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Constitutive androstane receptor

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Target id: 607

Nomenclature: Constitutive androstane receptor

Systematic Nomenclature: NR1I3

Family: 1I. Vitamin D receptor-like receptors

Contents:

Gene and Protein Information Click here for help
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 352 1q23.3 NR1I3 nuclear receptor subfamily 1 group I member 3 1
Mouse 358 1 79.21 cM Nr1i3 nuclear receptor subfamily 1, group I, member 3 2
Rat 358 13q24 Nr1i3 nuclear receptor subfamily 1, group I, member 3 21
Previous and Unofficial Names Click here for help
CAR | Constitutive activator of retinoid response | orphan nuclear receptor MB67 | Care2 | CAR1 | MB67 | nuclear receptor subfamily 1
Database Links Click here for help
Alphafold Q14994 (Hs), Q3V008 (Mm), Q9QUS1 (Rn)
CATH/Gene3D 3.30.50.10
ChEMBL Target CHEMBL5503 (Hs), CHEMBL3509594 (Rn)
Ensembl Gene ENSG00000143257 (Hs), ENSMUSG00000005677 (Mm), ENSRNOG00000003260 (Rn)
Entrez Gene 9970 (Hs), 12355 (Mm), 65035 (Rn)
Human Protein Atlas ENSG00000143257 (Hs)
KEGG Gene hsa:9970 (Hs), mmu:12355 (Mm), rno:65035 (Rn)
OMIM 603881 (Hs)
Pharos Q14994 (Hs)
RefSeq Nucleotide NM_001077481 (Hs), NM_001243062 (Mm), NM_009803 (Mm), NM_001243063 (Mm), NM_022941 (Rn)
RefSeq Protein NP_005113 (Hs), NP_033933 (Mm), NP_001229991 (Mm), NP_001229992 (Mm), NP_075230 (Rn)
SynPHARM 6443 (in complex with androstenol)
6440 (in complex with CITCO)
UniProtKB Q14994 (Hs), Q3V008 (Mm), Q9QUS1 (Rn)
Wikipedia NR1I3 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Mouse Constitutive Androstane Receptor - complexed with inverse agonist
PDB Id:  1XNX
Ligand:  androstenol   This ligand is endogenous
Resolution:  2.9Å
Species:  Mouse
References:  13
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of CAR/RXR heterodimer - complexed with agonist
PDB Id:  1XVP
Ligand:  CITCO
Resolution:  2.6Å
Species:  Human
References:  20
Natural/Endogenous Ligands Click here for help
Comments: Xenobiotics and androstanes have been proposed as the natural ligands

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists Click here for help
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
TCPOBOP Small molecule or natural product Ligand has a PDB structure Mm Agonist 7.7 pEC50 17
⤷ pEC50 7.7 [17]
meclizine Small molecule or natural product Approved drug Mm Agonist 7.6 pEC50 7
⤷ pEC50 7.6 [7]
CITCO Small molecule or natural product Ligand has a PDB structure Hs Agonist 7.3 pEC50 10
⤷ pEC50 7.3 [10]
5β-pregnane-3,20-dione Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 6.2 pEC50 11
⤷ pEC50 6.2 [11]
View species-specific agonist tables
Agonist Comments
Phenobarbital, chlorpromazine [15] and acetoaminophen [22] can activate CAR, but they do not bind directly to CAR.
Antagonists Click here for help
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
meclizine Small molecule or natural product Approved drug Hs Antagonist 7.2 pIC50 7
⤷ pIC50 7.2 [7]
androstanol Small molecule or natural product Mm Inverse agonist 6.4 pIC50 3
⤷ pIC50 6.4 [3]
androstenol Small molecule or natural product Ligand has a PDB structure Mm Inverse agonist 6.4 pIC50 3
⤷ pIC50 6.4 [3]
clotrimazole Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 6.2 pIC50 11
⤷ pIC50 6.2 [11]
View species-specific antagonist tables
Antagonist Comments
Clotrimazole has also been reported to have a pIC50 of is 7.24 [10]. Meclizine and clotrimazole suppress hCAR transcriptional activity by about 50%, but androstanol and androstenol suppress mCAR activity almost completely at about 10μM.
DNA Binding Click here for help
Structure:  Heterodimer, RXR partner
HRE core sequence:  AGGTCA
Response element:  DR4, DR5, Palindrome
DNA Binding Comments
It has been reported that CAR may bind DNA as monomers [4]. In addition to DR4, CAR may also bind to DR3/5 or ER6/8 [1,9,17].
Main Co-regulators Click here for help
Name Activity Specific Ligand dependent AF-2 dependent Comments References
NCOA1 Co-activator No No No 3
MED1 Co-activator No No No 8
PPARGC1A Co-activator No No No 14
Main Target Genes Click here for help
Name Species Effect Technique Comments References
UGT1A1 Human Activated Transient transfection, EMSA 16
Mdm2 Mouse Activated Transient transfection, EMSA, Other 6
Abcc2 Mouse Activated Transient transfection, EMSA Human MRP2 is also a target gene 9
cytochrome P450 None Activated Transient transfection, EMSA, Other mCYP2B10, hCYP2B6, rCYP2B1, mCYP3A11, hCYP3A4, hCYP2C9 5
Tissue Distribution Click here for help
Liver, kidney, intestine, stomach
Species:  Human
Technique:  Northern,Q-PCR,Immunohistology
References:  1-2,12,18
Tissue Distribution Comments
Similar patterns are observed in mice.
Functional Assays Click here for help
Liver growth
Species:  Mouse
Tissue:  liver
Response measured:  Liver hepatomegaly after PB or TCPOBOP treatment
References:  6,19
Drug clearance
Species:  Mouse
Tissue: 
Response measured:  Recovery from zoxazolamine-induced paralysis
References:  19
Induction of liver damage
Species:  Mouse
Tissue:  liver
Response measured:  acetaminophen liver toxicity after CAR activation
References:  19
Physiological Consequences of Altering Gene Expression Click here for help
Impaired drug metabolism induced by specific xenobiotics. Resistance to chronic xenobiotic stress induced liver tumorigenesis.
Species:  Mouse
Tissue: 
Technique:  Knock-out
References:  6,19
Responsive to human CAR ligands in human CAR transgenic models of CAR knock-out mice
Species:  Human
Tissue: 
Technique:  transgenesis, knock-out
References:  22
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Nr1i3tm1Dgen Nr1i3tm1Dgen/Nr1i3tm1Dgen
B6.129-Nr1i3		 MGI:1346307  MP:0002118 abnormal lipid homeostasis PMID: 18941143 
Nr1i3tm1Dgen Nr1i3tm1Dgen/Nr1i3tm1Dgen
B6.129-Nr1i3		 MGI:1346307  MP:0000609 abnormal liver physiology PMID: 18941143 
Nr1i3tm1Ddm Nr1i3tm1Ddm/Nr1i3tm1Ddm
involves: 129S7/SvEvBrd * C57BL/6		 MGI:1346307  MP:0003638 abnormal response/metabolism to endogenous compounds PMID: 12644704 
Nr1i3tm1Dgen Nr1i3tm1Dgen/Nr1i3tm1Dgen
involves: 129/Sv		 MGI:1346307  MP:0005469 abnormal thyroxine level PMID: 15004031 
Nr1i3tm1Dgen Nr1i3tm1Dgen/Nr1i3tm1Dgen
involves: 129/Sv		 MGI:1346307  MP:0005472 abnormal triiodothyronine level PMID: 15004031 
Nr1i3tm1(NR1I3)Arte Nr1i3tm1(NR1I3)Arte/Nr1i3tm1(NR1I3)Arte
involves: C57BL/6		 MGI:1346307  MP:0008875 abnormal xenobiotic pharmacokinetics PMID: 18677425 
Lepob|Nr1i3tm1Dgen Lepob/Lepob,Nr1i3tm1Dgen/Nr1i3tm1Dgen
B6.Cg-Nr1i3 Lep		 MGI:104663  MGI:1346307  MP:0002644 decreased circulating triglyceride level PMID: 18941143 
Nr1i3tm1Ddm Nr1i3tm1Ddm/Nr1i3tm1Ddm
involves: 129S7/SvEvBrd * C57BL/6		 MGI:1346307  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 11057673  12376703  12644704 
Nr1i3tm1Dgen Nr1i3tm1Dgen/Nr1i3tm1Dgen
involves: 129/Sv		 MGI:1346307  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 15004031 
Nr1i3tm1.1Arte Nr1i3tm1.1Arte/Nr1i3tm1.1Arte
involves: C57BL/6		 MGI:1346307  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 18677425 
Nr1i3tm1(NR1I3)Arte Nr1i3tm1(NR1I3)Arte/Nr1i3tm1(NR1I3)Arte
involves: C57BL/6		 MGI:1346307  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 18677425 
Nr1i2tm3Arte|Nr1i3tm1.1Arte Nr1i2tm3Arte/Nr1i2tm3Arte,Nr1i3tm1.1Arte/Nr1i3tm1.1Arte
involves: C57BL/6		 MGI:1337040  MGI:1346307  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 18677425 
Nr1i2tm1(NR1I2)Arte|Nr1i3tm1.1Arte Nr1i2tm1(NR1I2)Arte/Nr1i2tm1(NR1I2)Arte,Nr1i3tm1.1Arte/Nr1i3tm1.1Arte
involves: C57BL/6		 MGI:1337040  MGI:1346307  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 18677425 
Nr1i3tm1Neg Nr1i3tm1Neg/Nr1i3tm1Neg
C3H/HeNCrl-Nr1i3		 MGI:1346307  MP:0005559 increased circulating glucose level PMID: 15340055 
Nr1i3tm1Ddm|Tg(Alb1-NR1I3)1Ddm Nr1i3tm1Ddm/Nr1i3tm1Ddm,Tg(Alb1-NR1I3)1Ddm/0
involves: 129S7/SvEvBrd * C57BL/6		 MGI:1346307  MGI:2657135  MP:0008873 increased physiological sensitivity to xenobiotic PMID: 12376703 
Nr1i3tm1(NR1I3)Arte Nr1i3tm1(NR1I3)Arte/Nr1i3tm1(NR1I3)Arte
involves: C57BL/6		 MGI:1346307  MP:0008873 increased physiological sensitivity to xenobiotic PMID: 18677425 
Nr1i3tm1Dgen Nr1i3tm1Dgen/Nr1i3tm1Dgen
involves: 129/Sv		 MGI:1346307  MP:0010180 increased susceptibility to weight loss PMID: 15004031 

References

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1. Baes M, Gulick T, Choi HS, Martinoli MG, Simha D, Moore DD. (1994) A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements. Mol Cell Biol, 14 (3): 1544-52. [PMID:8114692]

2. Choi HS, Chung M, Tzameli I, Simha D, Lee YK, Seol W, Moore DD. (1997) Differential transactivation by two isoforms of the orphan nuclear hormone receptor CAR. J Biol Chem, 272 (38): 23565-71. [PMID:9295294]

3. Forman BM, Tzameli I, Choi HS, Chen J, Simha D, Seol W, Evans RM, Moore DD. (1998) Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta. Nature, 395 (6702): 612-5. [PMID:9783588]

4. Frank C, Gonzalez MM, Oinonen C, Dunlop TW, Carlberg C. (2003) Characterization of DNA complexes formed by the nuclear receptor constitutive androstane receptor. J Biol Chem, 278 (44): 43299-310. [PMID:12896978]

5. Honkakoski P, Sueyoshi T, Negishi M. (2003) Drug-activated nuclear receptors CAR and PXR. Ann Med, 35 (3): 172-82. [PMID:12822739]

6. Huang W, Zhang J, Washington M, Liu J, Parant JM, Lozano G, Moore DD. (2005) Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor. Mol Endocrinol, 19 (6): 1646-53. [PMID:15831521]

7. Huang W, Zhang J, Wei P, Schrader WT, Moore DD. (2004) Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR. Mol Endocrinol, 18 (10): 2402-8. [PMID:15272053]

8. Jia Y, Guo GL, Surapureddi S, Sarkar J, Qi C, Guo D, Xia J, Kashireddi P, Yu S, Cho YW, Rao MS, Kemper B, Ge K, Gonzalez FJ, Reddy JK. (2005) Transcription coactivator peroxisome proliferator-activated receptor-binding protein/mediator 1 deficiency abrogates acetaminophen hepatotoxicity. Proc Natl Acad Sci USA, 102 (35): 12531-6. [PMID:16109766]

9. Kast HR, Goodwin B, Tarr PT, Jones SA, Anisfeld AM, Stoltz CM, Tontonoz P, Kliewer S, Willson TM, Edwards PA. (2002) Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J Biol Chem, 277 (4): 2908-15. [PMID:11706036]

10. Maglich JM, Parks DJ, Moore LB, Collins JL, Goodwin B, Billin AN, Stoltz CA, Kliewer SA, Lambert MH, Willson TM, Moore JT. (2003) Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes. J Biol Chem, 278 (19): 17277-83. [PMID:12611900]

11. Moore LB, Parks DJ, Jones SA, Bledsoe RK, Consler TG, Stimmel JB, Goodwin B, Liddle C, Blanchard SG, Willson TM, Collins JL, Kliewer SA. (2000) Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J Biol Chem, 275 (20): 15122-7. [PMID:10748001]

12. Nishimura M, Naito S, Yokoi T. (2004) Tissue-specific mRNA expression profiles of human nuclear receptor subfamilies. Drug Metab Pharmacokinet, 19 (2): 135-49. [PMID:15499180]

13. Shan L, Vincent J, Brunzelle JS, Dussault I, Lin M, Ianculescu I, Sherman MA, Forman BM, Fernandez EJ. (2004) Structure of the murine constitutive androstane receptor complexed to androstenol: a molecular basis for inverse agonism. Mol Cell, 16 (6): 907-17. [PMID:15610734]

14. Shiraki T, Sakai N, Kanaya E, Jingami H. (2003) Activation of orphan nuclear constitutive androstane receptor requires subnuclear targeting by peroxisome proliferator-activated receptor gamma coactivator-1 alpha. A possible link between xenobiotic response and nutritional state. J Biol Chem, 278 (13): 11344-50. [PMID:12551939]

15. Sueyoshi T, Kawamoto T, Zelko I, Honkakoski P, Negishi M. (1999) The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene. J Biol Chem, 274 (10): 6043-6. [PMID:10037683]

16. Sugatani J, Kojima H, Ueda A, Kakizaki S, Yoshinari K, Gong QH, Owens IS, Negishi M, Sueyoshi T. (2001) The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology, 33 (5): 1232-8. [PMID:11343253]

17. Tzameli I, Pissios P, Schuetz EG, Moore DD. (2000) The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR. Mol Cell Biol, 20 (9): 2951-8. [PMID:10757780]

18. Wei P, Zhang J, Dowhan DH, Han Y, Moore DD. (2002) Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response. Pharmacogenomics J, 2 (2): 117-26. [PMID:12049174]

19. Wei P, Zhang J, Egan-Hafley M, Liang S, Moore DD. (2000) The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature, 407 (6806): 920-3. [PMID:11057673]

20. Xu SZ, Zeng F, Boulay G, Grimm C, Harteneck C, Beech DJ. (2005) Block of TRPC5 channels by 2-aminoethoxydiphenyl borate: a differential, extracellular and voltage-dependent effect. Br J Pharmacol, 145 (4): 405-14. [PMID:15806115]

21. Yoshinari K, Sueyoshi T, Moore R, Negishi M. (2001) Nuclear receptor CAR as a regulatory factor for the sexually dimorphic induction of CYB2B1 gene by phenobarbital in rat livers. Mol Pharmacol, 59 (2): 278-84. [PMID:11160864]

22. Zhang J, Huang W, Chua SS, Wei P, Moore DD. (2002) Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. Science, 298 (5592): 422-4. [PMID:12376703]

Contributors

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