The Constitutive Androstane Receptor (CAR): A Nuclear Receptor in Health and Disease

Jump To References Section

Authors

  • Amit K. Dash
     Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi-110067 ,IN
  • Ashutosh S. Yende
     Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi-110067 ,IN
  • Sudhir Kumar
     Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi-110067 ,IN
  • Shashi Kala Singh
     Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi-110067 ,IN
  • Deepak Kotiya
     Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi-110067 ,IN
  • Manjul Rana
     Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi-110067 ,IN
  • Rakesh K. Tyagi
     Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi-110067 ,IN

Keywords:

Nuclear Receptors, Transcription Factors, Constitutive Androstane Receptor, Xenosensor, Drug Metabolism, Metabolic Diseases, Sub-Cellular Localization, Cancer.

Abstract

Constitutive Androstane Receptor (CAR, NR1I3), a member of the nuclear receptor superfamily of transcription factors, has emerged as one of the key regulators of the drug and xenobiotic metabolism. The unique feature that separates CAR from other members of the superfamily is that it remains active in the absence of ligand and is further regulated by activators. From its first isolation in 1994, a number of studies related to its distribution, characteristics, functions, and relation to other members of the superfamily have been conducted that place it centrally, governing many key events of the body. Human CAR is expressed relatively higher in liver and epithelial cells of the small intestine villi and less in heart, muscle, kidney, brain and lung. Though there are some controversies regarding its subcellular localization in different cell lines, in general, the subcellular localization of CAR is reported to be predominantly cytoplasmic, in complex with co-chaperone partners HSP90 and CCRP (cytoplasmic CAR retention protein). To execute transcription functions, nuclear translocation is a prerequisite event for a NR, including CAR. In this context, existence of two pathways is suggested, i) direct mechanism of action; and ii) indirect mechanism of action that is governed via nuclear translocation of CAR. Additionally, existence of species-specific differences in its modulation with ligands acting either as an agonist, antagonist or inverse agonist is also apparent. Like the other xenobiotic receptor PXR, CAR also functions as an alternative 'xenosensor' to defend the body against persistent chemical insults. It responds to diverse array of chemically distinct compounds, including endobiotics and xenobiotics, to regulate the clearance of noxious chemicals and toxic metabolites in liver and intestine via induction of genes involved in their metabolism. The usefulness of targeting CAR in metabolic diseases including bilirubinemia, obesity, type 2 diabetes mellitus, atherosclerosis, preeclampsia, hypertension, cholestasis and also in liver cancer is being extensively studied in animal models. However, to determine the human relevance it requires further investigation. Though a large number of natural and synthetic compounds act as modulators of CAR, designing new derivatives with defined therapeutic benefit need to be investigated. The purpose of this review is to highlight the general aspects of nuclear receptor CAR, its mechanism of action and importance in human health and disease.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Downloads

Published

2014-06-01

How to Cite

Dash, A. K., Yende, A. S., Kumar, S., Singh, S. K., Kotiya, D., Rana, M., & Tyagi, R. K. (2014). The Constitutive Androstane Receptor (CAR): A Nuclear Receptor in Health and Disease. Journal of Endocrinology and Reproduction, 18(2), 59–74. Retrieved from https://informaticsjournals.co.in/index.php/jer/article/view/1884

Issue

Volume 18, Issue 2, December 2014

Section

Articles

 

References

Abass K, Lamsa V, Reponen P, Kublbeck J, Honkakoski P, Mattila S, Pelkonen O, Hakkola J. (2012) Characterization of human cytochrome P450 induction by pesticides. Toxicology 294:17 - 26.

Alnouti Y, Klaassen CD. (2008) Regulation of sulfotransferase enzymes by prototypical microsomal enzyme inducers in mice. J Pharmacol Exp Ther. 324: 612-21.

Auerbach SS, Ramsden R, Stoner MA, Verlinde C, Hassett C, Omiecinski C. (2003) Alternatively spliced isoforms of the human constitutive androstane receptor. Nucl Acid Res. 31: 3194-207.

Baes M, Gulick T, Choi H-S, 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: 1544-52.

Burk O, Arnold KA, Geick A, Tegude H, Eichelbaum M. (2005) A role for constitutive androstane receptor in the regulation of human intestinal MDR1 expression. Biol Chem. 386:503-13.

Burk O, Piedade R, Ghebreghiorghis L, Fait JT, Nussler AK, Gil JP, B Windshugel B, Schwab M. (2012) Differential effects of clinically used derivatives and metabolites of artemisinin in the activation of constitutive androstane receptor isoforms. Br J Pharmacol. 167:666-81.

Burris TP, Busby S, Griffin PR. (2012) Targeting orphan nuclear receptors for treatment of metabolic diseases and autoimmunity. Chem Bio. 19: 51-59.

Catz C, Yaffe SJ. (1962) Pharmacological modification of bilirubin conjugation in the newborn. Am J Dis Child. 104:516-17.Cerveny L, Svecova L, Anzenbacherova E, Vrzal R, Staud F, Dvorak Z, Ulrichova J, Anzenbacher P, Paveket P. (2007) Valproic acid induces CYP3A4 and MDR1 gene expression by activation of constitutive androstane receptor and pregnane x receptor pathways. Drug Metab Dispos. 35: 1032-41.

Chakraborty S, Kanakasabai S, Bright JJ. (2011) Constitutive androstane receptor agonist CITCO inhibits growth and expansion of brain tumour stem cells. Br J Cancer 104:448-59.

Chang TKH. (2009) Activation of pregnane x receptor (PXR) and constitutive androstane receptor (CAR) by herbal medicines. AAPS J. 11: 590-601.

Chiang JYL. (2009) Xenobiotic receptor cofactors and coregulators. In: Xie W (Ed), Nuclear Receptors in Drug Metabolism. pp167-68. John Wiley & Sons, Inc.

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: 23565-71.

Columbano A, Ledda-Columbano GM, Pibiri M, Cossu C, Menegazzi M, Moore DD, Huang W, Tian J, Locker J. (2005) Gadd45beta is induced through a CAR-dependent, TNF-independent pathway in murine liver hyperplasia. Hepatology 42:1118-26.

Dau PT, Sakai H, Hirano M, Ishibashi H, Tanaka Y, Kameda K, Fujino T, Kim E-Y, Iwataet H. (2013) Quantitative analysis of the interaction of constitutive androstane receptor with chemicals and steroid receptor coactivator 1 using surface plasmon resonance biosensor systems: a case study of the baikal seal (Pusa sibirica) and the mouse. Toxicol Sci. 131:116-27.

DeKeyser JG, Stagliano MC, Auerbach SS, Prabhu KS, Jones AD, Omiecinski CJ. (2009) Di(2-ethylhexyl) phthalate is a highly potent agonist for the human constitutive androstane receptor splice variant CAR2. Mol Pharmacol. 75:1005-13.

Ding X, Lichti K, Kim I, Gonzalez FJ, Staudinger JL (2006) Regulation of constitutive androstane receptor and its target genes by fasting, cAMP, hepatocyte nuclear factor alpha, and the coactivator peroxisome proliferatoractivated receptor gamma coactivator-1alpha. J Biol Chem. 281: 26540-51.

Doherty MM, Charman WN. (2002) The mucosa of the small intestine: how clinically relevant as an organ of drug metabolism? Clin Pharmacokinetics 41: 235-253.

Dong B, Saha PK, Huang W, Chen W, Abu-Elheiga LA, Wakil SJ, Stevens RD, Ilkayeva O, Newgard CB, Chan L, Moore DD. (2009) Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease. Proc Natl Acad Sci USA. 106:18831-36.

Duckitt K, Harrington D. (2005) Risk factors for pre-eclampsia at antenatal booking: Systematic review of controlled studies. BMJ. 330:565.

Faucette SR, Zhang TC, Moore R, Sueyoshi T, Omiecinski CJ, LeCluyse EL, Negishi M, Wang H. (2007) Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers. J Pharmacol Exp Ther. 320:72-80.

Ferguson SS, Chen Y, Le Cluyse EL, Negishi M. Goldstein JA. (2005) Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4 alpha. Mol Pharmacol. 68: 747-57.

Fisher CD, Augustine LM, Maher JM, Nelson DM, Slitt AL, Klaassen CD, Lehman-McKeeman LD, Cherrington NJ. (2007) Induction of drug-metabolizing enzymes by garlic and allyl sulfide compounds via activation of constitutive androstane receptor and nuclear factor E2-related factor 2. Drug Metab Dispos. 35: 995-1000.

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: 612-15.

Fukumasu H, Rochetti AL, Pires PR, Silva ER, Mesquita LG, Strefezzi RF, De Carvalho DD, Dagli ML. (2014) Constitutive androstane receptor ligands modulate the anti-tumor efficacy of paclitaxel in non-small cell lung cancer cells. PLoS One 9:e99484.

Gao J, Xie W. (2012) Targeting xenobiotic receptors PXR and CAR for metabolic diseases. Trends Pharmacol Sci. 33: 552-58.

Gao J, He J, Zhai Y, Wada T, Xie W. (2009) The constitutive androstane receptor is an anti-obesity nuclear receptor that improves insulin sensitivity. J Biol Chem. 284:25984-92.

Goodwin B, Hodgson E, D'Costa DJ, Robertson GR, Liddle C. (2002) Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor. Mol Pharmacol. 62:359-65.

Guo D, Sarkar J, Suino-Powell K, Xu Y, Matsumoto K, Jia Y, Yu S, Khare S, Haldar K, Rao MS, Foreman JE, Monga SP, Peters JM, Xu HE, Reddy JK. (2007) Induction of nuclear translocation of constitutive androstane receptor by peroxisome proliferator-activated receptor alpha synthetic ligands in mouse liver. J Biol Chem. 282: 36766- 76.

Hernandez JP, Mota LC, Baldwin WS. (2009) Activation of CAR and PXR by dietary, environmental and occupational chemicals alters drug metabolism, intermediary metabolism, and cell proliferation. Curr Pharmacogenomics Pers Med. 7:81-105.

Honkakoski P, Zelko I, Sueyoshi T, Negishi M. (1998) The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol Cell Biol. 18: 5652-58.

Huang W, Zhang J, Moore DD. (2004) A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. J Clin Invest. 113:137-43.

Huang W, Zhang J, Chua SS, Qatanani M, Han Y, Granata R, Moore DD. (2003) Induction of bilirubin clearance by the constitutive androstane receptor (CAR). Proc Natl Acad Sci USA. 100:4156-61.

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. 19:1646-1653.

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 : 2402-08.

Ihunnah CA, Jiang M, Xie W. (2011) Nuclear receptor PXR, transcriptional circuits and metabolic relevance. Biochim Biophys Acta. 1812: 956-63.

Innes KE, Wimsatt JH, McDuffie R. (2001) Relative glucose tolerance and subsequent development of hypertension in pregnancy. Obstet Gynecol. 97:905-10.

Jyrkkarinne J, Windsh–gel B, Rünkkü T, Tervo AJ, K –blbeck J, Lahtela-Kakkonen M, Sipp W, Poso A, Honkakoski P. (2008) Insights into ligand-elicited activation of human constitutive androstane receptor based on novel agonists and three-dimensional quantitative structure activity relationship. J Med Chem. 51:7181-92.

Kachaylo E, Yarushkin A, Pustylnyak V (2012) Constitutive androstane receptor activation by 2,4,6-triphenyldioxane1,3 suppresses the expression of the gluconeogenic genes. Eur J Pharmacol. 679:139-43.

Kanno Y, Suzuki M, Nakahama T, Inouye Y. (2005) Characterization of nuclear localization signals and cytoplasmic retention region in the nuclear receptor CAR. Biochim Biophys Acta. 1745:215-22.

Kanno Y, Tanuma N, Takahashi A, Inouye Y. (2013) TO901317, a potent LXR agonist, is an inverse agonist of CAR. J Toxicol Sci. 38:309-15.

Kanno Y, Tanuma N, Yatsu T, Li W, Koike K, Inouye Y. (2014) Nigramide J is a novel potent inverse agonist of the human constitutive androstane receptor. Pharma Res Per. 2: e00018.

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. 277:2908-15.

Kawamoto T, Sueyoshi T, Zelko I, Moore R, Washburn K, Negishi M. (1999) Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene. Mol Cell Biol. 19: 6318-22.

Kawana K, Ikuta T, Kobayashi Y, Gotoh O, Takeda K, Kawajiri K. (2003) Molecular mechanism of nuclear translocation of an orphan nuclear receptor, SXR. Mol Pharmacol. 63:524-31.

Kublbeck J, Jyrkkörinne J, Poso A, Turpeinen M, Sippl W, Honkakoski P, Windsh–gel B. (2008) Discovery of substituted sulfonamides and thiazolidin-4-one derivatives as agonists of human constitutive androstane receptor. Biochem Pharmacol. 76:1288 - 97.

Kublbeck J, Laitinen T, Jyrkk örinne J, Rousu T, Tolonen A, Abel T, Kortelainen T, Uusitalo J, Korjamo T, Honkakoski P, Molnar F. (2011a) Use of comprehensive screening methods to detect selective human CAR activators. Biochem Pharmacol. 82:1994 - 2007.

Kublbeck J, Jyrkkarinne J, Molnar F, Kuningas T, Patel J, Windshugel B, Nevalainen T, Laitinen T, Sippl W, Poso A, Honkakoski P. (2011b) New in vitro tools to study human constitutive androstane receptor (CAR) biology: discovery and comparison of human CAR inverse agonists. Mol Pharm. 8: 2424-33.

Kumar S, Saradhi M, Chaturvedi NK, Tyagi RK. (2006) Intracellular localization and nucleocytoplasmic trafficking of steroid receptors: an overview. Mol Cell Endocrinol. 26:147-56.

Ledda-Columbano GM, Pibiri M, Loi R, Perra A, Shinozuka H, Columbano A. (2000) Early increase in cyclin-D1 expression and accelerated entry of mouse hepatocytes into S phase after administration of the mitogen 1,4bis[2-(3,5-dichloropyridyloxy)]benzene. Am J Pathol. 156: 91-97.

Lempiainen H, Molnar F, Gonzalez MM, Perakyla M, Carlberg C. (2005) Antagonist- and inverse agonist-driven interactions of the vitamin D receptor and the constitutive androstane receptor with corepressor protein. Mol Endocrinol. 19: 2258-72.

Li L, Chen T, Stanton JD, Sueyoshi T, Negishi M, Wang H. (2008) The peripheral benzodiazepine receptor ligand 1(2-chlorophenyl-methylpropyl)-3-isoquinoline-carboxamide is a novel antagonist of human constitutive androstane receptor. Mol Pharmacol. 74: 443-53.

Lim YP, Cheng CH, Chen WC, Chang SY, Hung DZ, Chen JJ, Wan L, Ma WC, Lin YH, Chen CY, Yokoi T, Nakajima M, Chen CJ. (2015) Allyl isothiocyanate (AITC) inhibits pregnane X receptor (PXR) and constitutive androstane receptor (CAR) activation and protects against acetaminophen and amiodarone induced cytotoxicity. Arch Toxicol. 89:57-72.

Lynch C, Pan Y, Li L, Ferguson SS, Xia M, Swaan PW, Wang H. (2012) Identification of novel activators of constitutive androstane receptor from FDA-approved drugs by integrated computational and biological approaches. Pharm Res. 30:489-501.

Maglich JM, Lobe DC, Moore JT. (2009) The nuclear receptor CAR(NR1I3) regulates serum triglyceride levels under conditions of metabolic stress. J Lipid Res. 50: 439-45.

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. 278:17277-83.

Maglich JM, Watson J, McMillen PJ, Goodwin B, Willson TM, Moore JT. (2004) The nuclear receptor CAR is a regulator of thyroid hormone metabolism during caloric restriction. J Biol Chem. 279: 19832-38.

Mökinen J, Reinisalo M, Niemi K, Viitala P, Jyrkkarinne J, Chung H, Pelkonen O, Honkakoski P. (2003) Dual action of oestrogens on the mouse constitutive androstane receptor. Biochem J. 376: 465-72.

Makinen J, Frank C, Jyrkkarinne J, Gynther J, Carlberg C, Honkakoski P. (2002) Modulation of mouse and human phenobarbital-responsive enhancer module by nuclear receptors. Mol Pharmacol. 62:366-78.

Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM. (1995) The nuclear receptor superfamily: the second decade. Cell 83: 835-39.

Masson D, Qatanani M, Sberna AL, Xiao R, Barros JPP de, Grober J, Deckert V, Athias A, Gambert P, Lagrost L, Moore DD, Assem M. (2008) Activation of the constitutive androstane receptor decreases HDL in wild-type and human apoA-I transgenic mice. J Lipid Res. 49: 1682-91.

Masuyama H, Hiramatsu Y. (2012a) Treatment with a constitutive androstane receptor ligand ameliorates the signs of preeclampsia in high-fat diet-induced obese pregnant mice. Mol Cell Endocrinol. 348:120-27.

Masuyama H, Hiramatsu Y. (2012b) Treatment with constitutive androstane receptor ligand during pregnancy prevents insulin resistance in offspring from high-fat diet-induced obese pregnant mice. Am J Physiol Endocrinol Metab. 303:E293-E300

Miao J, Fang S, Bae Y, Kemper JK. (2006) Functional inhibitory cross-talk between constitutive androstane receptor and hepatic nuclear factor-4 in hepatic lipid/glucose metabolism is mediated by competition for binding to the DR1 motif and to the common coactivators, GRIP-1 and PGC-1alpha. J Biol Chem. 281:14537-46.

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: 15122-27.

Mutoh S, Sobhany M, Moore R, Perera L, Pedersen L, Sueyoshi T, Negishi M. (2013) Phenobarbital indirectly activates the constitutive active androstane receptor (CAR) by inhibition of epidermal growth factor receptor signaling. Sci Signal. 6: ra31.

Nuclear Receptors Nomenclature Committee (1999) A Unified Nomenclature System for the Nuclear Receptor Superfamily. Cell 97:161 - 63.

Osabe M, Sugatani J, Fukuyama T, Ikushiro S, Ikari A, Miwa M. (2008) Expression of hepatic UDPglucuronosyltransferase 1A1 and 1A6 correlated with increased expression of the nuclear constitutive androstane receptor and peroxisome proliferator-activated receptor alpha in male rats fed a high-fat and high-sucrose diet. Drug Metab Dispos. 36: 294-302.

Phillips JM, Yamamoto Y, Negishi M, Maronpot RR, Goodman JI. (2007) Orphan nuclear receptor constitutive active/androstane receptor-mediated alterations in DNA methylation during phenobarbital promotion of liver tumorigenesis. Toxicol Sci. 96:72-82.

Pondugula SR, Dong H, Chen T. (2009) Phosphorylation and protein-protein interactions in PXR-mediated CYP3A repression. Expert Opin Drug Metab Toxicol. 5: 861-73.

Rencurel F, Stenhouse A, Hawley SA, Friedberg T, Hardie DG, Sutherland C, Wolf CR. (2005) AMP-activated protein kinase mediates phenobarbital induction of CYP2B gene expression in hepatocytes and a newly derived human hepatoma cell line. J Biol Chem. 280: 4367-73.

Roth A, Looser R, Kaufmann M, Blattler SM, Rencurel F, Huang W, Moore DD, Meyer UA. (2008) Regulatory cross-talk between drug metabolism and lipid homeostasis: constitutive androstane receptor and pregnane X receptor increase Insig-1 expression. Mol Pharmacol. 73:1282-89.

Saradhi M, Kumar N, Reddy RC, Tyagi RK. (2006) Pregnane and Xenobiotic Receptor (PXR): A promiscuous xenosensor in human health and disease. J Endocrinol Reprod. 10: 1 - 12.

Saradhi M, Sengupta A, Mukhopadhyay G, Tyagi RK. (2005) Pregnane and Xenobiotic Receptor (PXR/SXR) resides predominantly in the nuclear compartment of the interphase cell and associates with the condensed chromosomes during mitosis. Biochim Biophys Acta 15:85-94.

Savkur RS, Wu Y, Bramlett KS, Wang M, Yao S, Perkins D, Totten M, Searfoss G 3rd, Ryan TP, Su EW, Burris TP. (2003) Alternative splicing within the ligand binding domain of the human constitutive androstane receptor. Mol Genet Metab. 80: 216-26.

Sberna AL, Assem M, Gautier T, Grober J, Guiu B, Jeannin A, Pais de Barros JP, Athias A, Lagrost L, Masson D. (2011a) Constitutive androstane receptor activation stimulates faecal bile acid excretion and reverse cholesterol transport in mice. J Hepatol. 55: 154-61.

Sberna AL, Assem M, Xiao R, Ayers S, Gautier T, Guiu B, Deckert V, Chevriaux A, Grober J, Le Guern N, Pais de Barros JP, Moore DD, Lagrost L, Masson D. (2011b) Constitutive androstane receptor activation decreases plasma apolipoprotein B-containing lipoproteins and atherosclerosis in low-density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol. 31:2232-39.

Seely EW, Solomon CG. (2003) Insulin resistance and its role in pregnancy induced hypertension. J Clin Endocrinol Metab. 88:2393-98.

Shank LC, Paschal BM. (2005) Nuclear transport of steroid hormone receptors. Crit Rev Eukaryot Gene Expr. 15: 49-73.

Squires EJ, Sueyoshi T, Negishi M. (2004) Cytoplasmic localization of pregnane X receptor and ligand-dependent nuclear translocation in mouse liver. J Biol Chem. 279: 49307-14.

Stedman CA, Liddle C, Coulter SA, Sonoda J, Alvarez JG, Moore DD, Evans RM, Downes M. (2005) Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury. Proc Natl Acad Sci USA. 102: 2063-68.

Sueyoshi T, Negishi M. (2001) Phenobarbital response elements of cytochrome P450 genes and nuclear receptors. Annu Rev Pharmacol Toxicol. 41: 123-43.

Sugatani J, Kojima H, Ueda A, Kakizaki S, Yoshinari K, Gong QH, Ida S, Owens IS, Negishi M, Sueyoshet T. (2001) The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology 33:1232-38.

Swales K, Negishi M. (2004) CAR, driving into the future. Mol Endocrinol. 18:1589-98.

Takizawa D, Kakizaki S, Horiguchi N, Yamazaki Y, Tojima H, Mori M. (2011) Constitutive active/androstane receptor promotes hepatocarcinogenesis in a mouse model of non-alcoholic steatohepatitis. Carcinogenesis 32:576-83.

Thigpen KG. (2004) International sequencing consortium. Environ Health Perspect. 112: A406.

Timsit YE, Negishi M. (2007) CAR and PXR: the xenobiotic-sensing receptors. Steroids 72: 231-46.

Tolson AH, Wang H. (2010) Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR. Adv Drug Deliv Rev. 62: 1238-49.

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: 2951-58.

Wagner M, Halilbasic E, Marschall H-U, Zollner G, Fickert P, Langner C, Zatloukal K, Denk H, Trauner M. (2005) CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice.Hepatology 42: 420-30.

Wallin A, Boräus LO. (1984) Phenobarbital prophylaxis for hyperbilirubinemia in preterm infants. A controlled study of bilirubin disappearance and infant behavior. Acta Paediatr Scand. 73:488-97.

Wang H, Faucette S, Moore R, Sueyoshi T, Negishi M, LeCluyse E. (2004) Human constitutive androstane receptor mediates induction of CYP2B6 gene expression by phenytoin. J Biol Chem. 279:29295-301.

Wienekea N, Hirsch-Ernstb KI, Kunaa M, Kerstenc S, Puschela GP. (2007) PPAR[alpha]-dependent induction of the energy homeostasis-regulating nuclear receptor NR1i3 (CAR) in rat hepatocytes: potential role in starvation adaptation. FEBS Lett. 581: 5617-26.

Yaffe SJ, Levy G, Matsuzawa T, Baliah T. (1966) Enhancement of glucuronide-conjugating capacity in a hyperbilirubinemic infant due to apparent enzyme induction by phenobarbital. N Engl J Med. 275:1461-66.

Yamamoto Y, Moore R, Goldsworthy TL, Negishi M, Maronpot RR. (2004) The orphan nuclear receptor constitutive active/androstane receptor is essential for liver tumor promotion by phenobarbital in mice. Cancer Res. 64:7197- 200.

Yamazaki Y, Kakizaki S, Horiguchi N, Sohara N, Sato K, Takagi H, Mori M, Negishi M. (2007) The role of the nuclear receptor constitutive androstane receptor in the pathogenesis of non-alcoholic steatohepatitis. Gut 56: 565-74.

Yao R, Yasuoka A, Kamei A, Kitagawa Y, Rogi T, Taieishi N, Tsuruoka N, Kiso Y, Misaka T, Abe K. (2011) Polyphenols in alcoholic beverages activating constitutive androstane receptor CAR. Biosci Biotechnol Biochem. 75:1635-37.

Yoshinari K, Kobayashi K, Moore R, Kawamoto T, Negishi M. (2003) Identification of the nuclear receptor CAR:HSP90 complex in mouse liver and recruitment of protein phosphatase 2A in response to phenobarbital. FEBS Lett. 548: 17-20.

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: 278-84.

Yoshinari K, Yoda N, Toriyabe T, Yamazoe Y. (2010) Constitutive androstane receptor transcriptionally activates human CYP1A1 and CYP1A2 genes through a common regulatory element in the 5'-flanking region. Biochem Pharmacol. 79:261-69.

Zelko I, Sueyoshi, T, Kawamoto, T, Moore R, Negishi M. (2001) The peptide near the C terminus regulates receptor CAR nuclear translocation induced by xenochemicals in mouse liver. Mol Cell Biol. 21: 2838-46.

Zhai Y, Wada T, Zhang B, Khadem S, Ren S, Kuruba R, Li S et al. (2010) A functional crosstalk between liver X receptor - α and Constitutive androstane receptor AR links lipogenesis and xenobiotic responses. Mol Pharmacol. 78 : 666-74.