Activation of xenobiotic receptors: Driving into the nucleus

Expert Opinion on Drug Metabolism and Toxicology

Volumn 6, Issue 4, 2010, Pages 409-426

  Li, Haishan ^a   Wang, Hongbing ^a  

^a UNIVERSITY OF MARYLAND SCHOOL OF PHARMACY   (United States)

Author keywords

Activation; Aryl hydrocarbon receptor; Constitutive androstane receptor; Pregnane X receptor; Translocation; Xenobiotic receptors

Indexed keywords

ALITRETINOIN; ANDROSTANE DERIVATIVE; AROMATIC HYDROCARBON RECEPTOR; CARBAMAZEPINE; COMPLEMENTARY DNA; CONSTITUTIVE ANDROSTANE RECEPTOR; CYTOCHROME P450 2B; CYTOCHROME P450 2B6; CYTOCHROME P450 3A4; EFAVIRENZ; FURYLFURAMIDE; HEAT SHOCK PROTEIN 90; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; N SEC BUTYL 1 (2 CHLOROPHENYL) N METHYL 3 ISOQUINOLINECARBOXAMIDE; NUCLEAR RECEPTOR COACTIVATOR 2; OMEPRAZOLE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PHENYTOIN; PREGNANE X RECEPTOR; PROTEIN P160; STEROID RECEPTOR COACTIVATOR 1;

CELL ACTIVATION; CELLULAR DISTRIBUTION; GENE CONTROL; GENE DELETION; GENE EXPRESSION; GENE TARGETING; GENETIC VARIABILITY; HUMAN; LIVER CELL; NONHUMAN; PROTEIN DEPHOSPHORYLATION; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; REGULATORY MECHANISM; REVIEW; TRANSACTIVATION; XENOBIOTIC METABOLISM;

ACTIVE TRANSPORT, CELL NUCLEUS; ANIMALS; HUMANS; RECEPTORS, CYTOPLASMIC AND NUCLEAR; XENOBIOTICS;

EID: 77949911622     PISSN: 17425255     EISSN: None     Source Type: Journal    
DOI: 10.1517/17425251003598886     Document Type: Review

References (155)

1. Sonoda J, Pei L, Evans RM. Nuclear receptors: decoding metabolic disease. FEBS Lett 2008;582(1):2-9
2. Tzameli I, Moore DD. Role reversal: new insights from new ligands for the xenobiotic receptor CAR. Trends Endocrinol Metab 2001;12(1):7-10
3. Nagy L, Schwabe JW. Mechanism of the nuclear receptor molecular switch. Trends Biochem Sci 2004;29(6):317-324
4. Petrick JS, Klaassen CD. Importance of hepatic induction of constitutive androstane receptor and other transcription factors that regulate xenobiotic metabolism and transport. Drug Metab Dispos 2007;35(10):1806-1815
5. di Masi A, Marinis ED, Ascenzi P, et al. Nuclear receptors CAR and PXR: molecular, functional, and biomedical aspects. Mol Aspects Med 2009;30(5):297-343
6. Burbach KM, Poland A, Bradfield CA. Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proc Natl Acad Sci USA 1992;89(17):8185-8189
7. Ikuta T, Eguchi H, Tachibana T, et al. Nuclear localization and export signals of the human aryl hydrocarbon receptor. J Biol Chem 1998;273(5):2895- 2904
8. Kawamoto T, Sueyoshi T, Zelko I, et al. Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene. Mol Cell Biol 1999;19(9):6318-6322
9. Kawana K, Ikuta T, Kobayashi Y, et al. Molecular mechanism of nuclear translocation of an orphan nuclear receptor, SXR. Mol Pharmacol 2003;63(3):524-531
10. Li H, Chen T, Cottrell J, Wang H. Nuclear translocation of Ad/EYFP-hCAR: a novel tool for screening human CAR activators in human primary hepatocytes. Drug Metab Dispos 2009;37(5):1098-1106
11. Mohan R, Heyman RA. Orphan nuclear receptor modulators. Curr Top Med Chem 2003;3(14):1637-1647
12. Olefsky JM. Nuclear receptor minireview series. J Biol Chem 2001;276(40):36863-36864
13. Orans J, Teotico DG, Redinbo MR. The nuclear xenobiotic receptor pregnane X receptor: recent insights and new challenges. Mol Endocrinol 2005;19(12):2891-2900
14. Watkins RE, Maglich JM, Moore LB, et al. 2.1 A crystal structure of human PXR in complex with the St. John's wort compound hyperforin. Biochemistry 2003;42(6):1430-1438
15. Fischer U, Huber J, Boelens WC, et al. The HIV-1 Rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs. Cell 1995;82(3):475-483
16. Kaffman A, O'Shea EK. Regulation of nuclear localization: a key to a door. Annu Rev Cell Dev Biol 1999;15:291-339
17. Baes M, Gulick T, Choi HS, et al. 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(3):1544-1552
18. Choi HS, Chung M, Tzameli I, et al. Differential transactivation by two isoforms of the orphan nuclear hormone receptor CAR. J Biol Chem 1997;272(38):23565-23571
19. Yoshinari K, Sueyoshi T, Moore R, et al. Nuclear receptor CAR as a regulatory factor for the sexually dimorphic induction of CYB2B1 gene by phenobarbital in rat livers. Mol Pharmacol 2001;59(2):278-284
20. Honkakoski P, Zelko I, Sueyoshi T, et al. The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol Cell Biol 1998;18(10):5652-5658
21. Kanno Y, Suzuki M, Nakahama T, et al. Characterization of nuclear localization signals and cytoplasmic retention region in the nuclear receptor CAR. Biochim Biophys Acta 2005;1745(2):215-222
22. Forman BM, Tzameli I, Choi HS, et al. Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta. Nature 1998;395(6702):612-615
23. Tzameli I, Pissios P, Schuetz EG, et al. The xenobiotic compound 1,4-bis [2-(3,5-dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR. Mol Cell Biol 2000;20(9):2951-2958
24. Maglich JM, Parks DJ, Moore LB, 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(19):17277-17283
25. Wei P, Zhang J, Dowhan DH, et al. Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response. Pharmacogenomics J 2002;2(2):117-126
26. Sueyoshi T, Moore R, Pascussi JM, et al. Direct expression of fluorescent protein-tagged nuclear receptor CAR in mouse liver. Methods Enzymol 2002;357:205-213
27. Wang H, Faucette S, Moore R, et al. Human constitutive androstane receptor mediates induction of CYP2B6 gene expression by phenytoin. J Biol Chem 2004;279(28):29295-29301
28. Huang W, Zhang J, Wei P, et al. Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR. Mol Endocrinol 2004;18(10):2402-2408
29. Huang W, Zhang J, Moore DD. A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. J Clin Invest 2004;113(1):137-143
30. Burk O, Arnold KA, Nussler AK, 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(6):1954-1965
31. Kobayashi K, Yamanaka Y, Iwazaki N, et al. Identification of HMG-CoA reductase inhibitors as activators for human, mouse and rat constitutive androstane receptor. Drug Metab Dispos 2005;33(7):924-929
32. Jyrkkarinne J, Windshugel B, Makinen J, et al. Amino acids important for ligand specificity of the human constitutive androstane receptor. J Biol Chem 2005;280(7):5960-5971
33. Faucette SR, Zhang TC, Moore R, 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(1):72-80
34. Kublbeck J, Jyrkkarinne J, Poso A, et al. Discovery of substituted sulfonamides and thiazolidin-4-one derivatives as agonists of human constitutive androstane receptor. Biochem Pharmacol 2008;76(10):1288-1297
35. Wei P, Zhang J, Egan-HafleyM, et al. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature 2000;407(6806):920-923
36. Kawamoto T, Kakizaki S, Yoshinari K, et al. Estrogen activation of the nuclear orphan receptor CAR (constitutive active receptor) in induction of the mouse Cyp2b10 gene. Mol Endocrinol 2000;14(11):1897-1905
37. Zhang J, Huang W, Chua SS, et al. Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. Science 2002;298(5592):422-424
38. Makinen J, Reinisalo M, Niemi K, et al. Dual action of oestrogens on the mouse constitutive androstane receptor. Biochem J 2003;376(Pt 2):465-472
39. Huang W, Zhang J, Chua SS, et al. Induction of bilirubin clearance by the constitutive androstane receptor (CAR). Proc Natl Acad Sci USA 2003;100(7):4156-4161
40. Murray M, Fiala-Beer E, Sutton D. Upregulation of cytochromes P450 2B in rat liver by orphenadrine. Br J Pharmacol 2003;139(4):787-796
41. Jackson JP, Ferguson SS, Moore R, et al. The constitutive active/androstane receptor regulates phenytoin induction of Cyp2c29. Mol Pharmacol 2004;65(6):1397-1404
42. Pustylnyak VO, Gulyaeva LF, Lyakhovich VV. CAR expression and inducibility of CYP2B genes in liver of rats treated with PB-like inducers. Toxicology 2005;216(2-3):147-153
43. Slitt AL, Cherrington NJ, Fisher CD, et al. Induction of genes for metabolism and transport by trans-stilbene oxide in livers of Sprague-Dawley and Wistar-Kyoto rats. Drug Metab Dispos 2006;34(7):1190-1197
44. Fisher CD, Augustine LM, Maher JM, et al. 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 2007;35(6):995-1000
45. Merrell MD, Jackson JP, Augustine LM, et al. The Nrf2 activator oltipraz also activates the constitutive androstane receptor. Drug Metab Dispos 2008;36(8):1716-1721
46. Cheng X, Klaassen CD. Perfluorocarboxylic acids induce cytochrome P450 enzymes in mouse liver through activation of PPAR-alpha and CAR transcription factors. Toxicol Sci 2008;106(1):29-36
47. Moore LB, Parks DJ, Jones SA, et al. Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J Biol Chem 2000;275(20):15122-15127
48. Jyrkkarinne J, Makinen J, Gynther J, et al. Molecular determinants of steroid inhibition for the mouse constitutive androstane receptor. J Med Chem 2003;46(22):4687-4695
49. Li L, Chen T, Stanton JD, et al. 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(2):443-453
50. Marc N, Galisteo M, Lagadic-Gossmann D, et al. Regulation of phenobarbital induction of the cytochrome P450 2b9/10 genes in primary mouse hepatocyte culture. Involvement of calcium- and cAMP-dependent pathways. Eur J Biochem 2000;267(4):963-970
51. Kakizaki S, Yamamoto Y, Ueda A, et al. Phenobarbital induction of drug/ steroid-metabolizing enzymes and nuclear receptor CAR. Biochim Biophys Acta 2003;1619(3):239-242
52. Ding X, Staudinger JL. The ratio of constitutive androstane receptor to pregnane X receptor determines the activity of guggulsterone against the Cyp2b10 promoter. J Pharmacol Exp Ther 2005;314(1):120-127
53. Guo D, Sarkar J, Suino-Powell K, et al. Induction of nuclear translocation of constitutive androstane receptor by peroxisome proliferator-activated receptor alpha synthetic ligands in mouse liver. J Biol Chem 2007;282(50):36766-36776
54. Zelko I, Sueyoshi T, Kawamoto T, et al. The peptide near the C terminus regulates receptor CAR nuclear translocation induced by xenochemicals in mouse liver. Mol Cell Biol 2001;21(8):2838-2846
55. Hache RJ, Tse R, Reich T, et al. Nucleocytoplasmic trafficking of steroid-free glucocorticoid receptor. J Biol Chem 1999;274(3):1432-1439
56. Rowlands JC, Gustafsson JA. Aryl hydrocarbon receptor-mediated signal transduction. Crit Rev Toxicol 1997;27(2):109-134
57. Kazlauskas A, Sundstrom S, Poellinger L, et al. The hsp90 chaperone complex regulates intracellular localization of the dioxin receptor. Mol Cell Biol 2001;21(7):2594-2607
58. Tai PK, Albers MW, Chang H, et al. Association of a 59-kilodalton immunophilin with the glucocorticoid receptor complex. Science 1992;256(5061):1315-1318
59. Kobayashi K, Sueyoshi T, Inoue K, et al. Cytoplasmic accumulation of the nuclear receptor CAR by a tetratricopeptide repeat protein in HepG2 cells. Mol Pharmacol 2003;64(5):1069-1075
60. Sueyoshi T, Moore R, Sugatani J, et al. PPP1R16A, the membrane subunit of protein phosphatase 1beta, signals nuclear translocation of the nuclear receptor constitutive active/androstane receptor. Mol Pharmacol 2008;73(4):1113-1121
61. Yoshinari K, Kobayashi K, Moore R, et al. Identification of the nuclear receptor CAR: HSP90 complex in mouse liver and recruitment of protein phosphatase 2A in response to phenobarbital. FEBS Lett 2003;548(1-3):17-20
62. Kanno Y, Suzuki M, Miyazaki Y, et al. Difference in nucleocytoplasmic shuttling sequences of rat and human constitutive active/androstane receptor Biochim Biophys Acta 2007;1773(6):934-944
63. Koike C, Moore R, Negishi M. Localization of the nuclear receptor CAR at the cell membrane of mouse liver. FEBS Lett 2005;579(30):6733-6736
64. Min G, Kemper JK, Kemper B. Glucocorticoid receptor-interacting protein 1 mediates ligand-independent nuclear translocation and activation of constitutive androstane receptor in vivo. J Biol Chem 2002;277(29):26356-26363
65. Guo D, Sarkar J, Ahmed MR, 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(2):485-495
66. Moore LB, Maglich JM, McKee DD, et al. Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptors. Mol Endocrinol 2002;16(5):977-986
67. Ueda A, Hamadeh HK, Webb HK, et al. Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. Mol Pharmacol 2002;61(1):1-6
68. Xiong H, Yoshinari K, Brouwer KL, et al. Role of constitutive androstane receptor in the in vivo induction of Mrp3 and CYP2B1/2 by phenobarbital. Drug Metab Dispos 2002;30(8):918-923
69. Xie W, Barwick JL, Downes M, et al. Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 2000;406(6794):435-439
70. Barwick JL, Quattrochi LC, Mills AS, et al. Trans-species gene transfer for analysis of glucocorticoid-inducible transcriptional activation of transiently expressed human CYP3A4 and rabbit CYP3A6 in primary cultures of adult rat and rabbit hepatocytes. Mol Pharmacol 1996;50(1):10-16
71. Arnold KA, Eichelbaum M, Burk O. Alternative splicing affects the function and tissue-specific expression of the human constitutive androstane receptor. Nucl Recept 2004;2(1):1
72. Auerbach SS, Ramsden R, Stoner MA, et al. Alternatively spliced isoforms of the human constitutive androstane receptor. Nucleic Acids Res 2003;31(12):3194-3207
73. Lamba JK, Lamba V, Yasuda K, et al. Expression of constitutive androstane receptor splice variants in human tissues and their functional consequences. J Pharmacol Exp Ther 2004;311(2):811-821
74. Savkur RS, Wu Y, Bramlett KS, et al. Alternative splicing within the ligand binding domain of the human constitutive androstane receptor. Mol Genet Metab 2003;80(1-2):216-226
75. Jinno H, Tanaka-Kagawa T, Hanioka N, 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(3):496-502
76. DeKeyser JG, Stagliano MC, Auerbach SS, et al. Di(2-ethylhexyl) phthalate is a highly potent agonist for the human constitutive androstane receptor splice variant CAR2. Mol Pharmacol 2009;75(5):1005-1013
77. Auerbach SS, Stoner MA, Su S, et al. Retinoid X receptor-alpha-dependent transactivation by a naturally occurring structural variant of human constitutive androstane receptor (NR1I3). Mol Pharmacol 2005;68(5):1239-1253
78. Chen T, Tompkins LM, Li L, 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(1):106-115
79. Xie W, Barwick JL, Simon CM, et al. Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev 2000;14(23):3014-3023
80. Lehmann JM, McKee DD, Watson MA, et al. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 1998;102(5):1016-1023
81. Faucette SR, Sueyoshi T, Smith CM, et al. Differential regulation of hepatic CYP2B6 and CYP3A4 genes by constitutive androstane receptor but not pregnane X receptor. J Pharmacol Exp Ther 2006;317(3):1200-1209
82. Roy P, Yu LJ, Crespi CL, et al. Development of a substrate-activity based approach to identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos 1999;27(6):655-666
83. Schwartz PS, Chen CS, Waxman DJ. Sustained P450 expression and prodrug activation in bolus cyclophosphamide-treated cultured tumor cells. Impact of prodrug schedule on P450 gene-directed enzyme prodrug therapy. Cancer Gene Ther 2003;10(8):571-582
84. Xu RX, Lambert MH, Wisely BB, et al. A structural basis for constitutive activity in the human CAR/RXRalpha heterodimer. Mol Cell 2004;16(6):919-928
85. Sueyoshi T, Negishi M. Phenobarbital response elements of cytochrome P450 genes and nuclear receptors. Annu Rev Pharmacol Toxicol 2001;41:123-143
86. Kodama S, Negishi M. Phenobarbital confers its diverse effects by activating the orphan nuclear receptor car. Drug Metab Rev 2006;38(1-2):75-87
87. Hosseinpour F, Moore R, Negishi M, et al. Serine 202 regulates the nuclear translocation of constitutive active/ androstane receptor. Mol Pharmacol 2006;69(4):1095-1102
88. Rencurel F, Foretz M, Kaufmann MR, et al. Stimulation of AMP-activated protein kinase is essential for the induction of drug metabolizing enzymes by phenobarbital in human and mouse liver. Mol Pharmacol 2006;70(6):1925-1934
89. Rencurel F, Stenhouse A, Hawley SA, et al. AMP-activated protein kinase mediates phenobarbital induction of CYP2B gene expression in hepatocytes and a newly derived human hepatoma cell line. J Biol Chem 2005;280(6):4367-4373
90. Zelko I, Negishi M. Phenobarbital-elicited activation of nuclear receptor CAR in induction of cytochrome P450 genes. Biochem Biophys Res Commun 2000;277(1):1-6
91. Honkakoski P, Sueyoshi T, Negishi M. Drug-activated nuclear receptors CAR and PXR. Ann Med 2003;35(3):172-182
92. Suino K, Peng L, Reynolds R, et al. The nuclear xenobiotic receptor CAR: structural determinants of constitutive activation and heterodimerization. Mol Cell 2004;16(6):893-905
93. Swales K, Kakizaki S, Yamamoto Y, et al. Novel CAR-mediated mechanism for synergistic activation of two distinct elements within the human cytochrome P450 2B6 gene in HepG2 cells. J Biol Chem 2005;280(5):3458-3466
94. Lempiainen H, Molnar F, Macias Gonzalez M, et al. Antagonist- and inverse agonist-driven interactions of the vitamin D receptor and the constitutive androstane receptor with corepressor protein. Mol Endocrinol 2005;19(9):2258-2272
95. Toell A, Kroncke KD, Kleinert H, et al. Orphan nuclear receptor binding site in the human inducible nitric oxide synthase promoter mediates responsiveness to steroid and xenobiotic ligands. J Cell Biochem 2002;85(1):72-82
96. Simonsson US, Lindell M, Raffalli-Mathieu F, et al. In vivo and mechanistic evidence of nuclear receptor CAR induction by artemisinin. Eur J Clin Invest 2006;36(9):647-653
97. Bertilsson G, Heidrich J, Svensson K, et al. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci USA 1998;95(21):12208-12213
98. Blumberg B, Sabbagh W, Jr.Juguilon H, et al. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev 1998;12(20):3195-3205
99. Kliewer SA, Moore JT, Wade L, et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 1998;92(1):73-82
100. Chang TK, Waxman DJ. Synthetic drugs and natural products as modulators of constitutive androstane receptor (CAR) and pregnane X receptor (PXR). Drug Metab Rev 2006;38(1-2):51-73
101. Teotico DG, Bischof JJ, Peng L, et al. Structural basis of human pregnane X receptor activation by the hops constituent colupulone. Mol Pharmacol 2008;74(6):1512-1520
102. Wada T, Gao J, Xie W. PXR and CAR in energy metabolism. Trends Endocrinol Metab 2009;20(6):273-279
103. Hariparsad N, Chu X, Yabut J, et al. Identification of pregnane-X receptor target genes and coactivator and corepressor binding to promoter elements in human hepatocytes. Nucleic Acids Res 2009;37(4):1160-1173
104. Li T, Chiang JY. Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7 alpha-hydroxylase gene transcription. Am J Physiol Gastrointest Liver Physiol 2005;288(1):G74-84
105. Matic M, Nakhel S, Lehnert AM, et al. A novel approach to investigate the subcellular distribution of nuclear receptors in vivo. Nucl Recept Signal 2009;7:e004
106. Squires EJ, Sueyoshi T, Negishi M. Cytoplasmic localization of pregnane X receptor and ligand-dependent nuclear translocation in mouse liver. J Biol Chem 2004;279(47):49307-49314
107. Lichti-Kaiser K, Brobst D, Xu C, et al. A systematic analysis of predicted phosphorylation sites within the human pregnane X receptor protein. J Pharmacol Exp Ther 2009;331(1):65-76
108. Koyano S, Kurose K, Saito Y, et al. Functional characterization of four naturally occurring variants of human pregnane X receptor (PXR): one variant causes dramatic loss of both DNA binding activity and the transactivation of the CYP3A4 promoter/enhancer region. Drug Metab Dispos 2004;32(1):149-154
109. Saradhi M, Sengupta A, Mukhopadhyay G, et al. 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 2005;1746(2):85-94
110. Takeshita A, Taguchi M, Koibuchi N, et al. Putative role of the orphan nuclear receptor SXR (steroid and xenobiotic receptor) in the mechanism of CYP3A4 inhibition by xenobiotics. J Biol Chem 2002;277(36):32453-32458
111. Zhou C, Tabb MM, Sadatrafiei A, et al. Tocotrienols activate the steroid and xenobiotic receptor, SXR, and selectively regulate expression of its target genes. Drug Metab Dispos 2004;32(10):1075-1082
112. Ding X, Staudinger JL. Induction of drug metabolism by forskolin: the role of the pregnane X receptor and the protein kinase a signal transduction pathway. J Pharmacol Exp Ther 2005;312(2):849-856
113. Bhalla S, Ozalp C, Fang S, et al. Ligand-activated pregnane X receptor interferes with HNF-4 signaling by targeting a common coactivator PGC-1alpha. Functional implications in hepatic cholesterol and glucose metabolism. J Biol Chem 2004;279(43):45139-45147
114. Masuyama H, Suwaki N, Tateishi Y, et al. The pregnane X receptor regulates gene expression in a ligand- and promoter-selective fashion. Mol Endocrinol 2005;19(5):1170-1180
115. Chrencik JE, Orans J, Moore LB, et al. Structural disorder in the complex of human pregnane X receptor and the macrolide antibiotic rifampicin. Mol Endocrinol 2005;19(5):1125-1134
116. Watkins RE, Wisely GB, Moore LB, et al. The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science 2001;292(5525):2329-2333
117. Watkins RE, Noble SM, Redinbo MR. Structural insights into the promiscuity and function of the human pregnane X receptor. Curr Opin Drug Discov Devel 2002;5(1):150-158
118. Teotico DG, Frazier ML, Ding F, et al. Active nuclear receptors exhibit highly correlated AF-2 domain motions. PLoS Comput Biol 2008;4(7):e1000111
119. Kliewer SA, Goodwin B, Willson TM. The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr Rev 2002;23(5):687-702
120. Xie W, Yeuh MF, Radominska-Pandya A, et al. Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor. Proc Natl Acad Sci USA 2003;100(7):4150-4155
121. Kast HR, Goodwin B, Tarr PT, et al. 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 2002;277(4):2908-2915
122. Alnouti Y, Klaassen CD. Tissue distribution, ontogeny, and regulation of aldehyde dehydrogenase (Aldh) enzymes mRNA by prototypical microsomal enzyme inducers in mice. Toxicol Sci 2008;101(1):51-64
123. Gibson GG, Phillips A, Aouabdi S, et al. Transcriptional regulation of the human pregnane-X receptor. Drug Metab Rev 2006;38(1-2):31-49
124. Wang H, Huang H, Li H, et al. Activated pregnenolone X-receptor is a target for ketoconazole and its analogs. Clin Cancer Res 2007;13(8):2488-2495
125. Synold TW, Dussault I, Forman BM. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 2001;7(5):584-590
126. Wang H, Li H, Moore LB, et al. The phytoestrogen coumestrol is a naturally occurring antagonist of the human pregnane X receptor. Mol Endocrinol 2008;22(4):838-857
127. Zhou C, Poulton EJ, Grun F, et al. The dietary isothiocyanate sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor. Mol Pharmacol 2007;71(1):220-229
128. Biswas A, Mani S, Redinbo MR, et al. Elucidating the 'Jekyll and Hyde' nature of PXR: the case for discovering antagonists or allosteric antagonists. Pharm Res 2009;26(8):1807-1815
129. Huang H, Wang H, Sinz M, et al. Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. Oncogene 2007;26(2):258-268
130. Das BC, Madhukumar AV, Anguiano J, et al. Synthesis of novel ketoconazole derivatives as inhibitors of the human pregnane X Receptor (PXR; NR1I2; also termed SXR, PAR). Bioorg Med Chem Lett 2008;18(14):3974-3977
131. Phelan D, Winter GM, Rogers WJ, et al. Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin. Arch Biochem Biophys 1998;357(1):155-163
132. Quattrochi LC, Tukey RH. Nuclear uptake of the Ah (dioxin) receptor in response to omeprazole: transcriptional activation of the human CYP1A1 gene. Mol Pharmacol 1993;43(4):504-508
133. Ebert B, Seidel A, Lampen A. Identification of BCRP as transporter of benzo[a]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists. Carcinogenesis 2005;26(10):1754-1763
134. Erichsen TJ, Ehmer U, Kalthoff S, et al. Genetic variability of aryl hydrocarbon receptor (AhR)-mediated regulation of the human UDP glucuronosyltransferase (UGT) 1A4 gene. Toxicol Appl Pharmacol 2008;230(2):252-260
135. Fujisawa-Sehara A, Sogawa K, Yamane M, et al. Characterization of xenobiotic responsive elements upstream from the drug-metabolizing cytochrome P-450c gene: a similarity to glucocorticoid regulatory elements. Nucleic Acids Res 1987;15(10):4179-4191
136. Lankisch TO, Gillman TC, Erichsen TJ, et al. Aryl hydrocarbon receptor-mediated regulation of the human estrogen and bile acid UDP-glucuronosyltransferase 1A3 gene. Arch Toxicol 2008;82(9):573-582
137. Munzel PA, Schmohl S, Buckler F, et al. Contribution of the Ah receptor to the phenolic antioxidant-mediated expression of human and rat UDP-glucuronosyltransferase UGT1A6 in Caco-2 and rat hepatoma 5L cells. Biochem Pharmacol 2003;66(5):841-847
138. Sugatani J, Kojima H, Ueda A, et al. The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology 2001;33(5):1232-1238
139. Zhang L, Savas U, Alexander DL, et al. Characterization of the mouse Cyp1B1 gene. Identification of an enhancer region that directs aryl hydrocarbon receptor-mediated constitutive and induced expression. J Biol Chem 1998;273(9):5174-5183
140. Lees MJ, Peet DJ, Whitelaw ML. Defining the role for XAP2 in stabilization of the dioxin receptor. J Biol Chem 2003;278(38):35878-35888
141. Hankinson O. The aryl hydrocarbon receptor complex. Annu Rev Pharmacol Toxicol 1995;35:307-340
142. Sogawa K, Fujii-Kuriyama Y. Ah receptor, a novel ligand-activated transcription factor. J Biochem 1997;122(6):1075-1079
143. Ikuta T, Tachibana T, Watanabe J, et al. Nucleocytoplasmic shuttling of the aryl hydrocarbon receptor. J Biochem 2000;127(3):503-509
144. Backlund M, Johansson I, Mkrtchian S, et al. Signal transduction-mediated activation of the aryl hydrocarbon receptor in rat hepatoma H4IIE cells. J Biol Chem 1997;272(50):31755-31763
145. Lesca P, Peryt B, Larrieu G, et al. Evidence for the ligand-independent activation of the AH receptor. Biochem Biophys Res Commun 1995;209(2):474-482
146. Ikuta T, Kobayashi Y, Kawajiri K. Cell density regulates intracellular localization of aryl hydrocarbon receptor. J Biol Chem 2004;279(18):19209-19216
147. Sadek CM, Allen-Hoffmann BL. Suspension-mediated induction of Hepa 1c1c7 Cyp1a-1 expression is dependent on the Ah receptor signal transduction pathway. J Biol Chem 1994;269(50):31505-31509
148. Cho YC, Zheng W, Jefcoate CR. Disruption of cell-cell contact maximally but transiently activates AhR-mediated transcription in 10T1/2 fibroblasts. Toxicol Appl Pharmacol 2004;199(3):220-238
149. Yeager RL, Reisman SA, Aleksunes LM, et al. Introducing the "TCDD-inducible AhR-Nrf2 gene battery". Toxicol Sci 2009;111(2):238-246
150. Baba T, Mimura J, Nakamura N, et al. Intrinsic function of the aryl hydrocarbon (dioxin) receptor as a key factor in female reproduction. Mol Cell Biol 2005;25(22):10040-10051
151. Kurose K, Tohkin M, Fukuhara M. A novel positive regulatory element that enhances hamster CYP2A8 gene expression mediated by xenobiotic responsive element. Mol Pharmacol 1999;55(2):279-287
152. Yueh MF, Huang YH, Hiller A, et al. Involvement of the xenobiotic response element (XRE) in Ah receptor-mediated induction of human UDP-glucuronosyltransferase 1A1. J Biol Chem 2003;278(17):15001-15006
153. Gerbal-Chaloin S, Pichard-Garcia L, Fabre JM, et al. Role of CYP3A4 in the regulation of the aryl hydrocarbon receptor by omeprazole sulphide. Cell Signal 2006;18(5):740-750
154. Patel RD, Hollingshead BD, Omiecinski CJ, et al. Aryl-hydrocarbon receptor activation regulates constitutive androstane receptor levels in murine and human liver. Hepatology 2007;46(1):209-218
155. Klinge CM, Kaur K, Swanson HI. The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1. Arch Biochem Biophys 2000;373(1):163-174