Regulation of gene expression by CAR: an update

Archives of Toxicology

Volumn 89, Issue 7, 2015, Pages 1045-1055

  Kobayashi, Kaoru ^a   Hashimoto, Mari ^a   Honkakoski, Paavo ^b,c   Negishi, Masahiko ^b  

^a CHIBA UNIVERSITY   (Japan)

^b NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES   (United States)

^c UNIVERSITY OF EASTERN FINLAND   (Finland)

Author keywords

Constitutive androstane receptor; Cytochrome P450; Drug metabolism; Epidermal growth factor receptor; Glucose metabolism; Liver injury

Indexed keywords

1,4 BIS(3,5 DICHLORO 2 PYRIDYLOXY)BENZENE; AMIODARONE; ARTEMISININ; CARVEDILOL; CERIVASTATIN; CHLORPHENOTANE; CHOLESTEROL; COMPACTIN; CONSTITUTIVE ANDROSTANE RECEPTOR; DIETHYLSTILBESTROL; DRUG METABOLIZING ENZYME; EPIDERMAL GROWTH FACTOR RECEPTOR; FLUINDOSTATIN; METHOXYCHLOR; MEVINOLIN; NEFAZODONE; NICARDIPINE; OKADAIC ACID; PARACETAMOL; PERMETHRIN; PHENOBARBITAL; PHENYTOIN; PHTHALIC ACID BIS(2 ETHYLHEXYL) ESTER; SCOPARONE; SIMVASTATIN; TELMISARTAN; TOLNAFTATE; XENOBIOTIC AGENT; CELL RECEPTOR; GLUCOSE;

CYTOPLASM; GENE EXPRESSION; GLUCOSE METABOLISM; HOMEOSTASIS; HUMAN; LIVER CELL CARCINOMA; LIVER INJURY; NONHUMAN; PRIORITY JOURNAL; REGULATORY MECHANISM; REVIEW; TRANSCRIPTION REGULATION; ACTIVE TRANSPORT; AGONISTS; ANIMAL; BIOTRANSFORMATION; CHEMICALLY INDUCED; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENETIC TRANSCRIPTION; LIVER; LIVER TUMOR; METABOLISM; PATHOLOGY; SIGNAL TRANSDUCTION;

ACTIVE TRANSPORT, CELL NUCLEUS; ANIMALS; BIOTRANSFORMATION; CARCINOMA, HEPATOCELLULAR; CHOLESTEROL; GENE EXPRESSION REGULATION; GLUCOSE; HUMANS; LIVER; LIVER NEOPLASMS; PHENOBARBITAL; RECEPTOR CROSS-TALK; RECEPTOR, EPIDERMAL GROWTH FACTOR; RECEPTORS, CYTOPLASMIC AND NUCLEAR; SIGNAL TRANSDUCTION; TRANSCRIPTION, GENETIC; XENOBIOTICS;

EID: 84930928488     PISSN: 03405761     EISSN: 14320738     Source Type: Journal    
DOI: 10.1007/s00204-015-1522-9     Document Type: Review

References (103)

1. Aleksunes LM, Klaassen CD (2012) Coordinated regulation of hepatic phase I and II drug-metabolizing genes and transporters using AhR-, CAR-, PXR-, PPARα-, and Nrf2-null mice. Drug Metab Dispos 40:1366–1379
2. Bae Y, Kemper JK, Kemper B (2004) Repression of CAR-mediated transactivation of CYP2B genes by the orphan nuclear receptor, short heterodimer partner (SHP). DNA Cell Biol 23:81–91
3. 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 14:1544–1552
4. Benet M, Lahoz A, Guzman C, Castell JV, Jover R (2010) CCAAT/enhancer-binding protein α (C/EBPα) and hepatocyte nuclear factor 4α (HNF4α) synergistically cooperate with constitutive androstane receptor to transactivate the human cytochrome P450 2B6 (CYP2B6) gene. J Biol Chem 285:28457–28471
5. Braeuning A, Gavrilov A, Brown S, Wolf CR, Henderson CJ, Schwarz M (2014) Phenobarbital-mediated tumor promotion in transgenic mice with humanized CAR and PXR. Toxicol Sci 140:259–270
6. Burk O, Arnold KA, Nussler AK, Schaeffeler E, Efimova E, Avery BA, Avery MA, Fromm MF, Eichelbaum M (2005a) Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol 67:1954–1965
7. Burk O, Arnold KA, Geick A, Tegude H, Eichelbaum M (2005b) A role for constitutive androstane receptor in the regulation of human intestinal MDR1 expression. Biol Chem 386:503–513
8. Chen Y, Ferguson SS, Negishi M, Goldstein JA (2003) Identification of constitutive androstane receptor and glucocorticoid receptor binding sites in the CYP2C19 promoter. Mol Pharmacol 64:316–324
9. Chen X, Zhang J, Baker SM, Chen G (2007) Human constitutive androstane receptor mediated methotrexate induction of human dehydroepiandrosterone sulfotransferase (hSULT2A1). Toxicology 231:224–233
10. Chen X, Meng Z, Wang X, Zeng S, Huang W (2011) The nuclear receptor CAR modulates alcohol-induced liver injury. Lab Invest 91:1136–1145
11. Chen T, Chen Q, Xu Y, Zhou Q, Zhu J, Zhang H, Wu Q, Xu J, Yu C (2012) SRC-3 is required for CAR-regulated hepatocyte proliferation and drug metabolism. J Hepatol 56:210–217
12. Cheung C, Yu AM, Ward JM, Krausz KW, Akiyama TE, Feigenbaum L, Gonzalez FJ (2005) The CYP2E1-humanized transgenic mouse: role of CYP2E1 in acetaminophen hepatotoxicity. Drug Metab Dispos 33:449–457
13. 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 272:23565–23571
14. Clemmesen J, Hjalgrim-Jensen S (1978) Is phenobarbital carcinogenic? A follow-up of 8078 epileptics. Ecotoxicol Environ Saf 1:457–470
15. Conney AH, Davison C, Gastel R, Burns JJ (1960) Adaptive increases in drug-metabolizing enzymes induced by phenobarbital and other drugs. J Pharmacol Exp Ther 130:1–8
16. 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 75:1005–1013
17. 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 proliferator-activated receptor gamma coactivator-1alpha. J Biol Chem 281:26540–26551
18. Diwan BA, Lubet RA, Ward JM, Hrabie JA, Rice JM (1992) Tumor-promoting and hepatocarcinogenic effects of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in DBA/2NCr and C57BL/6NCr mice and an apparent promoting effect on nasal cavity tumors but not on hepatocellular tumors in F344/NCr rats initiated with N-nitrosodiethylamine. Carcinogenesis 13:1893–1901
19. Dong B, Lee JS, Park YY, Yang F, Xu G, Huang W, Finegold MJ, Moore DD (2015) Activating CAR and β-catenin induces uncontrolled liver growth and tumorigenesis. Nat Commun 6:5944
20. Dussault I, Lin M, Hollister K, Fan M, Termini J, Sherman MA, Forman BM (2002) A structural model of the constitutive androstane receptor defines novel interactions that mediate ligand-independent activity. Mol Cell Biol 22:5270–5280
21. Ferguson SS, LeCluyse EL, Negishi M, Goldstein JA (2002) Regulation of human CYP2C9 by the constitutive androstane receptor: discovery of a new distal binding site. Mol Pharmacol 62:737–746
22. Ferguson SS, Chen Y, LeCluyse 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 4alpha. Mol Pharmacol 68:747–757
23. 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 395:612–615
24. Goerdt C, Keith M, Rubins HB (1995) Effects of phenytoin on plasma high-density lipoprotein cholesterol levels in men with low levels of high-density lipoprotein cholesterol. J Clin Pharmacol 35:767–775
25. 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 62:359–365
26. Harada N, Miyoshi H, Murai N, Oshima H, Tamai Y, Oshima M, Taketo MM (2002) Lack of tumorigenesis in the mouse liver after adenovirus-mediated expression of a dominant stable mutant of beta-catenin. Cancer Res 62:1971–1977
27. Honkakoski P, Negishi M (1998) Protein serine/threonine phosphatase inhibitors suppress phenobarbital-induced Cyp2b10 gene transcription in mouse primary hepatocytes. Biochem J 330:889–895
28. Honkakoski P, Zelko I, Sueyoshi T, Negishi M (1998a) The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol Cell Biol 18:5652–5658
29. Honkakoski P, Moore R, Washburn KA, Negishi M (1998b) Activation by diverse xenochemicals of the 51-base pair phenobarbital-responsive enhancer module in the CYP2B10 gene. Mol Pharmacol 53:597–601
30. Hosseinpour F, Moore R, Negishi M, Sueyoshi T (2006) Serine 202 regulates the nuclear translocation of constitutive active/androstane receptor. Mol Pharmacol 69:1095–1102
31. Huang W, Zhang J, Moore DD (2004) A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. J Clin Invest 113:137–143
32. 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
33. Imai J, Yamazoe Y, Yoshinari K (2013) Novel cell-based reporter assay system using epitope-tagged protein for the identification of agonistic ligands of constitutive androstane receptor (CAR). Drug Metab Pharmacokinet 28:290–298
34. Inoue K, Negishi M (2008) Nuclear receptor CAR requires early growth response 1 to activate the human cytochrome P450 2B6 gene. J Biol Chem 283:10425–10432
35. Inoue K, Negishi M (2009) Early growth response 1 loops the CYP2B6 promoter for synergistic activation by the distal and proximal nuclear receptors CAR and HNF4α. FEBS Lett 583:2126–2130
36. Jitrapakdee S (2012) Transcription factors and coactivators controlling nutrient and hormonal regulation of hepatic gluconeogenesis. Int J Biochem Cell Biol 44:33–45
37. 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 277:2908–2915
38. 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 19:6318–6322
39. Kiyosawa N, Tanaka K, Hirao J, Ito K, Niino N, Sakuma K, Kanbori M, Yamoto T, Manabe S, Matsunuma N (2004) Molecular mechanism investigation of phenobarbital-induced serum cholesterol elevation in rat livers by microarray analysis. Arch Toxicol 78:435–442
40. Kobayashi K, Sueyoshi T, Inoue K, Moore R, Negishi M (2003) Cytoplasmic accumulation of the nuclear receptor CAR by a tetratricopeptide repeat protein in HepG2 cells. Mol Pharmacol 64:1069–1075
41. Kobayashi K, Yamanaka Y, Iwazaki N, Nakajo I, Hosokawa M, Negishi M, Chiba K (2005) Identification of HMG-CoA reductase inhibitors as activators for human, mouse and rat constitutive androstane receptor. Drug Metab Dispos 33:924–929
42. Kodama S, Koike C, Negishi M, Yamamoto Y (2004) Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Mol Cell Biol 24:7931–7940
43. Koike C, Moore R, Negishi M (2005) Localization of the nuclear receptor CAR at the cell membrane of mouse liver. FEBS Lett 579:6733–6736
44. Koike C, Moore R, Negishi M (2007) 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 71:1217–1221
45. Korhonen T, Uusitupa M, Voutilainen E, Sarlund H, Laakso M, Laitinen M, Silvasti M, Pyörälä K (1987) Lack of effect of hepatic enzyme induction on metabolic control in patients with type 2 (non-insulin-dependent) diabetes. Clin Pharmacol Ther 41:633–638
46. Küblbeck J, Laitinen T, Jyrkkärinne J, Rousu T, Tolonen A, Abel T, Kortelainen T, Uusitalo J, Korjamo T, Honkakoski P, Molnár F (2011) Use of comprehensive screening methods to detect selective human CAR activators. Biochem Pharmacol 82:1994–2007
47. Lamminpää A, Pukkala E, Teppo L, Neuvonen PJ (2002) Cancer incidence among patients using antiepileptic drugs: a long-term follow-up of 28,000 patients. Eur J Clin Pharmacol 58:137–141
48. Laurenzana EM, Chen T, Kannuswamy M, Sell BE, Strom SC, Li Y, Omiecinski CJ (2012) The orphan nuclear receptor DAX-1 functions as a potent corepressor of the constitutive androstane receptor (NR1I3). Mol Pharmacol 82:918–928
49. Lee SS, Buters JT, Pineau T, Fernandez-Salguero P, Gonzalez FJ (1996) Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Biol Chem 271:12063–12067
50. Lempiäinen H, Molnár F, Macias Gonzalez M, Peräkylä 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 19:2258–2272
51. Liu MJ, Takahashi Y, Wada T, He J, Gao J, Tian Y, Li S, Xie W (2009) The aldo-keto reductase Akr1b7 gene is a common transcriptional target of xenobiotic receptors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol 76:604–611
52. Lynch C, Pan Y, Li L, Ferguson SS, Xia M, Swaan PW, Wang H (2013) Identification of novel activators of constitutive androstane receptor from FDA-approved drugs by integrated computational and biological approaches. Pharm Res 30:489–501
53. Maglich JM, Stoltz CM, Goodwin B, Hawkins-Brown D, Moore JT, Kliewer SA (2002) Nuclear pregnane X receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol Pharmacol 62:638–646
54. 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 278:17277–17283
55. 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 279:19832–19838
56. Mäkinen J, Frank C, Jyrkkärinne J, Gynther J, Carlberg C, Honkakoski P (2002) Modulation of mouse and human phenobarbital-responsive enhancer module by nuclear receptors. Mol Pharmacol 62:366–378
57. Masson D, Qatanani M, Sberna AL, Xiao R, Pais de Barros JP, 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 49:1682–1691
58. 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 281:14537–14546
59. Miller M, Burgan RG, Osterlund L, Segrest JP, Garber DW (1995) A prospective, randomized trial of phenytoin in nonepileptic subjects with reduced HDL cholesterol. Arterioscler Thromb Vasc Biol 15:2151–2156
60. Min G, Kemper JK, Kemper B (2002) Glucocorticoid receptor-interacting protein 1 mediates ligand-independent nuclear translocation and activation of constitutive androstane receptor in vivo. J Biol Chem 277:26356–26363
61. Moennikes O, Buchmann A, Romualdi A, Ott T, Werringloer J, Willecke K, Schwarz M (2000) Lack of phenobarbital-mediated promotion of hepatocarcinogenesis in connexin32-null mice. Cancer Res 60:5087–5091
62. Muangmoonchai R, Smirlis D, Wong SC, Edwards M, Phillips IR, Shephard EA (2001) Xenobiotic induction of cytochrome P450 2B1 (CYP2B1) is mediated by the orphan nuclear receptor constitutive androstane receptor (CAR) and requires steroid co-activator 1 (SRC-1) and the transcription factor Sp1. Biochem J 355:71–78
63. Mutoh S, Osabe M, Inoue K, Moore R, Pedersen L, Perera L, Rebolloso Y, Sueyoshi T, Negishi M (2009) Dephosphorylation of threonine 38 is required for nuclear translocation and activation of human xenobiotic receptor CAR (NR1I3). J Biol Chem 284:34785–34792
64. 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(274):ra31
65. Ohno M, Kanayama T, Moore R, Ray M, Negishi M (2014) The roles of co-chaperone CCRP/DNAJC7 in Cyp2b10 gene activation and steatosis development in mouse livers. PLoS ONE 9:e115663
66. Osabe M, Negishi M (2011) 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 286:35763–35769
67. Papa S, Zazzeroni F, Bubici C, Jayawardena S, Alvarez K, Matuda S, Nguyen DU, Pham CG, Nelsbach AH, Melis T et al (2004) Gadd45 beta mediates the NF-kappa B suppression of JNK signaling by targeting MEK7/JNKK2. Nat Cell Biol 6:146–153
68. Pellinen P, Honkakoski P, Stenbäck F, Niemitz M, Alhava E, Pelkonen O, Lang MA, Pasanen M (1994) Cocaine N-demethylation and the metabolism-related hepatotoxicity can be prevented by cytochrome P450 3A inhibitors. Eur J Pharmacol 270:35–43
69. Pellinen P, Stenbäck F, Kojo A, Honkakoski P, Gelboin HV, Pasanen M (1996) Regenerative changes in hepatic morphology and enhanced expression of CYP2B10 and CYP3A during daily administration of cocaine. Hepatology 23:515–523
70. Rezen T, Tamasi V, Lövgren-Sandblom A, Björkhem I, Meyer UA, Rozman D (2009) Effect of CAR activation on selected metabolic pathways in normal and hyperlipidemic mouse livers. BMC Genom 10:384
71. Rhee J, Inoue Y, Yoon JC, Puigserver P, Fan M, Gonzalez FJ, Spiegelman BM (2003) Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis. Proc Natl Acad Sci USA 100:4012–4017
72. Rignall B, Braeuning A, Buchmann A, Schwarz M (2011) Tumor formation in liver of conditional β-catenin-deficient mice exposed to a diethylnitrosamine/phenobarbital tumor promotion regimen. Carcinogenesis 32:52–57
73. Saito K, Moore R, Negishi M (2013) p38 mitogen-activated protein kinase regulates nuclear receptor CAR that activates the CYP2B6 gene. Drug Metab Dispos 41:1170–1173
74. 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 55:154–161
75. 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 31:2232–2239
76. 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 278:11344–11350
77. Sidhu JS, Omiecinski CJ (1999) Insulin-mediated modulation of cytochrome P450 gene induction profiles in primary rat hepatocyte cultures. J Biochem Mol Toxicol 13:1–9
78. Slosky LM, Thompson BJ, Sanchez-Covarrubias L, Zhang Y, Laracuente ML, Vanderah TW, Ronaldson PT, Davis TP (2013) Acetaminophen modulates P-glycoprotein functional expression at the blood-brain barrier by a constitutive androstane receptor-dependent mechanism. Mol Pharmacol 84:774–786
79. Sueyoshi T, Negishi M (2001) Phenobarbital response elements of cytochrome P450 genes and nuclear receptors. Annu Rev Pharmacol Toxicol 41:123–143
80. 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 274:6043–6046
81. Sueyoshi T, Moore R, Sugatani J, Matsumura Y, Negishi M (2008) PPP1R16A, the membrane subunit of protein phosphatase 1beta, signals nuclear translocation of the nuclear receptor constitutive active/androstane receptor. Mol Pharmacol 73:1113–1121
82. Sugatani J, Nishitani S, Yamakawa K, Yoshinari K, Sueyoshi T, Negishi M, Miwa M (2005) Transcriptional regulation of human UGT1A1 gene expression: activated glucocorticoid receptor enhances constitutive androstane receptor/pregnane X receptor-mediated UDP-glucuronosyltransferase 1A1 regulation with glucocorticoid receptor-interacting protein 1. Mol Pharmacol 67:845–855
83. Swales K, Kakizaki S, Yamamoto Y, Inoue K, Kobayashi K, Negishi M (2005) Novel CAR-mediated mechanism for synergistic activation of two distinct elements within the human cytochrome P450 2B6 gene in HepG2 cells. J Biol Chem 280:3458–3466
84. Timsit YE, Negishi M (2014) Coordinated regulation of nuclear receptor CAR by CCRP/DNAJC7, HSP70 and the ubiquitin-proteasome system. PLoS ONE 9:e96092
85. Tojima H, Kakizaki S, Yamazaki Y, Takizawa D, Horiguchi N, Sato K, Mori M (2012) Ligand dependent hepatic gene expression profiles of nuclear receptors CAR and PXR. Toxicol Lett 212:288–297
86. Tsuda H, Asamoto M, Baba H, Iwahori Y, Matsumoto K, Iwase T, Nishida Y, Nagao S, Hakoi K, Yamaguchi S, Ozaki K, Yamasaki H (1995) Cell proliferation and advancement of hepatocarcinogenesis in the rat are associated with a decrease in connexin 32 expression. Carcinogenesis 16:101–105
87. 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 20:2951–2958
88. Ueda A, Hamadeh HK, Webb HK, Yamamoto Y, Sueyoshi T, Afshari CA, Lehmann JM, Negishi M (2002) Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. Mol Pharmacol 61:1–6
89. 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 279:29295–29301
90. Wei P, Zhang J, Egan-Hafley M, Liang S, Moore DD (2000) The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature 407:920–923
91. Xu C, Wang X, Staudinger JL (2009) Regulation of tissue-specific carboxylesterase expression by pregnane X receptor and constitutive androstane receptor. Drug Metab Dispos 37:1539–1547
92. Yamamoto Y, Negishi M (2008) The antiapoptotic factor growth arrest and DNA-damage-inducible 45 beta regulates the nuclear receptor constitutive active/androstane receptor-mediated transcription. Drug Metab Dispos 36:1189–1193
93. Yamamoto Y, Kawamoto T, Negishi M (2003) The role of the nuclear receptor CAR as a coordinate regulator of hepatic gene expression in defense against chemical toxicity. Arch Biochem Biophys 409:207–211
94. 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 64:7197–7200
95. Yamamoto Y, Moore R, Flavell RA, Lu B, Negishi M (2010) Nuclear receptor CAR represses TNFalpha-induced cell death by interacting with the anti-apoptotic GADD45B. PLoS ONE 5:e10121
96. Yamazaki Y, Moore R, Negishi M (2011) Nuclear receptor CAR (NR1I3) is essential for DDC-induced liver injury and oval cell proliferation in mouse liver. Lab Invest 91:1624–1633
97. Yang H, Garzel B, Heyward S, Moeller T, Shapiro P, Wang H (2013) Metformin represses drug-induced expression of CYP2B6 by modulating the constitutive androstane receptor signaling. Mol Pharmacol 85:249–260
98. Yoshida Y, Kimura N, Oda H, Kakinuma A (1996) Insulin suppresses the induction of CYP2B1 and CYP2B2 gene expression by phenobarbital in adult rat cultured hepatocytes. Biochem Biophys Res Commun. 229:182–188
99. 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
100. 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 79:261–269
101. Yoshinari K, Ohno H, Benoki S, Yamazoe Y (2012) Constitutive androstane receptor transactivates the hepatic expression of mouse Dhcr24 and human DHCR24 encoding a cholesterogenic enzyme 24-dehydrocholesterol reductase. Toxicol Lett 208:185–191
102. 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 21:2838–2846
103. Zhang J, Huang W, Chua SS, Wei P, Moore DD (2002) Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. Science 298:422–424