into bone homeostasis.

    Evidence Ligand binding, CYP3A4 reporter assays, RT-PCR, primary osteocytes from Pxr-knockout mice

    PMID:12920130

    Open questions at the time
    • Direct bone marker genes as PXR targets not promoter-mapped
    • In vivo skeletal phenotype of Pxr loss not addressed
  8. 2004 Medium

    Expanded the ligand repertoire (neurosteroids, nicotine, tocotrienols) and tissue distribution, and showed NCoR corepressor levels drive tissue-specific target gene selection, explaining context-dependent PXR output.

    Evidence RT-PCR across 36 tissues, CYP3A4-luciferase reporters, ligand binding, SXR-NCoR co-IP, dominant-negative NCoR

    PMID:15269186 PMID:15364541

    Open questions at the time
    • Functional roles of alternatively spliced isoforms unclear
    • Mechanism of differential NCoR release by ligand not resolved
  9. 2007 Medium

    Defined a SREBP-independent lipogenic program controlled by PXR through direct induction of CD36 and PPARγ, establishing NR1I2 as a regulator of hepatic lipid metabolism.

    Evidence Promoter/reporter analysis, RT-PCR for CD36/PPARγ/SCD-1/FAE, liver-specific expression

    PMID:18072748

    Open questions at the time
    • In vivo metabolic consequence not tested in this study
    • Promoter binding shown only for subset of targets
  10. 2009 Medium

    Connected NR1I2 to coactivator/coregulator energy-sensing networks (PGC-1α, PPARα, SIRT1) and to a p53/iNOS tumor-suppressive program, broadening its regulatory inputs and outputs.

    Evidence PGC-1α overexpression/siRNA, mammalian two-hybrid, co-IP, siRNA of SXR/p53, iNOS inhibition in breast cancer cells

    PMID:19123943 PMID:21933665

    Open questions at the time
    • Direct vs indirect coregulator effects partly inferred
    • Cancer-cell-type specificity of p53/iNOS axis unclear
  11. 2011 High

    Demonstrated that NR1I2 activity is modulated by ligand-independent coactivator disruption (metformin–SRC1) and confirmed activation-dependent nuclear translocation and native-promoter binding, refining the activation mechanism.

    Evidence Two-hybrid PXR-SRC1, reporter/qRT-PCR in human hepatocytes and Pxr-KO mice, ChIP on native CYP3A4 promoter, nuclear-translocation imaging, drug sensitivity assays

    PMID:21733184 PMID:21920351 PMID:21977915 PMID:27709012

    Open questions at the time
    • Structural basis of pocket-independent SRC1 disruption unknown
    • Isoform-specific interaction differences (PXR1 vs PXR3) carry low-confidence support
  12. 2013 High

    Linked NR1I2 to systemic metabolic disease, showing Pxr ablation protects against diet-induced obesity and insulin resistance via JNK and the novel target lipin-1.

    Evidence Pxr-KO mice on HFD and ob/ob backgrounds, oxygen consumption, euglycemic clamp, RT-PCR, lipin-1 analysis

    PMID:23349477

    Open questions at the time
    • Tissue-specific contribution of PXR not dissected
    • Relationship between lipogenic CD36/PPARγ program and lipin-1 axis unresolved
  13. 2016 Medium

    Established post-translational control of NR1I2 through an acetylation–SUMOylation switch executed in an HDAC3/SMRT complex, and a host-pathogen role via mycolic acid binding, deepening regulatory and immunological mechanism.

    Evidence Mass spectrometry of acetylation sites, TSA transactivation assays, localization imaging, PXR-HDAC3-SMRT co-IP, SUMOylation assays; macrophage infection and hPXR-transgenic mice

    PMID:26883953 PMID:27233963

    Open questions at the time
    • Enzymes writing/erasing the SUMO-acetyl switch only partly defined
    • Physiological triggers of the modification switch unknown
  14. 2020 High

    Identified tissue-protective and anti-inflammatory mechanisms, defining the PXR/AKR1B7/mitochondrial axis in kidney injury and direct NF-κB/AP-1 antagonism suppressing CXCL2.

    Evidence Luciferase reporters, PXR silencing/activation, proteomics, cisplatin/IR AKI rat models; Cxcl2 promoter mutagenesis and CCl4 liver injury mouse model

    PMID:32404507 PMID:33076328

    Open questions at the time
    • Direct PXR binding to AKR1B7 promoter vs indirect regulation not fully resolved
    • Generality of anti-inflammatory mechanism across tissues unclear
  15. 2021 High

    Resolved the mechanism by which PXR impairs glucose metabolism, showing it suppresses HNF4α recruitment to the GLUT2 promoter, completing a metabolic regulatory picture.

    Evidence PXR overexpression/silencing in hepatocytes, ChIP for HNF4α at Slc2a2, reporter assays, liver-specific Hnf4α-KO mice, glucose tolerance tests

    PMID:35646519

    Open questions at the time
    • Whether PXR directly represses HNF4α or competes for cofactors unresolved
    • Integration with insulin signaling pathway not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse ligand inputs, coregulator balance, and post-translational modification switch are integrated to select among detoxification, metabolic, anti-inflammatory, and tissue-protective transcriptional programs in a tissue-specific manner remains unresolved.
  • No unified model of program selection across tissues
  • Genome-wide direct target catalog not consolidated
  • Functional consequences of splice isoforms largely uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0008289 lipid binding 4 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-9748784 Drug ADME 4 R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 3 R-HSA-162582 Signal Transduction 2
Partners
HDAC3NCOR1PPARGC1ARXRSIRT1SMRTSRC1TP53
Complex memberships
HDAC3/SMRT corepressor complexNR1I2-RXR heterodimer

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 SXR (NR1I2) was identified as a novel nuclear receptor that activates transcription in response to a diversity of natural and synthetic steroid and xenobiotic compounds. It forms a heterodimer with RXR that binds to and induces transcription from response elements present in steroid-inducible cytochrome P-450 genes (CYP3A). SXR is expressed in liver and intestine, the same tissues where these catabolic enzymes are expressed. Receptor cloning, transactivation assays, heterodimer binding/RXR co-transfection, tissue expression analysis Genes & development High 9784494
1998 BXR (an NR1I2 ortholog/related receptor) heterodimerizes with RXR and binds high-affinity DNA sites composed of a variant thyroid hormone response element. Alkyl esters of amino and hydroxy benzoic acids (benzoates) were identified as bona fide BXR ligands by in vitro cofactor association studies and competitive radiolabeled compound binding, establishing benzoates as a new molecular class of nuclear receptor ligand. Receptor cloning, in vitro ligand binding (radiolabeled compound displacement), cofactor association studies, mass spectrometry, 1H NMR, transactivation assays Genes & development High 9573044
2000 Targeted disruption of mouse PXR (NR1I2) abolishes induction of CYP3A by prototypic inducers dexamethasone and pregnenolone-16α-carbonitrile (PCN), establishing PXR as the necessary mediator of CYP3A induction. Transgenic mice expressing an activated form of human SXR showed constitutive upregulation of CYP3A gene expression and enhanced protection against toxic xenobiotic compounds. The species origin of the receptor (not promoter structure) dictates species-specific CYP3A inducibility. PXR knockout mice, transgenic mice expressing activated SXR, CYP3A gene expression analysis, xenobiotic toxicity assays Nature High 10935643
2000 SXR/PXR can regulate CYP2B genes (not only CYP3A) via adaptive recognition of the phenobarbital response element (PBRE) in cultured cells and transgenic mice, revealing cross-regulation of CYP gene families. Reciprocally, orphan receptor CAR activates CYP3A through SXR/PXR response elements, establishing a metabolic safety net of overlapping xenobiotic receptor function. Transactivation assays in cultured cells, transgenic mouse studies, reporter gene assays with CYP2B PBRE and CYP3A XREM Genes & development High 11114890
2001 SXR/PXR directly regulates MDR1 gene expression (encoding P-glycoprotein/ABCB1), coordinating both drug catabolism (CYP3A4) and drug efflux. Paclitaxel activated SXR and enhanced P-glycoprotein-mediated drug clearance, while docetaxel did not activate SXR. Docetaxel's inactivity was linked to its inability to displace transcriptional corepressors from SXR. ET-743 suppressed MDR1 transcription by acting as an SXR inhibitor. Reporter gene assays, RT-PCR for MDR1/CYP3A4 expression, corepressor displacement assays, pharmacokinetic studies Nature medicine High 11329060
2001 Human SXR and rodent PXR function as bile acid receptors; the secondary bile acid lithocholic acid (LCA) is a metabolic substrate for CYP3A hydroxylation and activates SXR/PXR. Using PXR knockout and SXR transgenic animals, SXR/PXR activation was shown to be necessary and sufficient to induce CYP3A enzymes and confer resistance to LCA hepatotoxicity, as well as to other xenotoxicants. PXR knockout mice, transgenic mice, LCA toxicity assays, CYP3A induction assays, cell-based transactivation Proceedings of the National Academy of Sciences of the United States of America High 11248086
2002 Comparative pharmacological profiling of NR1I subfamily members identified three distinct receptor classes: PXRs (activated by broad range of xenobiotics and steroids), CARs (high basal activity, generally repressed), and BXRs (selectively activated by benzoate analogs). PXRs possess a unique H1-3 insert (stretch of amino acids between helices 1 and 3 absent in CARs and BXRs) that modeling suggests expands the ligand binding pocket by facilitating unwinding of helices 6 and 7, explaining PXR promiscuity. Ligand activation assays of LBD fusion proteins across species, structural modeling, sequence analysis Molecular endocrinology (Baltimore, Md.) Medium 11981033
2003 Vitamin K2 (menaquinone) binds to and activates the orphan nuclear receptor SXR/PXR and induces expression of the SXR target gene CYP3A4, identifying it as a bona fide SXR ligand. Vitamin K2 treatment increased mRNA levels for osteoblast markers (bone alkaline phosphatase, osteoprotegerin, osteopontin, matrix Gla protein) in osteosarcoma cells. Vitamin K2 could induce bone markers in primary osteocytes from wild-type but not PXR-deficient mice, establishing SXR as a mediator of bone homeostasis. Ligand binding assays, CYP3A4 reporter assays, RT-PCR, primary osteocyte cultures from PXR knockout mice The Journal of biological chemistry High 12920130
2004 PXR (NR1I2) is expressed in many tissues beyond liver and intestine, including human bone marrow and select regions of human brain. Multiple alternatively spliced PXR isoforms (PXR.2 lacking 37 aa from LBD, PXR.3 lacking 41 aa from LBD) were identified. Neurosteroids allopregnanolone and pregnanolone activated PXR and induced CYP3A4-luciferase reporter transcription. Nicotine was identified as an efficacious PXR activator inducing CYP3A4 transcription. RT-PCR across 36 human tissues, CYP3A4-luciferase reporter assays, quantitative mRNA analysis in human liver Toxicology and applied pharmacology Medium 15364541
2004 All four tocotrienols (but not tocopherols) specifically bind to and activate SXR/PXR. Tocotrienols show tissue-specific induction of SXR target genes: they upregulate CYP3A4 but not UGT1A1 or MDR1 in primary hepatocytes, whereas in intestinal LS180 cells they induce MDR1 and UGT1A1 but not CYP3A4. Unliganded SXR interacts with NCoR (nuclear receptor corepressor), and this interaction is only partially disrupted by tocotrienols; NCoR is expressed at higher levels in LS180 cells, contributing to tissue-specific gene regulation. Ligand binding assays, reporter gene assays, RT-PCR in primary hepatocytes and LS180 cells, co-immunoprecipitation of SXR-NCoR, dominant-negative NCoR overexpression Drug metabolism and disposition: the biological fate of chemicals High 15269186
2009 Activation of SXR/PXR in p53 wild-type breast cancer cells (MCF-7, ZR-75-1) inhibited proliferation by inducing G1/S cell cycle arrest and apoptosis. This was mechanistically dependent on SXR-induced upregulation of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) production, leading to p53 stabilization and upregulation of p21, PUMA, and BAX. siRNA knockdown of SXR blocked iNOS induction; p53 knockdown blocked p21 and BAX upregulation. Cell proliferation assays, FACS cell cycle analysis, RT-PCR, western blotting, siRNA knockdown of SXR and p53, iNOS inhibition BMC cancer Medium 19123943
2009 PGC-1α overexpression upregulates PXR expression in mouse primary hepatocytes, and siRNA knockdown of PPARα attenuates PGC-1α-mediated induction of PXR mRNA, indicating PPARα mediates PGC-1α's effect on PXR transcription. SIRT1 interacts with PXR (by co-immunoprecipitation) and pyruvate/SIRT1 activation interferes with PXR-PGC-1α interaction in mammalian two-hybrid assays, inhibiting synergistic CYP3A11 induction. PGC-1α overexpression and siRNA knockdown in primary hepatocytes, mammalian two-hybrid assay, co-immunoprecipitation, RT-PCR Biochemical pharmacology Medium 21933665
2011 Metformin suppresses PXR-mediated CYP3A4 expression in human hepatocytes. Mechanistically, metformin disrupts PXR's interaction with steroid receptor coactivator-1 (SRC1) in a two-hybrid assay independently of the PXR ligand binding pocket. Metformin suppressed Cyp3a11 mRNA in wild-type but not Pxr−/− mice. AMPK activation and SHP upregulation were not required for this effect. Reporter gene assays, qRT-PCR in human hepatocytes and Pxr−/− mice, mammalian two-hybrid assay for PXR-SRC1 interaction, AMPK inhibition studies Biochemical pharmacology High 21920351
2011 In colon cancer cells, SN-38 (active metabolite of irinotecan) activates endogenous SXR/PXR, causing its translocation into the nucleus where it associates with RXR. ChIP demonstrated that endogenous SXR binds to the native CYP3A4 gene promoter upon activation. siRNA confirmed SXR involvement in CYP3A4 overexpression and identified CYP3A5 and MRP2 transporter as SXR target genes. SXR overexpression reduced cellular sensitivity to irinotecan. Immunofluorescence (nuclear translocation), ChIP, siRNA knockdown, RT-PCR, drug sensitivity assays Molecular cancer High 21733184
2013 PXR ablation in mice inhibited high-fat diet-induced obesity, hepatic steatosis, and insulin resistance through increased oxygen consumption, increased mitochondrial β-oxidation, inhibition of hepatic lipogenesis and inflammation, and sensitization of insulin signaling. Mechanistically, PXR ablation was associated with inhibition of c-Jun N-terminal kinase (JNK) activation and downregulation of lipin-1, identified as a novel PXR target gene. PXR ablation in ob/ob mice also improved metabolic phenotype. PXR knockout mice on HFD and ob/ob background, oxygen consumption measurements, euglycemic clamp, RT-PCR, lipin-1 promoter/target gene analysis Diabetes High 23349477
2016 PXR is modified by acetylation on lysine residues. Increased acetylation of PXR stimulates its increased SUMOylation to support active transcriptional suppression (a 'SUMO-acetyl switch'). Pharmacologic inhibition of lysine deacetylation with trichostatin A (TSA) alters PXR subcellular localization in cultured hepatocytes and profoundly impacts PXR transactivation capacity. PXR associates with the lysine deacetylating enzyme HDAC3 in a complex with SMRT corepressor. Mass spectrometry identification of acetylation sites, cell-based transactivation assays with TSA, immunofluorescence for subcellular localization, co-immunoprecipitation of PXR-HDAC3-SMRT complex, SUMOylation assays Biochimica et biophysica acta Medium 26883953
2020 PXR was robustly downregulated in kidneys with acute kidney injury (AKI). PXR targeted Aldo-keto reductase family 1 member B7 (AKR1B7) to improve mitochondrial function, determined by luciferase reporter assays and genomic manipulation. Silencing PXR in rats enhanced cisplatin-induced AKI with severe mitochondrial abnormalities; activating PXR protected against AKI. The PXR/AKR1B7/mitochondrial metabolism axis was validated in ischemia/reperfusion AKI model. Luciferase reporter assays, genomic manipulation (PXR silencing and activation), proteomics, cisplatin and ischemia/reperfusion AKI models in rats, renal function assays Science translational medicine High 32404507
2020 PXR functionally interacts with both NF-κB and AP-1 transcription factors to downregulate inflammation-induced expression of chemokine CXCL2 in mouse liver. Reporter assays with mutated Cxcl2 promoter showed that mutation of both NF-κB and AP-1 binding sites abolished PXR-dependent suppression; mutation of either alone only partially reduced it. PXR activation (PCN) suppressed neutrophil infiltration and plasma transaminase activity in CCl4-injured mice. In vivo mouse liver injury model, qRT-PCR, reporter assays with wild-type and NF-κB/AP-1 mutated Cxcl2 promoters, plasma transaminase assays, histology Cells Medium 33076328
2021 PXR activation impaired hepatic glucose metabolism by inhibiting the HNF4α–GLUT2 pathway. PXR agonists downregulated HNF4α and GLUT2 expression; PXR overexpression decreased and PXR silencing increased HNF4α/GLUT2. HNF4α recruits to the Slc2a2 (GLUT2) promoter, and PCN suppressed this recruitment. Liver-specific Hnf4α deletion and PCN treatment impaired glucose tolerance and hepatic glucose uptake in mice. HepG2 cells and mouse/human primary hepatocytes with PXR overexpression/silencing, ChIP for HNF4α at Slc2a2 promoter, luciferase reporter assays, liver-specific Hnf4α knockout mice, glucose tolerance tests Acta pharmaceutica Sinica. B High 35646519
2016 Human PXR (hPXR) interacts with mycobacterial cell wall lipids (particularly mycolic acids) via its promiscuous ligand binding domain, as shown in macrophage infection studies. hPXR augments M. tuberculosis survival inside host macrophages by promoting foamy macrophage formation and abrogating phagolysosomal fusion, inflammation, and apoptosis. Expression of hPXR in humanized transgenic mice promoted M. tuberculosis survival in vivo. Human monocyte-derived macrophages, hPXR-transgenic mice, phagolysosomal fusion assays, lipid ligand binding studies, infection survival assays Journal of immunology (Baltimore, Md. : 1950) Medium 27233963
2011 Upon stimulation with lithocholic acid, PXR translocates from cytoplasm to the nucleus of OE19 adenocarcinoma cells, as demonstrated by immunofluorescence in cell line experiments. Immunohistochemistry and immunofluorescence in esophageal cell lines and tissue, PXR stimulation with lithocholic acid BMC gastroenterology Low 21977915
2015 In mouse hippocampal neurons, nonylphenol induced translocation of PXR immunofluorescence from cytoplasm to the nucleus. siRNA knockdown of Pxr reduced nonylphenol-induced caspase-3 activation and LDH release, demonstrating that PXR signaling contributes to nonylphenol-induced apoptosis and neurotoxicity. Primary mouse hippocampal cell cultures, immunofluorescence for nuclear translocation, siRNA knockdown, caspase-3 activity assay, LDH release assay The Journal of steroid biochemistry and molecular biology Medium 26643981
2016 PXR transcript variant 1 (PXR1) interacts with p53, whereas PXR transcript variant 3 (PXR3) does not, establishing a differential protein-protein interaction profile of PXR isoforms. Variants PXR3 and PXR4 do not induce target gene expression upon agonist treatment, whereas PXR1 and PXR2 do. PXR1 and PXR4 mRNA are downregulated by methylation in cancerous tissue. Protein-protein interaction assays (PXR1 vs PXR3 with p53), reporter gene assays for target gene transactivation, methylation analysis Acta pharmaceutica Sinica. B Low 27709012
2007 PXR activates a SREBP-independent lipogenic pathway by inducing expression of the free fatty acid uptake transporter CD36, PPARγ, and accessory lipogenic enzymes stearoyl-CoA desaturase-1 (SCD-1) and long-chain free fatty acid elongase (FAE) in a liver-specific manner. Promoter analysis established CD36 as a transcriptional target of PXR. PPARγ is also a direct transcriptional target of PXR. Promoter analysis/reporter assays, RT-PCR for target gene expression, liver-specific expression analysis Molecular pharmaceutics Medium 18072748
2019 Patchouli alcohol (PA) activates PXR (identified as a PXR agonist by hPXR transactivation assays and CYP3A4 expression/activity induction). PA-mediated PXR activation attenuated NF-κB activity and nuclear translocation. PXR knockdown abolished the anti-inflammatory effect of PA on NF-κB, demonstrating that the anti-inflammatory effect is PXR-dependent. In vivo, PA prevented DSS-induced colitis by regulating PXR/NF-κB signaling. hPXR transactivation assays, NF-κB luciferase assays, NF-κB nuclear translocation imaging, PXR knockdown, DSS colitis mouse model, pharmacological PXR inhibition Journal of ethnopharmacology Medium 31614203

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 707 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
1999 P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Archives of biochemistry and biophysics 590 10462436
2000 Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 542 10935643
2015 New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. Journal of hepatology 410 25920087
2002 PXR, CAR and drug metabolism. Nature reviews. Drug discovery 406 12120277
2000 Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes & development 391 11114890
2006 CAR and PXR: the xenobiotic-sensing receptors. Steroids 329 17284330
2010 Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR. Advanced drug delivery reviews 315 20727377
2002 Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptors. Molecular endocrinology (Baltimore, Md.) 302 11981033
2003 Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor SXR. The Journal of biological chemistry 298 12920130
2009 Nuclear receptors CAR and PXR: Molecular, functional, and biomedical aspects. Molecular aspects of medicine 242 19427329
2005 CAR and PXR: xenosensors of endocrine disrupters? Chemico-biological interactions 214 16054614
2009 PXR and CAR in energy metabolism. Trends in endocrinology and metabolism: TEM 202 19595610
2012 Role of CAR and PXR in xenobiotic sensing and metabolism. Expert opinion on drug metabolism & toxicology 191 22554043
2007 Xenoreceptors CAR and PXR activation and consequences on lipid metabolism, glucose homeostasis, and inflammatory response. Molecular pharmaceutics 187 18159929
2011 Nuclear receptor PXR, transcriptional circuits and metabolic relevance. Biochimica et biophysica acta 185 21295138
2004 PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators. Toxicology and applied pharmacology 174 15364541
2017 PXR: More Than Just a Master Xenobiotic Receptor. Molecular pharmacology 139 29113993
2003 Drug-activated nuclear receptors CAR and PXR. Annals of medicine 138 12822739
2009 The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism. Nuclear receptor signaling 136 19240808
2016 Pregnane X Receptor (PXR)-Mediated Gene Repression and Cross-Talk of PXR with Other Nuclear Receptors via Coactivator Interactions. Frontiers in pharmacology 134 27932985
2008 PXR: a xenobiotic receptor of diverse function implicated in pharmacogenetics. Pharmacogenomics 132 19018724
2013 PXR ablation alleviates diet-induced and genetic obesity and insulin resistance in mice. Diabetes 131 23349477
2011 FXR and PXR: potential therapeutic targets in cholestasis. The Journal of steroid biochemistry and molecular biology 131 21801835
2005 Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR. Archives of biochemistry and biophysics 127 15581595
2013 Nuclear receptors PXR and CAR: implications for drug metabolism regulation, pharmacogenomics and beyond. Expert opinion on drug metabolism & toxicology 126 23327618
2000 Use of the nuclear receptor PXR to predict drug interactions. Toxicology 125 11090943
2012 Targeting xenobiotic receptors PXR and CAR for metabolic diseases. Trends in pharmacological sciences 124 22889594
2008 The roles of nuclear receptors CAR and PXR in hepatic energy metabolism. Drug metabolism and pharmacokinetics 116 18305370
2006 Synthetic drugs and natural products as modulators of constitutive androstane receptor (CAR) and pregnane X receptor (PXR). Drug metabolism reviews 115 16684648
2006 PXR and CAR: nuclear receptors which play a pivotal role in drug disposition and chemical toxicity. Drug metabolism reviews 107 16877263
2003 Functional and structural comparison of PXR and CAR. Biochimica et biophysica acta 101 12573482
2005 Genetic variants of PXR (NR1I2) and CAR (NR1I3) and their implications in drug metabolism and pharmacogenetics. Current drug metabolism 98 16101575
2014 Targeting xenobiotic receptors PXR and CAR in human diseases. Drug discovery today 94 25463033
2019 PXR: a center of transcriptional regulation in cancer. Acta pharmaceutica Sinica. B 91 32082968
2013 Post-translational and post-transcriptional modifications of pregnane X receptor (PXR) in regulation of the cytochrome P450 superfamily. Current drug metabolism 89 24329114
2004 Tocotrienols activate the steroid and xenobiotic receptor, SXR, and selectively regulate expression of its target genes. Drug metabolism and disposition: the biological fate of chemicals 89 15269186
2013 PXR antagonists and implication in drug metabolism. Drug metabolism reviews 85 23330542
2009 Activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) by herbal medicines. The AAPS journal 83 19688601
2005 Structure and function of the human nuclear xenobiotic receptor PXR. Current drug metabolism 80 16101574
2016 Regulation of hepatic energy metabolism by the nuclear receptor PXR. Biochimica et biophysica acta 79 27041449
2013 Role of PPAR, LXR, and PXR in epidermal homeostasis and inflammation. Biochimica et biophysica acta 79 24315978
2011 Metformin suppresses pregnane X receptor (PXR)-regulated transactivation of CYP3A4 gene. Biochemical pharmacology 79 21920351
2008 A gut feeling of the PXR, PPAR and NF-kappaB connection. Journal of internal medicine 74 18479261
2016 RNA-Seq reveals common and unique PXR- and CAR-target gene signatures in the mouse liver transcriptome. Biochimica et biophysica acta 70 27113289
2021 The xenobiotic receptors PXR and CAR in liver physiology, an update. Biochimica et biophysica acta. Molecular basis of disease 68 33600998
2002 The nuclear receptor PXR: a master regulator of "homeland" defense. Critical reviews in eukaryotic gene expression 67 12433065
2010 Nuclear receptor-mediated induction of CYP450 by antiretrovirals: functional consequences of NR1I2 (PXR) polymorphisms and differential prevalence in whites and sub-Saharan Africans. Journal of acquired immune deficiency syndromes (1999) 65 20861742
2020 Regulation of CAR and PXR Expression in Health and Disease. Cells 64 33142929
2022 The role of pregnane X receptor (PXR) in substance metabolism. Frontiers in endocrinology 60 36111293
2016 Small-molecule modulators of PXR and CAR. Biochimica et biophysica acta 60 26921498
2009 Phosphorylation and protein-protein interactions in PXR-mediated CYP3A repression. Expert opinion on drug metabolism & toxicology 59 19505191
1998 BXR, an embryonic orphan nuclear receptor activated by a novel class of endogenous benzoate metabolites. Genes & development 59 9573044
2020 Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI. Science translational medicine 58 32404507
2013 Expression of the PXR gene in various types of cancer and drug resistance. Oncology letters 58 23599746
2018 Effects of Oridonin on Hepatic Cytochrome P450 Expression and Activities in PXR-Humanized Mice. Biological & pharmaceutical bulletin 55 29709908
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 53 27709012
2009 Elucidating the 'Jekyll and Hyde' nature of PXR: the case for discovering antagonists or allosteric antagonists. Pharmaceutical research 53 19415465
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2009 Activation of the steroid and xenobiotic receptor, SXR, induces apoptosis in breast cancer cells. BMC cancer 50 19123943
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2007 Phytoestrogen exposure is associated with circulating sex hormone levels in postmenopausal women and interact with ESR1 and NR1I2 gene variants. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 49 17507630
2020 PXR Functionally Interacts with NF-κB and AP-1 to Downregulate the Inflammation-Induced Expression of Chemokine CXCL2 in Mice. Cells 47 33076328
2023 AhR, PXR and CAR: From Xenobiotic Receptors to Metabolic Sensors. Cells 45 38067179
2011 Irinotecan induces steroid and xenobiotic receptor (SXR) signaling to detoxification pathway in colon cancer cells. Molecular cancer 44 21733184
2008 Activation of steroid and xenobiotic receptor (SXR, NR1I2) and its orthologs in laboratory, toxicologic, and genome model species. Environmental health perspectives 44 18629309
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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
2013 Pregnane X receptor (PXR) at the crossroads of human metabolism and disease. Current drug metabolism 40 23237007
2011 Energy sensing factors PGC-1α and SIRT1 modulate PXR expression and function. Biochemical pharmacology 40 21933665
2012 Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders. Current topics in medicinal chemistry 38 22242859
2011 Nuclear receptors CAR and PXR; therapeutic targets for cholestatic liver disease. Frontiers in bioscience (Landmark edition) 37 21622216
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2017 PXR as a mediator of herb-drug interaction. Journal of food and drug analysis 36 29703383
2010 Pregnane X receptor (PXR/NR1I2) gene haplotypes modulate susceptibility to inflammatory bowel disease. Inflammatory bowel diseases 34 21830270
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2015 Environmental contaminants activate human and polar bear (Ursus maritimus) pregnane X receptors (PXR, NR1I2) differently. Toxicology and applied pharmacology 27 25680588
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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
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