An update on the constitutive androstane receptor (CAR)

References

1. Honkakoski P, Sueyoshi T, Negishi M. Drug-activated nuclear receptors CAR and PXR. Ann Med 2003;35:172–82.10.1080/07853890310008224Search in Google Scholar PubMed

2. Stanley LA, Horsburgh BC, Ross J, Scheer N, Wolf CR. PXR and CAR: nuclear receptors which play a pivotal role in drug disposition and chemical toxicity. Drug Metab Rev 2006;38: 515–97.10.1080/03602530600786232Search in Google Scholar PubMed

3. Timsit YE, Negishi M. CAR and PXR: the xenobiotic-sensing receptors. Steroids 2007;72:231–46.10.1016/j.steroids.2006.12.006Search in Google Scholar PubMed PubMed Central

4. di Masi A, De Marinis E, Ascenzi P, Marino M. Nuclear receptors CAR and PXR: molecular, functional, and biomedical aspects. Mol Asp Med 2009;30:297–343.10.1016/j.mam.2009.04.002Search in Google Scholar PubMed

5. Reschly EJ, Krasowski MD. Evolution and function of the NR1I nuclear hormone receptor subfamily (VDR, PXR, and CAR) with respect to metabolism of xenobiotics and endogenous compounds. Curr Drug Metab 2006;7:349–65.10.2174/138920006776873526Search in Google Scholar PubMed PubMed Central

6. Graham MJ, Lake BG. Induction of drug metabolism: species differences and toxicological relevance. Toxicology 2008;254:184–91.10.1016/j.tox.2008.09.002Search in Google Scholar PubMed

7. Lamba J, Lamba V, Schuetz E. Genetic variants of PXR (NR1I2) and CAR (NR1I3) and their implications in drug metabolism and pharmacogenetics. Curr Drug Metab 2005;6:369–83.10.2174/1389200054633880Search in Google Scholar PubMed

8. Lamba JK. Pharmacogenetics of the constitutive androstane receptor. Pharmacogenomics 2008;9:71–83.10.2217/14622416.9.1.71Search in Google Scholar PubMed

9. Tirona RG, Kim RB. Nuclear receptors and drug disposition gene regulation. J Pharmacol Sci 2005;94:1169–86.10.1002/jps.20324Search in Google Scholar PubMed

10. Zhou J, Zhang J, Xie W. Xenobiotic nuclear receptor-mediated regulation of UDP-glucuronosyl-transferases. Curr Drug Metab 2005;6:289–98.10.2174/1389200054633853Search in Google Scholar PubMed

11. Tolson AH, Wang H. Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR. Adv Drug Deliv Rev 2010;62:1238–49.10.1016/j.addr.2010.08.006Search in Google Scholar PubMed PubMed Central

12. Staudinger JL, Xu C, Cui YJ, Klaassen CD. Nuclear receptor-mediated regulation of carboxylesterase expression and activity. Expert Opin Drug Metab 2010;6:261–71.10.1517/17425250903483215Search in Google Scholar PubMed PubMed Central

13. Higgins LG, Hayes JD. Mechanisms of induction of cytosolic and microsomal glutathione transferase (GST) genes by xenobiotics and pro-inflammatory agents. Drug Metab Rev 2011;43:92–137.10.3109/03602532.2011.567391Search in Google Scholar PubMed

14. Chai X, Zeng S, Xie W. Nuclear receptors PXR and CAR: implications for drug metabolism regulation, pharmacogenomics and beyond. Expert Opin Drug Metab 2013;9:253–66.10.1517/17425255.2013.754010Search in Google Scholar PubMed

15. Swales K, Negishi M. CAR, driving into the future. Mol Endocrinol 2004;18:1589–98.10.1210/me.2003-0397Search in Google Scholar PubMed

16. Pascussi J-M, Gerbal-Chaloin S, Duret C, Daujat-Chavanieu M, Vilarem M-J, Maurel P. The tangle of nuclear receptors that controls xenobiotic metabolism and transport: crosstalk and consequences. Annu Rev Pharmacol Toxicol 2008;48:1–32.10.1146/annurev.pharmtox.47.120505.105349Search in Google Scholar PubMed

17. Li H, Wang H. Activation of xenobiotic receptors: driving into the nucleus. Expert Opin Drug Metab 2010;6:409–26.10.1517/17425251003598886Search in Google Scholar PubMed PubMed Central

18. Moreau A, Vilarem MJ, Maurel P, Pascussi JM. Xenoreceptors CAR and PXR activation and consequences on lipid metabolism, glucose homeostasis, and inflammatory response. Mol Pharmaceutics 2008;5:35–41.10.1021/mp700103mSearch in Google Scholar PubMed

19. Wada T, Gao J, Xie W. PXR and CAR in energy metabolism. Trends Endocr Met 2009;20:273–9.10.1016/j.tem.2009.03.003Search in Google Scholar PubMed

20. Gao J, Xie W. Targeting xenobiotic receptors PXR and CAR for metabolic diseases. Trends Pharmacol Sci 2012;33:552–8.10.1016/j.tips.2012.07.003Search in Google Scholar PubMed PubMed Central

21. Wagner M, Zollner G, Trauner M. Nuclear receptor regulation of the adaptive response of bile acid transporters in cholestasis. Semin Liver Dis 2010;30:160–77.10.1055/s-0030-1253225Search in Google Scholar

22. Poso A, Honkakoski P. Ligand recognition by drug-activated nuclear receptors PXR and CAR: structural, site-directed mutagenesis and molecular modeling studies. Mini Rev Med Chem 2006;6:937–47.10.2174/138955706777935008Search in Google Scholar

23. Raucy JL, Lasker JM. Current in vitro high throughput screening approaches to assess nuclear receptor activation. Curr Drug Metab 2010;11:806–14.10.2174/138920010794328896Search in Google Scholar

24. Köhle C, Schwarz M, Bock KW. Promotion of hepatocarcinogenesis in humans and animal models. Arch Toxicol 2008;82:623–31.10.1007/s00204-007-0273-7Search in Google Scholar

25. Baes M, Gulick T, Choi H, Stinoli MG, Simha D, Moore DD. A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements. Mol Cell Biol 1994;14:1544–52.Search in Google Scholar

26. Choi HS, Chung M, Tzameli I, Simha D, Lee YK, Seol W, et al. Differential transactivation by two isoforms of the orphan nuclear hormone receptor CAR. J Biol Chem 1997;272: 23565–71.10.1074/jbc.272.38.23565Search in Google Scholar

27. Trottier E, Belzil A, Stoltz C, Anderson A. Localization of a phenobarbital-responsive element (PBRE) in the 5′-flanking region of the rat CYP2B2 gene. Gene 1995;158:263–8.10.1016/0378-1119(94)00916-GSearch in Google Scholar

28. Honkakoski P, Negishi M. Characterization of a phenobarbital-responsive enhancer module in mouse P450 Cyp2b10 gene. J Biol Chem 1997;272:14943–9.10.1074/jbc.272.23.14943Search in Google Scholar PubMed

29. Honkakoski P, Moore R, Washburn KA, Negishi M. Activation by diverse xenochemicals of the 51-base pair phenobarbital-responsive enhancer module in the CYP2B10 gene. Mol Pharmacol 1998;53:597–601.10.1124/mol.53.4.597Search in Google Scholar PubMed

30. Honkakoski P, Zelko I, Sueyoshi T, Negishi M. The nuclear orphan receptor car-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol Cell Biol 1998;18:5652–8.10.1128/MCB.18.10.5652Search in Google Scholar PubMed PubMed Central

31. Wei P, Zhang J, Egan-Hafley M, Liang S, Moore DD. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature 2000;407:920–3.10.1038/35038112Search in Google Scholar PubMed

32. Ueda A, Hamadeh HK, Webb HK, Yamamoto Y, Sueyoshi T, Afshari CA, et al. Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. Mol Pharmacol 2002;61:1–6.10.1124/mol.61.1.1Search in Google Scholar PubMed

33. Yamamoto Y, Moore R, Goldsworthy TL, Negishi Monpot RR. The orphan nuclear receptor constitutive active/androstane receptor is essential for liver tumor promotion by phenobarbital in mice. Cancer Res 2004;64:7197–200.10.1158/0008-5472.CAN-04-1459Search in Google Scholar PubMed

34. Zhang Q, Bae Y, Kemper JK, Kemper B. Analysis of multiple nuclear receptor binding sites for CAR/RXR in the phenobarbital responsive unit of CYP2B2. Arch Biochem Biophys 2006;451:119–27.10.1016/j.abb.2006.04.016Search in Google Scholar PubMed

35. Lau AJ, Yang G, Rajaraman G, Baucom CC, Chang TK. Species-dependent and receptor-selective action of bilobalide on the function of constitutive androstane receptor and pregnane X receptor. Drug Metab Dispos 2012;40:178–86.10.1124/dmd.111.042879Search in Google Scholar PubMed

36. Huang W, Zhang J, Washington M, Liu J, Parant JM, Lozano G, et al. Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor. Mol Endocrinol 2005;19:1646–53.10.1210/me.2004-0520Search in Google Scholar PubMed

37. Kiyosawa N, Kwekel JC, Burgoon LD, Dere E, Williams KJ, Tashiro C, et al. Species-Specific regulation of PXR/CAR/ER-target genes in the mouse and rat liver elicited by o,p′-DDT. BMC Genomics 2008;9:487.10.1186/1471-2164-9-487Search in Google Scholar PubMed PubMed Central

38. Chen T, Chen Q, Xu Y, Zhou Q, Zhu J, Zhang H, et al. SRC-3 is required for car-regulated hepatocyte proliferation and drug metabolism. J Hepatol 2012;56:210–7.10.1016/j.jhep.2011.07.015Search in Google Scholar PubMed PubMed Central

39. Tian J, Huang H, Hoffman B, Liebermann DA, Ledda-Columbano GM, Columbano A, et al. Gadd45Β is an inducible coactivator of transcription that facilitates rapid liver growth in mice. J Clin Invest 2011;121:4491–502.10.1172/JCI38760Search in Google Scholar PubMed PubMed Central

40. Kodama S, Koike C, Negishi M, Yamamoto Y. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Mol Cell Biol 2004;24:7931–40.10.1128/MCB.24.18.7931-7940.2004Search in Google Scholar PubMed PubMed Central

41. Xu RX, Lambert MH, Wisely BB, Warren EN, Weinert EE, Waitt GM, et al. A structural basis for constitutive activity in the human CAR/RXRα heterodimer. Mol Cell 2004;16:919–28.10.1016/j.molcel.2004.11.042Search in Google Scholar PubMed

42. Suino K, Peng L, Reynolds R, Li Y, Cha JY, Repa JJ, et al. The nuclear xenobiotic receptor CAR: structural determinants of constitutive activation and heterodimerization. Mol Cell 2004;16:893–905.Search in Google Scholar

43. Shan L, Vincent J, Brunzelle JS, Dussault I, Lin M, Ianculescu I, et al. Structure of the murine constitutive androstane receptor complexed to androstenol: a molecular basis for inverse agonism. Mol Cell 2004;16:907–17.Search in Google Scholar

44. Moras D, Gronemeyer H. The nuclear receptor ligand-binding domain: structure and function. Curr Opin Cell Biol 1998;10:384–91.10.1016/S0955-0674(98)80015-XSearch in Google Scholar

45. Rochel N, Wurtz JM, Mitschler A, Klaholz B, Moras D. The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Mol Cell 2000;5:173–9.10.1016/S1097-2765(00)80413-XSearch in Google Scholar

46. Stehlin C, Wurtz JM, Steinmetz A, Greiner E, Schüle R, Moras D, et al. X-ray structure of the orphan nuclear receptor RORβ ligand-binding domain in the active conformation. EMBO J 2001;20:5822–31.10.1093/emboj/20.21.5822Search in Google Scholar

47. Kallen JA, Schlaeppi JM, Bitsch F, Geisse S, Geiser M, Delhon I, et al. X-ray structure of the hRORα LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORα. Structure (Camb) 2002;10:1697–707.10.1016/S0969-2126(02)00912-7Search in Google Scholar

48. Gampe RT, Montana VG, Lambert MH, Wisely GB, Milburn MV, Xu HE. Structural basis for autorepression of retinoid X receptor by tetramer formation and the AF-2 helix. Genes Dev 2000;14:2229–41.10.1101/gad.802300Search in Google Scholar PubMed PubMed Central

49. Jyrkkärinne J, Windshügel B, Mäkinen J, Ylisirniö M, Peräkylä M, Poso A, et al. Amino acids important for ligand specificity of the human constitutive androstane receptor. J Biol Chem 2005;280:5960–71.10.1074/jbc.M411241200Search in Google Scholar PubMed

50. Dussault I, Lin M, Hollister K, Fan M, Termini J, Sherman MA, et al. A structural model of the constitutive androstane receptor defines novel interactions that mediate ligand-independent activity. Mol Cell Biol 2002;22:5270–80.10.1128/MCB.22.15.5270-5280.2002Search in Google Scholar PubMed PubMed Central

51. Windshügel B, Jyrkkärinne J, Poso A, Honkakoski P, Sippl W. Molecular dynamics simulations of the human CAR ligand-binding domain: deciphering the molecular basis for constitutive activity. J Mol Model 2005;11:69–79.10.1007/s00894-004-0227-4Search in Google Scholar PubMed

52. Windshügel B, Jyrkkärinne J, Vanamo J, Poso A, Honkakoski P, Sippl W. Comparison of homology models and x-ray structures of the nuclear receptor CAR: assessing the structural basis of constitutive activity. J Mol Graph 2007;25:644–57.10.1016/j.jmgm.2006.05.002Search in Google Scholar PubMed

53. Windshügel B, Poso A. Constitutive activity and ligand-dependent activation of the nuclear receptor car-insights from molecular dynamics simulations. J Mol Recogn 2011;24:875–82.10.1002/jmr.1132Search in Google Scholar PubMed

54. Jyrkkärinne J, Küblbeck J, Pulkkinen J, Honkakoski P, Laatikainen R, Poso A, et al. Molecular dynamics simulations for human CAR inverse agonists. J Chem Inf Model 2012;52:457–64.10.1021/ci200432kSearch in Google Scholar PubMed

55. Repo S, Jyrkkärinne J, Pulkkinen JT, Laatikainen R, Honkakoski P, Johnson MS. Ligand specificity of constitutive androstane receptor as probed by induced-fit docking and mutagenesis. J Med Chem 2008;51:7119–31.10.1021/jm800337rSearch in Google Scholar PubMed

56. Küblbeck J, Laitinen T, Jyrkkärinne J, Rousu T, Tolonen A, Abel T, et al. Use of comprehensive screening methods to detect selective human CAR activators. Biochem Pharmacol 2011;82:1994–2007.10.1016/j.bcp.2011.08.027Search in Google Scholar PubMed

57. Küblbeck J, Jyrkkärinne J, Molnár F, Kuningas T, Patel J, Windshügel B, et al. New in vitro tools to study human constitutive androstane receptor (CAR) biology: discovery and comparison of human CAR inverse agonists. Mol Pharm 2011;8:2424–33.10.1021/mp2003658Search in Google Scholar PubMed

58. Jyrkkärinne J, Mäkinen J, Gynther J, Savolainen H, Poso A, Honkakoski P. Molecular determinants of steroid inhibition for the mouse constitutive androstane receptor. J Med Chem 2003;46:4687–95.10.1021/jm030861tSearch in Google Scholar PubMed

59. Küblbeck J, Jyrkkärinne J, Poso A, Turpeinen M, Sippl W, Honkakoski P, et al. Discovery of substituted sulfonamides and thiazolidin-4-one derivatives as agonists of human constitutive androstane receptor. Biochem Pharmacol 2008;76:1288–97.10.1016/j.bcp.2008.08.014Search in Google Scholar PubMed

60. Dring AM, Anderson LE, Qamar S, Stoner MA. Rational quantitative structure-activity relationship (RQSAR) screen for PXR and CAR isoform-specific nuclear receptor ligands. Chem Biol Interact 2010;188:512–25.10.1016/j.cbi.2010.09.018Search in Google Scholar PubMed PubMed Central

61. Jyrkkärinne J, Windshügel B, Rönkkö T, Tervo AJ, Küblbeck J, Lahtela-Kakkonen M, et al. Insights into ligand-elicited activation of human constitutive androstane receptor based on novel agonists and three-dimensional quantitative structure-activity relationship. J Med Chem 2008;51:7181–92.10.1021/jm800731bSearch in Google Scholar PubMed

62. Burk O, Piedade R, Ghebreghiorghis L, Fait JT, Nussler AK, Gil JP, et al. Differential effects of clinically used derivatives and metabolites of artemisinin in the activation of constitutive androstane receptor isoforms. Br J Pharmacol 2012; 167:666–81.10.1111/j.1476-5381.2012.02033.xSearch in Google Scholar PubMed PubMed Central

63. Lynch C, Pan Y, Li L, Ferguson SS, Xia M, Swaan PW, et al. Identification of novel activators of constitutive androstane receptor from FDA-approved drugs by integrated computational and biological approaches. Pharm Res 2013;30:489–501.10.1007/s11095-012-0895-1Search in Google Scholar PubMed PubMed Central

64. Ekins S, Reschly EJ, Hagey LR, Krasowski MD. Evolution of pharmacologic specificity in the pregnane X receptor. BMC Evol Biol 2008;8:103.10.1186/1471-2148-8-103Search in Google Scholar

65. Handschin C, Podvinec M, Meyer UA. CXR, a chicken xenobiotic-sensing orphan nuclear receptor, is related to both mammalian pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Proc Natl Acad Sci USA 2000;97:10769–74.10.1073/pnas.97.20.10769Search in Google Scholar

66. Lindblom TH, Pierce GJ, Sluder AE. A C. elegans orphan nuclear receptor contributes to xenobiotic resistance. Curr Biol 2001;11:864–8.10.1016/S0960-9822(01)00236-6Search in Google Scholar

67. Maglich JM, Caravella JA, Lambert MH, Willson TM, Moore JT, Ramamurthy L. The first completed genome sequence from a teleost fish (Fugu rubripes) adds significant diversity to the nuclear receptor superfamily. Nucleic Acids Res 2003;31:4051–8.10.1093/nar/gkg444Search in Google Scholar PubMed PubMed Central

68. Makino T, McLysaght A. Ohnologs in the human genome are dosage balanced and frequently associated with disease. Proc Natl Acad Sci USA 2010;107:9270–4.10.1073/pnas.0914697107Search in Google Scholar PubMed PubMed Central

69. Mathäs M, Burk O, Qiu H, Nusshag C, Gödtel-Armbrust U, Baranyai D, et al. Evolutionary history and functional characterization of the amphibian xenosensor CAR. Mol Endocrinol 2012;26:14–26.10.1210/me.2011-1235Search in Google Scholar PubMed PubMed Central

70. Krasowski MD, Yasuda K, Hagey LR, Schuetz EG. Evolution of the pregnane X receptor: adaptation to cross-species differences in biliary bile salts. Mol Endocrinol 2005;19:1720–39.10.1210/me.2004-0427Search in Google Scholar PubMed PubMed Central

71. Krasowski MD, Yasuda K, Hagey LR, Schuetz EG. Evolutionary selection across the nuclear hormone receptor superfamily with a focus on the NR1I subfamily (vitamin D, pregnane X, and constitutive androstane receptors). Nucl Receptor 2005;3:2.10.1186/1478-1336-3-2Search in Google Scholar PubMed PubMed Central

72. Yoshinari K, Sueyoshi T, Moore R, Negishi M. Nuclear receptor CAR as a regulatory factor for the sexually dimorphic induction of CYB2B1 gene by phenobarbital in rat livers. Mol Pharmacol 2001;59:278–84.10.1124/mol.59.2.278Search in Google Scholar PubMed

73. Omiecinski CJ, Coslo DM, Chen T, Laurenzana EM, Peffer RC. Multi-species analyses of direct activators of the constitutive androstane receptor. Toxicol Sci 2011;123:550–62.10.1093/toxsci/kfr191Search in Google Scholar PubMed PubMed Central

74. Arnold KA, Eichelbaum M, Burk O. Alternative splicing affects the function and tissue-specific expression of the human constitutive androstane receptor. Nucl Receptor 2004;2:1.10.1186/1478-1336-2-1Search in Google Scholar PubMed PubMed Central

75. Lamba JK, Lamba V, Yasuda K, Lin YS, Assem M, Thompson E, et al. Expression of constitutive androstane receptor splice variants in human tissues and their functional consequences. J Pharmacol Exp Ther 2004;311:811–21.10.1124/jpet.104.069310Search in Google Scholar PubMed

76. DeKeyser JG, Laurenzana EM, Peterson EC, Chen T, Omiecinski CJ. Selective phthalate activation of naturally occurring human constitutive androstane receptor splice variants and the pregnane X receptor. Toxicol Sci 2011;120:381–91.10.1093/toxsci/kfq394Search in Google Scholar PubMed PubMed Central

77. Auerbach SS, Ramsden R, Stoner MA, Verlinde C, Hassett C, Omiecinski CJ. Alternatively spliced isoforms of the human constitutive androstane receptor. Nucleic Acids Res 2003;31:3194–207.10.1093/nar/gkg419Search in Google Scholar PubMed PubMed Central

78. Jinno H, Tanaka-Kagawa T, Hanioka N, Ishida S, Saeki M, Soyama A, et al. Identification of novel alternative splice variants of human constitutive androstane receptor and characterization of their expression in the liver. Mol Pharmacol 2004;65:496–502.10.1124/mol.65.3.496Search in Google Scholar PubMed

79. Faucette SR, Zhang T-C, Moore R, Sueyoshi T, Omiecinski CJ, LeCluyse EL, et al. Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers. J Pharmacol Exp Ther 2007;320:72–80.10.1124/jpet.106.112136Search in Google Scholar PubMed PubMed Central

80. Thompson EE, Kuttab-Boulos H, Krasowski MD, Di Rienzo A. Functional constraints on the constitutive androstane receptor inferred from human sequence variation and cross-species comparisons. Hum Genomics 2005;2:168–78.10.1186/1479-7364-2-3-168Search in Google Scholar PubMed PubMed Central

81. Ikeda S, Kurose K, Jinno H, Sai K, Ozawa S, Hasegawa R, et al. Functional analysis of four naturally occurring variants of human constitutive androstane receptor. Mol Gen Metab 2005;86:314–9.10.1016/j.ymgme.2005.05.011Search in Google Scholar PubMed

82. Swart M, Whitehorn H, Ren Y, Smith P, Ramesar RS, Dandara C. PXR and CAR single nucleotide polymorphisms influence plasma efavirenz levels in South African HIV/AIDS patients. BMC Med Genet 2012;13:112–23.10.1186/1471-2350-13-112Search in Google Scholar PubMed PubMed Central

83. Cortes CP, Siccardi M, Chaikan A, Owen A, Zhang G, Porte CJ. Correlates of efavirenz exposure in Chilean patients affected with human immunodeficiency virus reveals a novel association with a polymorphism in the constitutive androstane receptor. Ther Drug Monitor 2013;35:78–83.10.1097/FTD.0b013e318274197eSearch in Google Scholar PubMed

84. Turpeinen M, Zanger UM. Cytochrome P450 2B6: function, genetics, and clinical relevance. Drug Metabol Drug Interact 2012;27:185–97.10.1515/dmdi-2012-0027Search in Google Scholar PubMed

85. Ding X, Lichti K, Kim I, Gonzalez FJ, Staudinger JL. Regulation of constitutive androstane receptor and its target genes by fasting, camp, hepatocyte nuclear factor alpha, and the coactivator peroxisome proliferator-activated receptor gamma coactivator-1α. J Biol Chem 2006;281:26540–51.10.1074/jbc.M600931200Search in Google Scholar PubMed PubMed Central

86. Pascussi JM, Robert A, Moreau A, Ramos J, Bioulac-Sage P, Navarro F, et al. Differential regulation of constitutive androstane receptor expression by hepatocyte nuclear factor-4 alpha isoforms. Hepatology 2007;45:1146–53.10.1002/hep.21592Search in Google Scholar PubMed

87. Pascussi JM, Gerbal-Chaloin S, Fabre JM, Maurel P, Vilarem MJ. Dexamethasone enhances constitutive androstane receptor expression in human hepatocytes: consequences on cytochrome P450 gene regulation. Mol Pharmacol 2000;58:1441–50.10.1124/mol.58.6.1441Search in Google Scholar PubMed

88. Saito K, Kobayashi K, Mizuno Y, Fukuchi Y, Furihata T, Chiba K. Peroxisome proliferator-activated receptor alpha (PPARalpha) agonists induce constitutive androstane receptor (CAR) and cytochrome P450 2B in rat primary hepatocytes. Drug Metab Pharmacokinet 2010;25:108–11.10.2133/dmpk.25.108Search in Google Scholar PubMed

89. Maglich JM, Stoltz CM, Goodwin B, Hawkins-Brown D, Moore JT, Kliewer SA. Nuclear pregnane X receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol Pharmacol 2002;62:638–46.10.1124/mol.62.3.638Search in Google Scholar PubMed

90. Ooe H, Kon J, Oshima H, Mitaka T. Thyroid hormone is necessary for expression of constitutive androstane receptor in rat hepatocytes. Drug Metab Dispos 2009;37:1963–9.10.1124/dmd.108.022905Search in Google Scholar PubMed

91. Osabe M, Sugatani J, Takemura A, Kurosawa M, Yamazaki Y, Ikari A, et al. Up-regulation of CAR expression through Elk-1 in HepG2 and SW480 cells by serum starvation stress. FEBS Lett 2009;583:885–9.10.1016/j.febslet.2009.01.051Search in Google Scholar PubMed

92. Koike C, Moore R, Negishi M. Extracellular signal-regulated kinase is an endogenous signal retaining the nuclear constitutive active/androstane receptor (CAR) in the cytoplasm of mouse primary hepatocytes. Mol Pharmacol 2007;71: 1217–21.10.1124/mol.107.034538Search in Google Scholar PubMed PubMed Central

93. Osabe M, Negishi M. Active ERK1/2 protein interacts with the phosphorylated nuclear constitutive active/androstane receptor (CAR; NR1I3), repressing dephosphorylation and sequestering CAR in the cytoplasm. J Biol Chem 2011;286:35763–9.10.1074/jbc.M111.284596Search in Google Scholar PubMed PubMed Central

94. Gachon F, Olela FF, Schaad O, Descombes P, Schibler U. The circadian PAR-domain basic leucine zipper TFs DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification. Cell Metab 2006;4:25–36.10.1016/j.cmet.2006.04.015Search in Google Scholar PubMed

95. Kobayashi K, Sueyoshi T, Inoue K, Moore R, Negishi M. Cytoplasmic accumulation of the nuclear receptor CAR by a tetratricopeptide repeat protein in HepG2 cells. Mol Pharmacol 2003;64:1069–75.10.1124/mol.64.5.1069Search in Google Scholar PubMed

96. Mutoh S, Osabe M, Inoue K, Moore R, Pedersen L, Perera L, et al. Dephosphorylation of threonine 38 is required for nuclear translocation and activation of human xenobiotic receptor CAR (NR1I3). J Biol Chem 2009;284:34785–92.10.1074/jbc.M109.048108Search in Google Scholar PubMed PubMed Central

97. Hosseinpour F, Moore R, Negishi M, Sueyoshi T. Serine 202 regulates the nuclear translocation of constitutive active/androstane receptor. Mol Pharmacol 2006;69:1095–102.10.1124/mol.105.019505Search in Google Scholar PubMed

98. Sueyoshi T, Moore R, Sugatani J, Matsumura Y, Negishi M. PPP1R16A, the membrane subunit of protein phosphatase 1β, signals nuclear translocation of the nuclear receptor constitutive active/androstane receptor. Mol Pharmacol 2008;73:1113–21.10.1124/mol.107.042960Search in Google Scholar PubMed

99. Blättler SM, Rencurel F, Kaufmann MR, Meyer UA. In the regulation of cytochrome P450 genes, phenobarbital targets LKB1 for necessary activation of AMP-activated protein kinase. Proc Natl Acad Sci USA 2007;104:1045–50.10.1073/pnas.0610216104Search in Google Scholar PubMed PubMed Central

100. Chakraborty S, Kanakasabai S, Bright JJ. Constitutive androstane receptor agonist CITCO inhibits growth and expansion of brain tumour stem cells. Br J Cancer 2011;104:448–59.10.1038/sj.bjc.6606064Search in Google Scholar PubMed PubMed Central

101. Kamino H, Negishi M. The nuclear receptor constitutive active/androstane receptor arrests DNA-damaged human hepatocellular carcinoma Huh7 cells at the G2/M phase. Mol Carcinogen 2012;51:206–12.10.1002/mc.20783Search in Google Scholar PubMed PubMed Central

102. Sidhu JS, Omiecinski CJ. cAMP-associated inhibition of phenobarbital-inducible cytochrome P450 gene expression in primary rat hepatocyte cultures. J Biol Chem 1995;270:12762–73.10.1074/jbc.270.21.12762Search in Google Scholar PubMed

103. Honkakoski P, Negishi M. Protein serine/threonine phosphatase inhibitors suppress phenobarbital-induced Cyp2b10 gene transcription in mouse primary hepatocytes. Biochem J 1998;330:889–95.10.1042/bj3300889Search in Google Scholar PubMed PubMed Central

104. Ito S, Tsuda M, Yoshitake A, Yanai T, Masegi T. Effect of phenobarbital on hepatic gap junctional intercellular communication in rats. Toxicol Pathol 1998;26:253–9.10.1177/019262339802600210Search in Google Scholar

105. Warner KA, Fernstrom MJ, Ruch RJ. Inhibition of mouse hepatocyte gap junctional intercellular communication by phenobarbital correlates with strain-specific hepatocarcinogenesis. Toxicol Sci 2003;71:190–7.10.1093/toxsci/71.2.190Search in Google Scholar

106. Sugatani J, Sueyoshi T, Negishi M, Miwa M. Regulation of the human UGT1A1 gene by nuclear receptors constitutive active/androstane receptor, pregnane X receptor, and glucocorticoid receptor. Method Enzymol 2005;400:92–104.10.1016/S0076-6879(05)00006-6Search in Google Scholar

107. Goodwin B, Hodgson E, D’Costa DJ, Robertson GR, Liddle C. Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor. Mol Pharmacol 2002;62:359–65.10.1124/mol.62.2.359Search in Google Scholar PubMed

108. Mäkinen J, Frank C, Jyrkkärinne J, Gynther J, Carlberg C, Honkakoski P. Modulation of mouse and human phenobarbital-responsive enhancer module by nuclear receptors. Mol Pharmacol 2002;62:366–78.10.1124/mol.62.2.366Search in Google Scholar PubMed

109. Kassam A, Winrow CJ, Fernandez-Rachubinski F, Capone JP, Rachubinski RA. The peroxisome proliferator response element of the gene encoding the peroxisomal beta-oxidation enzyme enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase is a target for constitutive androstane receptor beta/9-cis-retinoic acid receptor-mediated transactivation. J Biol Chem 2000;275:4345–50.10.1074/jbc.275.6.4345Search in Google Scholar PubMed

110. Miao J, Fang S, Bae Y, Kemper JK. 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-1α. J Biol Chem 2006;281:14537–46.10.1074/jbc.M510713200Search in Google Scholar PubMed

111. Kachaylo EM, Yarushkin AA, Pustylnyak VO. Constitutive androstane receptor activation by 2,4,6-triphenyl-1,3-dioxane suppresses the expression of the gluconeogenic genes. Eur J Pharmacol 2012;679:139–43.10.1016/j.ejphar.2012.01.007Search in Google Scholar PubMed

112. Frank C, Gonzalez MM, Oinonen C, Dunlop TW, Carlberg C. Characterization of DNA complexes formed by the nuclear receptor constitutive androstane receptor. J Biol Chem 2003;278:43299–310.10.1074/jbc.M305186200Search in Google Scholar PubMed

113. Burk O, Katja AA, Geick A, Tegude H, Eichelbaum M. A role for constitutive androstane receptor in the regulation of human intestinal MDR1 expression. Biol Chem 2005;386:503–13.10.1515/BC.2005.060Search in Google Scholar PubMed

114. Heery DM, Kalkhoven E, Hoare S, Parker MG. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 1997;387:733–6.10.1038/42750Search in Google Scholar PubMed

115. McKenna NJ, Lanz RB, O’Malley BW. Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 1999;20:321–44.Search in Google Scholar

116. Molnár F, Matilainen M, Carlberg C. Structural determinants of the agonist-independent association of human peroxisome proliferator-activated receptors with coactivators. J Biol Chem 2005;280:26543–56.10.1074/jbc.M502463200Search in Google Scholar PubMed

117. Xia J, Liao L, Sarkar J, Matsumoto K, Reddy JK, Xu J, et al. Redundant enhancement of mouse constitutive androstane receptor transactivation by p160 coactivator family members. Arch Biochem Biophys 2007;468:49–57.10.1016/j.abb.2007.09.005Search in Google Scholar PubMed PubMed Central

118. Choi E, Lee S, Yeom S-Y, Kim GH, Lee JW, Kim S-W. Characterization of activating signal cointegrator-2 as a novel transcriptional coactivator of the xenobiotic nuclear receptor constitutive androstane receptor. Mol Endocrinol 2005;19:1711–9.10.1210/me.2005-0066Search in Google Scholar PubMed

119. Jia Y, Guo GL, Surapureddi S, Sarkar J, Qi C, Guo D, et al. Transcription coactivator peroxisome proliferator-activated receptor-binding protein/mediator 1 deficiency abrogates acetaminophen hepatotoxicity. Proc Natl Acad Sci USA 2005;102:12531–6.10.1073/pnas.0506000102Search in Google Scholar PubMed PubMed Central

120. Sarkar J, Qi C, Guo D, Ahmed MR, Jia Y, Usuda N, et al. Transcription coactivator PRIP, the peroxisome proliferator-activated receptor (PPAR)-interacting protein, is redundant for the function of nuclear receptors pparalpha and CAR, the constitutive androstane receptor, in mouse liver. Gene Expression 2007;13:255–69.10.3727/000000006780666948Search in Google Scholar PubMed PubMed Central

121. Guo D, Sarkar J, Ahmed MR, Viswakarma N, Jia Y, Yu S, et al. Peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP) but not PPAR-interacting protein (PRIP) is required for nuclear translocation of constitutive androstane receptor in mouse liver. Biochem Biophys Res Commun 2006;347:485–95.10.1016/j.bbrc.2006.06.129Search in Google Scholar PubMed

122. Malik S, Roeder RG. The metazoan mediator co-activator complex as an integrative hub for transcriptional regulation. Nat Rev Genet 2010;11:761–72.10.1038/nrg2901Search in Google Scholar PubMed PubMed Central

123. Surapureddi S, Viswakarma N, Yu S, Guo D, Rao MS, Reddy JK. PRIC320, a transcription coactivator, isolated from peroxisome proliferator-binding protein complex. Biochem Biophys Res Commun 2006;343:535–43.10.1016/j.bbrc.2006.02.160Search in Google Scholar PubMed

124. Shiraki T, Sakai N, Kanaya E, Jingami H. 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 2003;278:11344–50.10.1074/jbc.M212859200Search in Google Scholar PubMed

125. Mäkinen J, Reinisalo M, Niemi K, Viitala P, Jyrkkärinne J, Chung H, et al. Dual action of oestrogens on the mouse constitutive androstane receptor. Biochem J 2003;376:465–72.10.1042/bj20030553Search in Google Scholar PubMed PubMed Central

126. Lempiäinen H, Molnár F, Macias Gonzalez M, Peräkylä M, Carlberg C. Antagonist- and inverse agonist-driven interactions of the vitamin D receptor and the constitutive androstane receptor with corepressor protein. Mol Endocrinol 2005;19:2258–72.10.1210/me.2004-0534Search in Google Scholar PubMed

127. Konno Y, Kodama S, Moore R, Kamiya N, Negishi M. Nuclear xenobiotic receptor pregnane X receptor locks corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) onto the CYP24A1 promoter to attenuate vitamin D₃ activation. Mol Pharmacol 2009;75:265–71.10.1124/mol.108.051904Search in Google Scholar PubMed PubMed Central

128. Bae Y, Kemper JK, Kemper B. Repression of CAR-mediated transactivation of CYP2B genes by the orphan nuclear receptor, short heterodimer partner (SHP). DNA Cell Biol 2004;23:81–91.10.1089/104454904322759894Search in Google Scholar PubMed

129. Laurenzana EM, Chen T, Kannuswamy M, Sell BE, Strom SC, Li Y, et al. The orphan nuclear receptor DAX-1 functions as a potent corepressor of the constitutive androstane receptor (NR1I3). Mol Pharmacol 2012;82:918–28.10.1124/mol.112.080721Search in Google Scholar PubMed PubMed Central

130. Xie Y-B, Lee O-H, Nedumaran B, Seong H-A, Lee K-M, Ha H, et al. SMILE, a new orphan nuclear receptor SHP-interacting protein, regulates SHP-repressed estrogen receptor transactivation. Biochem J 2008;416:463–73.10.1042/BJ20080782Search in Google Scholar PubMed

131. Xie Y-B, Nedumaran B, Choi H-S. Molecular characterization of SMILE as a novel corepressor of nuclear receptors. Nucleic Acids Res 2009;37:4100–15.10.1093/nar/gkp333Search in Google Scholar PubMed PubMed Central

132. Lahtela JT, Arranto AJ, Sotaniemi EA. Enzyme inducers improve insulin sensitivity in non-insulin-dependent diabetic subjects. Diabetes 1985;34:911–6.10.2337/diab.34.9.911Search in Google Scholar PubMed

133. Argaud D, Halimi S, Catelloni F, Leverve XM. Inhibition of gluconeogenesis in isolated rat hepatocytes after chronic treatment with phenobarbital. Biochem J 1991;280:663–9.10.1042/bj2800663Search in Google Scholar PubMed PubMed Central

134. Gao J, He J, Zhai Y, Wada T, Xie W. The constitutive androstane receptor is an anti-obesity nuclear receptor that improves insulin sensitivity. J Biol Chem 2009;284:25984–92.10.1074/jbc.M109.016808Search in Google Scholar PubMed PubMed Central

135. Ledda-Columbano GM, Pibiri M, Loi R, Perra A, Shinozuka H, Columbano A. Early increase in cyclin D1 expression and accelerated entry of mouse hepatocytes into S phase after administration of the mitogen 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene. Am J Pathol 2000;156:91–7.10.1016/S0002-9440(10)64709-8Search in Google Scholar

136. Yun HJ, Kwon J, Seol W. Specific inhibition of transcriptional activity of the constitutive androstane receptor (CAR) by the splicing factor SF3a. Biol Chem 2008;389:1313–8.10.1515/BC.2008.149Search in Google Scholar PubMed

137. Dau PT, Sakai H, Hirano M, Ishibashi H, Tanaka Y, Kameda K, et al. 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 2013;131:116–27.10.1093/toxsci/kfs288Search in Google Scholar PubMed

138. Maglich JM, Parks DJ, Moore LB, Collins JL, Goodwin B, Billin AN, et al. Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes. J Biol Chem 2003;278:17277–83.10.1074/jbc.M300138200Search in Google Scholar PubMed

139. Abass K, Lämsä V, Reponen P, Küblbeck J, Honkakoski P, Mattila S, et al. Characterization of human cytochrome P450 induction by pesticides. Toxicology 2012;294:17–26.10.1016/j.tox.2012.01.010Search in Google Scholar PubMed

140. Huang W, Zhang J, Wei P, Schrader WT, Moore DD. Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR. Mol Endocrinol 2004;18:2402–8.10.1210/me.2004-0046Search in Google Scholar PubMed

141. Yao R, Yasuoka A, Kamei A, Kitagawa Y, Rogi T, Taieishi N, et al. Polyphenols in alcoholic beverages activating constitutive androstane receptor CAR. Biosci Biotechnol Biochem 2011;75:1635–7.10.1271/bbb.110444Search in Google Scholar PubMed

142. DeKeyser JG, Stagliano MC, Auerbach SS, Prabhu KS, Jones AD, Omiecinski CJ. Di(2-ethylhexyl)phthalate is a highly potent agonist for the human constitutive androstane receptor splice variant CAR2. Mol Pharmacol 2009;75:1005–13.10.1124/mol.108.053702Search in Google Scholar PubMed PubMed Central

143. Li L, Chen T, Stanton JD, Sueyoshi T, Negishi M, Wang H. The peripheral benzodiazepine receptor ligand 1-(2-chlorophenyl-methylpropyl)-3-isoquinoline-carboxamide is a novel antagonist of human constitutive androstane receptor. Mol Pharmacol 2008;74:443–53.10.1124/mol.108.046656Search in Google Scholar PubMed PubMed Central

144. Kawamoto T, Kakizaki S, Yoshinari K, Negishi M. Estrogen activation of the nuclear orphan receptor CAR (constitutive active receptor) in induction of the mouse Cyp2b10 gene. Mol Endocrinol 2000;14:1897–905.10.1210/mend.14.11.0547Search in Google Scholar PubMed

145. Yao R, Yasuoka A, Kamei A, Kitagawa Y, Tateishi N, Tsuruoka N, et al. Dietary flavonoids activate the constitutive androstane receptor (CAR). J Agric Food Chem 2010;58:2168–73.10.1021/jf903711qSearch in Google Scholar PubMed PubMed Central

146. Imai J, Yamazoe Y, Yoshinari K. Novel cell-based reporter assay system using epitope-tagged protein for the identification of agonistic ligands of constitutive androstane receptor (CAR). Drug Metab Pharmacokinet 2012. DOI: http://dx.doi.org/10.2133/dmpk.DMPK-12-RG-112.10.2133/dmpk.DMPK-12-RG-112Search in Google Scholar PubMed

147. Huang W, Zhang J, Chua SS, Qatanani M, Han Y, Granata R, et al. Induction of bilirubin clearance by the constitutive androstane receptor (CAR). Proc Natl Acad Sci USA 2003;100:4156–61.10.1073/pnas.0630614100Search in Google Scholar PubMed PubMed Central

148. Chen T, Tompkins LM, Li L, Li H, Kim G, Zheng Y, et al. A single amino acid controls the functional switch of human constitutive androstane receptor (CAR) 1 to the xenobiotic-sensitive splicing variant CAR3. J Pharmacol Exp Ther 2010;332:106–15.10.1124/jpet.109.159210Search in Google Scholar PubMed PubMed Central

149. Lau AJ, Yang G, Chang TK. Isoform-selective activation of human constitutive androstane receptor by Ginkgo biloba extract: functional analysis of the SV23, SV24, and SV25 splice variants. J Pharmacol Exp Ther 2011;339:704–15.10.1124/jpet.111.186130Search in Google Scholar PubMed

150. Choi E-J, Jang Y-J, Cha E-Y, Shin J-G, Lee SS. Identification and characterization of novel alternative splice variants of human constitutive androstane receptor in liver samples of Koreans and Caucasians. Drug Metab Dispos 2013;41:888–96.10.1124/dmd.112.049791Search in Google Scholar PubMed

151. Tzameli I, Chua SS, Cheskis B, Moore DD. Complex effects of rexinoids on ligand dependent activation or inhibition of the xenobiotic receptor, CAR. Nucl Receptor 2003;1:2.10.1186/1478-1336-1-2Search in Google Scholar PubMed PubMed Central

152. Chen S, Wang K, Wan Y-J. Retinoids activate RXR/CAR-mediated pathway and induce CYP3A. Biochem Pharmacol 2010;79:270–6.10.1016/j.bcp.2009.08.012Search in Google Scholar PubMed PubMed Central

153. Howe K, Sanat F, Thumser AE, Coleman T, Plant N. The statin class of HMG-CoA reductase inhibitors demonstrate differential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes. Xenobiotica 2011;41:519–29.10.3109/00498254.2011.569773Search in Google Scholar PubMed

154. Kanno Y, Inouye Y. A consecutive three alanine residue insertion mutant of human CAR: a novel CAR ligand screening system in HepG2 cells. J Toxicol Sci 2010;35:515–25.10.2131/jts.35.515Search in Google Scholar PubMed

155. Pissios P, Tzameli I, Kushner P, Moore DD. Dynamic stabilization of nuclear receptor ligand binding domains by hormone or corepressor binding. Mol Cell 2000;6:245–53.10.1016/S1097-2765(00)00026-5Search in Google Scholar

156. Burk O, Arnold KA, Nussler AK, Schaeffeler E, Efimova E, Avery BA, et al. Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol 2005;67:1954–65.10.1124/mol.104.009019Search in Google Scholar PubMed

157. Kobayashi K, Saito K, Takagi S, Chiba K. Ligand-dependent assembly of pregnane X receptor, constitutive androstane receptor and liver X receptor is applicable to identify ligands. Drug Metab Lett 2010;4:88–94.10.2174/187231210791292744Search in Google Scholar PubMed

158. Li H, Chen T, Cottrell J, Wang H. Nuclear translocation of adenoviral-enhanced yellow fluorescent protein-tagged-human constitutive androstane receptor (hCAR): a novel tool for screening hCAR activators in human primary hepatocytes. Drug Metab Dispos 2009;37:1098–106.10.1124/dmd.108.026005Search in Google Scholar PubMed PubMed Central

159. Moore LB, Parks DJ, Jones SA, Bledsoe RK, Consler TG, Stimmel JB, et al. Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J Biol Chem 2000;275:15122–7.10.1074/jbc.M001215200Search in Google Scholar PubMed