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Overview
| Alternate Names: | orphan nuclear receptor PXR; steroid and xenobiotic receptor |
|---|---|
| Alternate Symbols: | BXR; ONR1; PAR; PAR1; PAR2; PARq; PRR; PXR; SAR; SXR |
| PharmGKB Accession Id: | PA378 |
Details
| Cytogenetic Location: | chr3 : q13.33 |
|---|---|
| GP mRNA Boundary†: | chr3 : 120982021 - 121020022 |
| GP Gene Boundary†: | chr3 : 120972021 - 121023022 |
| Strand: | plus |
| Product Name: | pregnane X receptor, pregnane X receptor isoform 1, pregnane X receptor isoform 1l, pregnane X receptor isoform 2, pregnane X receptor isoform 3, steroid and xenobiotic receptor |
Introduction
Overview
The NR1I2 gene codes for the pregnane X receptor (PXR)-- also referred to as pregnane activating receptor (PAR) and steroid xenobiotic receptor (SXR) )-- a member of the nuclear receptor (NR) superfamily of transcription factors that regulates the induction of many genes. (In this summary, we will use the term NR1I2 to refer to the gene and PXR to refer to the protein encoded by gene.) PXR is a well established regulator of CYP3A4 expression (references listed in Table 1), an enzyme involved in the metabolism of 40-50% of all drugs [PMID: 16954191, 9187528] as well as many other genes. The NR1I2 gene maps to chromosome 3q12-13 and has ten exons although only nine form the referemce transcript (see [PMID: 16101575] Figure 3 for a representation of exons and transcripts and section below, Splice Variants for NR1I2). The reference transcript encodes a protein of 434 amino acids and has the domain structure characteristic of the nuclear receptor superfamily: there is an N-terminus region; a DNA binding domain (DBD), consisting of two zinc fingers (amino acids 41-107); a hinge region (amino acids 107-141) and ligand binding domain (LBD) containing the ligand binding pocket and a ligand-depending activation factor (AF-2) domain (amino acids 141-434) [PMID: 16101574, 14657421]. Unique to PXR is an approximately 60 amino acid sequence in the LBD that appears to allow accommodation of a wide variety of ligands; see [PMID: 11408620, 15705662] and other references in Structure section below.
A simplified view of the steps in PXR gene regulation is as follows: PXR is activated by a ligand, forms a heterodimer with 9-cis retinoic acid receptor RXRalpha (gene= RXRA ) [PMID: 9784494, 9727070, 9489701, 11706036], that binds to specific DNA response elements in the target gene [PMID: 9784494, 9489701, 11706036, 12372848, 9727070], and induces gene expression. The full story of transcriptional regulation is much more complicated: PXR is constitutively inactive and is generally thought to reside in the nucleus regardless of the presence or absence of its inducers [PMID: 11264453, 14709632] (although work by Squires, et al [PMID: 15347657] in mouse livers, show that PXR is localized in the cytoplasm and translocates to the nucleus upon ligand binding.) Ligand-free PXR is bound to corepressors NCOR1 [PMID: 11329060] and NCOR2 (also known as the silencing mediator of retinoid and thyroid hormone receptor; SMRT) [PMID: 11329060, 16219912]; ligand binding causes dissociation of this complex [PMID: 16219912]. Ligand binding and PXR activation of gene transcription also involves recruitment of other proteins, in particular, the Steroid receptor coactivator 1 (SRC-1, gene= NCOA1 ) [PMID: 16455805, 9727070, 15650019, 17998298], but other proteins are also involved, including PGC-1 (gene= PPRC1 ) [PMID: 16455805] and Hepatic Nuclear Factor 4 alpha (gene= HNF4A ), another NR [PMID: 16455805, 12514743, 20086032] and protein arginine methyltransferase 1 (gene= PRMT1 ) another co-activator [PMID: 19144646].
Expression of NR1I2 itself is regulated by other NRs, including the glucocorticoid receptor (GR, gene= NR3C1 )[PMID: 10908304, 12511605, 16718615], HNF4A [PMID: 17827783], farnesoid X receptor (FXR, gene= NR1H4 ) [PMID: 16682417] and FOXA2 [PMID: 19934400]. Expression of NR1I2 is repressed by interleukin-6 [PMID: 10924340], small heterodimer partner, (SHP, gene= NR0B2 ), another NR [PMID: 12805410, 16455805], NF-kb p65 (gene= RELA ) [PMID: 16608838] and protein kinase c alpha (gene= PRKCA ) [PMID: 15710363]; consequently repression of PXR-mediated CYP3A4 induction occurs.
Gene Targets
PXR, like other NRs, regulates transcription of many genes, in particular those genes that metabolize and transport drugs. The most-studied PXR gene target is CYP3A4 ; see Table 1 for list of references. Other gene targets listed in Table 1 and identified via functional assays include ABCB1 [PMID: 11329060, 20041327, 11297522], ABCC2 [PMID: 11466304, 11706036], ABCC3 [PMID: 11323161], ALAS1 [PMID: 12181440], AHR [PMID: 12181440], ALDH1A1 [PMID: 12181440], CYP1A1 [PMID: 12181440, 19326768], CYP1A2 [PMID: 12181440, 10820139], CYP2A6 [PMID: 12181440, 19326768], CYP2B6 [PMID: 16718615, 12181440, 11560876, 18096673, 19326768, 15761118, 19520773, 9157990, 10820139], CYP2C8 [PMID: 12181440, 11329060, 9157990], CYP2C9 [PMID: 16718615, 12181440, 11560876, 18096673, 19369937, 17513950, 11466304, 9157990, 11714868, 14600250], CYP3A5 [PMID: 18725505, 15252010], GSTA2 [PMID: 12181440], POR [PMID: 12181440], SULT1A1 [PMID: 12181440]. Additionally, PXR DNA binding elements have been found in other genes, via in silico analysis, then verified experimentally; these genes are UGT1A6 [PMID: 15316010], UGT1A3 [PMID: 15316010, 15077869], UGT1A4 [PMID: 15077869], CASP10 [PMID: 15316010]. Microarray experiments [PMID: 11714868] with rifampin identified other genes presumed to be PXR targets: CYP2A6 , CYP3A7 , CYP4F3 , CYP1B1 , GSTA1 , GSTA3 , SLC22A5 , TTR , MAOB , FMO4 , FMO5 , GSTA2 , GSTM1 , GSTP1. There are conflicting data about UGT1A1 [PMID: 15077869, 16718615, 12181440, 15316010], CYP1A2 [PMID: 11714868, 12181440], CYP2E1 [PMID: 11714868, 12181440].
In addition to transactivation of genes, PXR is also involved with inhibition/repression: Rifampin-liganded PXR suppresses SULT2A1 expression by interfering with HNF4A activity [PMID: 17687072]; PXR inhibits CYP7A1 gene transcription [PMID: 15331348]; activation of PXR by rifampin and other agonists inhibits NF-kB signaling [PMID: 16841097]. PXR is also involved in regulation of CYP4F12 that does not involve rifampin [PMID: 19129222].
Curated Annotations (
)
-
rs2472677
at chr3:121001107
in
NR1I2
The CC homozygote of the NR1I2:63396C>T variant is associated with a high level of NR1I2 (PXR) gene induction by rifampicin as measured by increased activity of CYP3A4. This observation was particularly pronounced in livers from male subjects. Samples with the T allele had higher basal levels of NR1I2 mRNA and higher basal activity of CYP3A4. This SNP is predicted to be within a FOXA2 (HNF3beta) transcription factor binding site. This SNP is in LD with 63704G>A (rs12492296), 63813(CAAA)n/(CA)n, and 65104T>C.- Variant Name:
- NR1I2:63396C>T, PXR 63396C>T
- Related Drugs:
- rifampin
- Evidence:
-
PMID:17925385
-
rs2461823
at chr3:121002815
in
NR1I2
Risk or phenotype-associated allele: A. Phenotype: The multimarker composed of rs2461823/A-rs7643645/G was significantly associated with severity of nonalcoholic fatty liver disease (NAFLD). Study size: 290. Study population/ethnicity: 188 NAFLD patients with different stages of disease severity and 102 healthy individuals. metric(s): P<6.9x10, beta: 0.45. Type of association: GN.- Related Diseases:
- Fatty Liver
- Evidence:
-
PMID:19940802
-
rs7643645
at chr3:121008187
in
NR1I2
Risk or phenotype-associated allele: G. Phenotype: The multimarker composed of rs2461823/A-rs7643645/G was significantly associated with severity of nonalcoholic fatty liver disease (NAFLD) (P<6.9x10, beta: 0.45). In univariate analysis rs7643645/G was significantly associated with fatty liver disease (P<0.04), with an odds ratio of 1.457 (95% confidence interval: 1.018-2.086). Study size: 290. Study population/ethnicity: 188 NAFLD patients with different stages of disease severity and 102 healthy individuals. Type of association: GN.- Related Diseases:
- Fatty Liver
- Evidence:
-
PMID:19940802
-
rs59371185
at chr3:121008839
in
NR1I2
cell based studies; transcription and induction same as WT- Variant Name:
- E18K
- Evidence:
-
PMID:11602521
-
rs12721613
at chr3:121008866
in
NR1I2
cell based studies; transcription and induction same as WT- Variant Name:
- P27S
- Evidence:
-
PMID:11602521
-
rs12721613
at chr3:121008866
in
NR1I2
study of 54 livers; variant not associated with altered midazolam clearance- Variant Name:
- g.79C>T; Pro27Ser
- Related Drugs:
- midazolam
- Evidence:
-
PMID:17050801
-
rs12721607
at chr3:121008893
in
NR1I2
cell based studies; increased induction w/ corticosterone- Variant Name:
- G36R
- Evidence:
-
PMID:11602521
-
rs1464603
at chr3:121009039
in
NR1I2
risk allele: G; part of haplotype g.252A>G (rs1464603), g.275A>G (rs1464602), and g.4760G>A ; AF364606 significantly (P < .05) associated with oral midazolam clearance in the African American subpopulation (n = 14) but not in European Americans (n = 9).- Variant Name:
- g.252A>G
- Related Drugs:
- midazolam
- Evidence:
-
PMID:17050801
-
rs1464602
at chr3:121009062
in
NR1I2
risk allele: G; part of haplotype g.252A>G (rs1464603), g.275A>G (rs1464602), and g.4760G>A ; AF364606 significantly (P < .05) associated with oral midazolam clearance in the African American subpopulation (n = 14) but not in European Americans (n = 9).- Variant Name:
- g.275A>G
- Related Drugs:
- midazolam
- Evidence:
-
PMID:17050801
-
rs72551371
at chr3:121011692
in
NR1I2
cell-based studies; failed to transactivate the CYP3A4; doesn't bind DNA- Variant Name:
- R98C
- Evidence:
-
PMID:14709632
-
rs12721608
at chr3:121013109
in
NR1I2
The variant NR1I2 R122Q protein had significantly decreased affinity for the PXR binding sequence in electromobility shift assays. In a transient transfection assays this SNP showed attenuated ligand activation of the CYP3A4 reporter plasmids. The study reports that the person heterozygous for PXR*4 is normal for CYP3A4 metabolism phenotype.- Variant Name:
- NR1I2: PXR*4; R122Q; 4321G>A
- Evidence:
-
PMID:11668216
-
rs72551372
at chr3:121013162
in
NR1I2
cell based studies; enhanced basal activity of cyp3a4 transcription wrt WT- Variant Name:
- V140M
- Related Drugs:
- rifampin
- Evidence:
-
PMID:11602521
-
rs72551373
at chr3:121013187
in
NR1I2
cell-based studies; similar to WT- Variant Name:
- R148Q
- Evidence:
-
PMID:14709632
-
rs72551374
at chr3:121013232
in
NR1I2
cell based studies; decreased basal activity on cyp3a4 transcription wrt WT; increased fold induction w/ rifampicin- Variant Name:
- D163G
- Related Drugs:
- rifampin
- Evidence:
-
PMID:11602521
-
rs35761343
at chr3:121017316
in
NR1I2
cell based studies; enhanced basal activity on cyp3a4 transcription wrt WT- Variant Name:
- A370T
- Evidence:
-
PMID:11602521
-
rs35761343
at chr3:121017316
in
NR1I2
cell based studies; transcription and induction same as WT- Variant Name:
- A370T
- Evidence:
-
PMID:11602521
-
rs72551375
at chr3:121017349
in
NR1I2
cell-based studies; reduced fold induction or same as WT in transactivation of CYP3A4, depending upon ligand- Variant Name:
- R381W
- Evidence:
-
PMID:14709632
-
rs72551376
at chr3:121018651
in
NR1I2
cell-based studies; reduced fold induction or same as WT in transactivation of CYP3A4, depending upon ligand- Variant Name:
- I403V
- Evidence:
-
PMID:14709632
Curated Information
The following genes are in curated knowledge about this gene.
| Gene | Relationship | Evidence | |
|---|---|---|---|
|
ABCB1 |
|
Publications |
|
ABCC2 |
|
Publications |
|
|
AHR |
|
Publications |
|
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ALAS1 |
|
Publications |
|
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ALDH1A1 |
|
Publications |
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|
CYP1A1 |
|
Publications |
|
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CYP1A2 |
|
Publications |
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CYP1B1 |
|
Publications |
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CYP2A6 |
|
Publications |
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CYP2B6 |
|
Publications |
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CYP2C9 |
|
Publications |
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CYP2E1 |
|
Publications |
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CYP3A |
|
Publications |
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CYP3A4 |
|
Publications |
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CYP3A5 |
|
Publications |
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CYP3A7 |
|
Publications |
|
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GSTA2 |
|
Publications |
|
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NCOA1 |
|
Publications |
|
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NCOR2 |
|
Publications |
|
|
POR |
|
Publications |
|
|
RXRA |
|
Publications |
|
|
SREBF1 |
|
Publications |
|
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SULT1A1 |
|
Publications |
|
|
UGT1A1 |
|
Publications |
Non-Curated Information
A list of non-curated publications that mention this gene along with other genes is available.
PharmGKB Curated Pathways
Curated Information
The following drugs are in curated knowledge about this gene.
| Drug Class | Relationship | Evidence | |
|---|---|---|---|
|
|
antineoplastic agents |
|
Publications |
|
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artemisinin and derivatives |
|
Publications |
|
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non-nucleoside reverse transcriptase inhibitors |
|
Publications |
|
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protease inhibitors |
|
Publications |
|
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vitamin d and analogues |
|
Publications |
|
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xenobiotics |
|
Publications |
Non-Curated Information
A list of non-curated publications that mention this gene along with other drugs is available.
Curated Information
The following diseases are in curated knowledge about this gene.
| Disease | Relationship | Evidence | |
|---|---|---|---|
|
|
aspirin-induced asthma |
|
Publications |
|
|
Epilepsy |
|
Publications |
|
|
Fatty Liver |
|
Publications, Variants |
|
|
HIV |
|
Publications |
|
|
HIV Infections |
|
Publications |
|
|
Inflammatory Bowel Diseases |
|
Publications |
|
|
Leukemia |
|
Publications |
|
|
Osteosarcoma |
|
Publications |
Non-Curated Information
A list of non-curated publications that mention this gene along with other diseases is available.
Curated Phenotype Datasets
These datasets are sorted alphabetically by title.
- In vivo and in vitro characterization of variants
- PD
- PK
- FA
Submitted by Mary Relling, PharmD involving CYP3A, CYP3A4, CYP3A5, NR1I2, , midazolam, nifedipine, rifampin and troleandomycin - mRNA expression levels of PXR splice variants in livers
- FA
Submitted by Erin G. Schuetz, PhD involving CYP3A4, NR1I2, , amiodarone, cimetidine, dopamine, erythromycin, ethanol, glucocorticoids, hmg coa reductase inhibitors, midazolam, nicotine, phenobarbital, phenytoin, propofol, thyroid preparations and vasopressin
Downloads
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LinkOuts
- Entrez Gene ID:
- 8856
- OMIM Accession:
- 603065
- UCSC Genome Browser ID:
- NM_003889
- Ref Seq NM Accession:
- NM_003889
- NM_022002
- NM_033013
- Ref Seq NP Accession:
- AAC64557
- AAC64558
- AAD05436
- AAG23345
- AAH17304
- AAK38720
- AAK38721
- AAK38722
- AAM26736
- ABJ52965
- BAG53837
- BAH02292
- CAB55489
- CAB55490
- CAB55491
- CAB55492
- CAB55493
- CAB55494
- EAW79537
- EAW79538
- EAW79539
- NP_003880
- NP_071285
- NP_148934
- O75469
- Q9H4M8
- Ref Seq NT Accession:
- AC_000046
- AC_000135
- NC_000003
- NG_011856
- NT_005612
- NW_001838881
- NW_921807
- UniProtKB Accesssion:
- NR1I2_HUMAN (O75469)
- Ensembl ID:
- ENSG00000144852
- GenAtlas ID:
- NR1I2
- GeneCard ID:
- NR1I2
Common Searches
Non-Curated Publications
A list of non-curated publications that mention this gene is available.