TABLE 2

CAR

Receptor Nomenclature NR1I3
Receptor code 4.10.1:XE:1:I3
Other names MB67
Molecular information Hs: 348aa, Q14994, chr. 1q23.31
Rn: 358aa, Q9QUS1, chr. 13q24
Mm: 358aa, Q3V008, chr. 1 H32
DNA binding
   Structure Heterodimer, RXR partner
   HRE core sequence AGGTCA (DR4, DR5, palindrome)1,3–5
Partners
Agonists TCPOBOP (20 nM),* meclizine (25 nM), CITCO (49 nM), pregnanedione (670 nM) [EC50]4,6–8
Antagonists Androstanol (400 nM), androstenol (400 nM), meclizine (69 nM), clotrimazole (690 nM) [IC50]6,8,9
Coactivator NCOA1, PPARBP, PGC-19–11
Corepressor
Biologically important isoforms CAR1 {Mm}: main isoform in mouse2; CAR2 {Mm}: truncated form, lacking C-terminal sequence2
Tissue distribution Liver, low levels in the kidney, intestine, stomach {Hs, Mm} [Northern blot, Q-PCR, immunohistology]1,2,12,13
Functional assay Liver hepatomegaly after PB or TCPOBOP treatment {Mm}14,15; drug clearance: recovery from zoxazolamine-induced paralysis {Mm}15; acetaminophen liver toxicity {Mm}15
Main target genes Activated: cytochrome P450 genes {Hs, Mm, Rn},16 Mdm2 {Mm},14 MRP2 {Mm}5
Mutant phenotype Impaired drug metabolism induced by specific xenobiotics; resistance to chronic xenobiotic stress-induced liver tumorigenesis {Mm} [knockout]14,15; responsive to human CAR ligands {Mm} [human CAR transgenic with CAR knockout background]17
Human disease

  • aa, amino acids; chr., chromosome; HRE, hormonse response element; PPARBP, PPAR-binding protein; Q-PCR, quantitative polymerase chain reaction; PB, phenobarbital

  • ↵* Radioligand

  • ↵1. Baes M, Gulick T, Choi HS, Martinoli MG, Simha D, and Moore DD (1994) A new orphan member of the nuclear hormone receptor superfamily that interacts with subset of retinoic acid response elements. Mol Cell Biol 14: 1544-1552

  • ↵2. Choi HS, Chung M, Tzameli I, Simha D, Lee YK, Seol W, and Moore DD (1997) Differential transactivation by two isoforms of the orphan nuclear hormone receptor CAR. J Biol Chem 272: 23565-23571

  • ↵3. Frank C, Gonzalez MM, Oinonen C, Dunlop TW, and Carlberg C (2003) Characterization of DNA complexes formed by the nuclear receptor constitutive androstane receptor. J Biol Chem 278: 43299-43310

  • ↵4. Tzameli I, Pissios P, Schuetz EG, and 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: 2951-2958

  • ↵5. Kast HR, Goodwin B, Tarr PT, Jones SA, Anisfeld AM, Stoltz CM, Tontonoz P, Kliewer S, Willson TM, and 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: 2908-2915

  • ↵6. Huang W, Zhang J, Wei P, Schrader WT, and Moore DD (2004) Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR. Mol Endocrinol 18: 2402-2408

  • ↵7. Maglich JM, Parks DJ, Moore LB, Collins JL, Goodwin B, Billin AN, Stoltz CA, Kliewer SA, Lambert MH, Willson TM, et al. (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: 17277-17283

  • ↵8. Moore LB, Parks DJ, Jones SA, Bledsoe RK, Consler TG, Stimmel JB, Goodwin B, Liddle C, Blanchard SG, Willson TM, et al. (2000) Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J Biol Chem 275: 15122-15127

  • ↵9. Forman BM, Tzameli I, Choi HS, Chen J, Simha D, Seol W, Evans RM, and Moore DD (1998) Androstane metabolites bind to and deactivate the nuclear receptor CAR-β Nature 395: 612-615

  • ↵10. Jia Y, Guo GL, Surapureddi S, Sarkar J, Qi C, Guo D, Xia J, Kashireddi P, Yu S, Cho YW, et al. (2005) Transcription coactivator peroxisome proliferator-activated receptor-binding protein/mediator 1 deficiency abrogates acetaminophen hepatotoxicity. Proc Natl Acad Sci USA 102: 12531-12536

  • ↵11. Shiraki T, Sakai N, Kanaya E, and Jingami H (2003) Activation of orphan nuclear constitutive androstane receptor requires subnuclear targeting by peroxisome proliferator-activated receptor γ coactivator-1α : a possible link between xenobiotic response and nutritional state. J Biol Chem 278: 11344-11350

  • ↵12 Nishimura M, Naito S, and Yokoi T (2004)Tissue-specific mRNA expression profiles of human nuclear receptor subfamilies. Drug Metab Pharmacokinet 19: 135-149

  • ↵13. Wei P, Zhang J, Dowhan DH, Han Y, and Moore DD (2002) Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response. Pharmacogenomics J 2: 117-126

  • ↵14. Huang W, Zhang J, Washington M, Liu J, Parant JM, Lozano G, and Moore DD (2005) Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor. Mol Endocrinol 19: 1646-1653

  • ↵15. Wei P, Zhang J, Egan-Hafley M, Liang S, and Moore DD (2000) The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature (Lond) 407: 920-923

  • ↵16. Honkakoski P, Sueyoshi T, and Negishi M (2003) Drug-activated nuclear receptors CAR and PXR. Ann Med 35: 172-182

  • ↵17. Zhang J, Huang W, Chua SS, Wei P, and Moore DD (2002) Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. Science 298: 422-424, 2002