Role of CAR and PXR in xenobiotic sensing and metabolism

Expert Opinion on Drug Metabolism and Toxicology

Volumn 8, Issue 7, 2012, Pages 803-817

  Wang, Yue Ming ^a   Ong, Su Sien ^a   Chai, Sergio C ^a   Chen, Taosheng ^a  

^a ST JUDE CHILDREN S RESEARCH HOSPITAL   (United States)

Author keywords

constitutive androstane receptor; drug drug interactions; pregnane X receptor; xenobiotic detoxification

Indexed keywords

CARBAMAZEPINE; CHOLESTEROL 7ALPHA MONOOXYGENASE; COMPLEMENTARY DNA; CONSTITUTIVE ANDROSTANE RECEPTOR; CYTOCHROME P450 2B6; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; CYTOCHROME P450 3A; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; FATTY ACID BINDING PROTEIN; GLUCURONOSYLTRANSFERASE 1A1; GLUTATHIONE TRANSFERASE A1; GLUTATHIONE TRANSFERASE M1; GLUTATHIONE TRANSFERASE M2; HYPERFORIN; MESSENGER RNA; OKADAIC ACID; ORGANIC ANION TRANSPORTER 1; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PHENOBARBITAL; PHENYTOIN; PREGNANE X RECEPTOR; RETINOID X RECEPTOR; RETINOID X RECEPTOR ALPHA; RIFAMPICIN; XENOBIOTIC AGENT;

CRYSTAL STRUCTURE; DRUG DETOXIFICATION; GENE CONTROL; GENE EXPRESSION; GENE EXPRESSION REGULATION; GENETIC CODE; HORMONE RESPONSIVE ELEMENT; HUMAN; LIGAND BINDING; LIVER TOXICITY; MORBIDITY; MORTALITY; NONHUMAN; PROMOTER REGION; PROTEIN EXPRESSION; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; REVIEW; SPECIES DIFFERENCE; XENOBIOTIC METABOLISM; ZINC FINGER MOTIF;

ANIMALS; DRUG INTERACTIONS; GENE EXPRESSION REGULATION; HUMANS; LIGANDS; METABOLIC DETOXICATION, DRUG; MODELS, ANIMAL; PROTEIN BINDING; PROTEIN PROCESSING, POST-TRANSLATIONAL; RECEPTORS, CYTOPLASMIC AND NUCLEAR; RECEPTORS, STEROID; SIGNAL TRANSDUCTION; XENOBIOTICS;

EID: 84862579001     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2012.685237     Document Type: Review

References (136)

1. Guengerich FP. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol 2001;14:611-50 (Pubitemid 32565712)
2. Nebert DW, Gonzalez FJ. P450 genes: structure, evolution, and regulation. Annu Rev Biochem 1987;56:945-93
3. Willson TM, Kliewer SA. PXR, CAR and drug metabolism. Nat Rev Drug Discov 2002;1:259-66 (Pubitemid 37361442)
4. McCarver DG, Hines RN. The ontogeny of human drug-metabolizing enzymes: phase II conjugation enzymes and regulatory mechanisms. J Pharmacol Exp Ther 2002;300:361-6 (Pubitemid 34106224)
5. Ayrton A, Morgan P. Role of transport proteins in drug discovery and development: a pharmaceutical perspective. Xenobiotica 2008;38:676-708
6. El-Sheikh AA, Masereeuw R, Russel FG. Mechanisms of renal anionic drug transport. Eur J Pharmacol 2008;585:245-55
7. Tolson AH, Wang H. Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR. Adv Drug Deliv Rev 2010;62:1238-49
8. 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;14:1544-52 (Pubitemid 24074550)
9. Kliewer SA, Moore JT, Wade L, et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 1998;92:73-82 This is the first report of the identification of PXR. (Pubitemid 28053299)
10. Ekins S, Mirny L, Schuetz EG. A ligand-based approach to understanding selectivity of nuclear hormone receptors PXR, CAR, FXR, LXRalpha, and LXRbeta. Pharm Res 2002;19:1788-800 (Pubitemid 36016024)
11. 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;278:17277-83 (Pubitemid 36799610)
12. 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;275:15122-7 (Pubitemid 30337234)
13. Tzameli I, Pissios P, Schuetz EG, Moore DD. The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene is an agonist ligand for the nuclear receptor CAR. Mol Cell Biol 2000;20:2951-8 (Pubitemid 30215008)
14. Xie W, Barwick JL, Downes M, et al. Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 2000;406:435-9 This is the first report of the humanized PXR mouse model. (Pubitemid 30625566)
15. Zhang J, Huang W, Chua SS, et al. Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. Science 2002;298:422-4 This is the first report of the humanized CAR mouse model. (Pubitemid 35176352)
16. Gong H, Singh SV, Singh SP, et al. Orphan nuclear receptor pregnane X receptor sensitizes oxidative stress responses in transgenic mice and cancerous cells. Mol Endocrinol 2006;20:279-90 (Pubitemid 43152504)
17. Ma X, Shah Y, Cheung C, et al. The Pregnane X receptor gene-humanized mouse: a model for investigating drug-drug interactions mediated by cytochromes P450 3A. Drug Metab Dispos 2007;35:194-200 (Pubitemid 46148730)
18. Scheer N, Ross J, Rode A, et al. A novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response. J Clin Invest 2008;118:3228-39
19. Cui JY, Gunewardena SS, Rockwell CE, Klaassen CD. ChIPing the cistrome of PXR in mouse liver. Nucleic Acids Res 2010;38:7943-63
20. Goodwin B, Moore LB, Stoltz CM, et al. Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor. Mol Pharmacol 2001;60:427-31 (Pubitemid 32781548)
21. Sueyoshi T, Kawamoto T, Zelko I, et al. The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene. J Biol Chem 1999;274:6043-6 (Pubitemid 29111006)
22. Ferguson SS, LeCluyse EL, Negishi M, Goldstein JA. Regulation of human CYP2C9 by the constitutive androstane receptor: discovery of a new distal binding site. Mol Pharmacol 2002;62:737-46 (Pubitemid 36329394)
23. Chen Y, Ferguson SS, Negishi M, Goldstein JA. Induction of human CYP2C9 by rifampicin, hyperforin, and phenobarbital is mediated by the pregnane X receptor. J Pharmacol Exp Ther 2004;308:495-501 (Pubitemid 38134210)
24. Chen Y, Ferguson SS, Negishi M, Goldstein JA. Identification of constitutive androstane receptor and glucocorticoid receptor binding sites in the CYP2C19 promoter. Mol Pharmacol 2003;64:316-24 (Pubitemid 36909995)
25. Gardner-Stephen D, Heydel JM, Goyal A, et al. Human PXR variants and their differential effects on the regulation of human UDP- glucuronosyltransferase gene expression. Drug Metab Dispos 2004;32:340-7 (Pubitemid 38263893)
26. Goodwin B, Hodgson E, D'Costa DJ, et al. Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor. Mol Pharmacol 2002;62:359-65 (Pubitemid 34804117)
27. 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;102:1016-23 (Pubitemid 28419246)
28. Blumberg B, Sabbagh W Jr, Juguilon H, et al. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev 1998;12:3195-205 (Pubitemid 28496264)
29. Burk O, Koch I, Raucy J, et al. The induction of cytochrome P450 3A5 (CYP3A5) in the human liver and intestine is mediated by the xenobiotic sensors pregnane X receptor (PXR) and constitutively activated receptor (CAR). J Biol Chem 2004;279:38379-85 (Pubitemid 39295987)
30. 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;317:1200-9 An improved model on asymmetrical cross-regulation by hCAR but not hPXR was proposed. (Pubitemid 43764125)
31. Xie W, Barwick JL, Simon CM, et al. Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev 2000;14:3014-23 This is the first report on cross-regulation of xenobiotic response by PXR and CAR.
32. Kakizaki S, Yamamoto Y, Ueda A, et al. Phenobarbital induction of drug/steroid-metabolizing enzymes and nuclear receptor CAR. Biochim Biophys Acta 2003;1619:239-42 (Pubitemid 36160602)
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;320:72-80 (Pubitemid 46025721)
34. Yoshinari K, Ohno H, Benoki S, Yamazoe Y. Constitutive androstane receptor transactivates the hepatic expression of mouse Dhcr24 and human DHCR24 encoding a cholesterogenic enzyme 24-dehydrocholesterol reductase. Toxicol Lett 2012;208:185-91
35. 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;33:1232-8 (Pubitemid 32378224)
36. 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;100:4150-5 (Pubitemid 36418172)
37. Younes M, Schlichting R, Siegers CP. Glutathione S-transferase activities in rat liver: effect of some factors influencing the metabolism of xenobiotics. Pharmacol Res Commun 1980;12:115-29 (Pubitemid 10130246)
38. Pickett CB, Telakowski-Hopkins CA, Ding GJ, et al. Rat liver glutathione S-transferases. Complete nucleotide sequence of a glutathione S-transferase mRNA and the regulation of the Ya, Yb, and Yc mRNAs by 3-methylcholanthrene and phenobarbital. J Biol Chem 1984;259:5182-8 (Pubitemid 14140625)
39. Nims RW, Sinclair PR, Sinclair JF, et al. Dose-response relationships for the induction of P450 2B by 1,4-bis[2-(3,5- dichloropyridyloxy)]benzene (TCPOBOP) in rat and cultured rat hepatocytes. Xenobiotica 1993;23:1411-26 (Pubitemid 24036138)
40. Maglich JM, Stoltz CM, Goodwin B, et al. 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 (Pubitemid 36329382)
41. 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
42. Burk O, Arnold KA, Geick A, et al. A role for constitutive androstane receptor in the regulation of human intestinal MDR1 expression. Biol Chem 2005;386:503-13 (Pubitemid 41447572)
43. Jigorel E, Le VM, Boursier-Neyret C, et al. Differential regulation of sinusoidal and canalicular hepatic drug transporter expression by xenobiotics activating drug-sensing receptors in primary human hepatocytes. Drug Metab Dispos 2006;34:1756-63 (Pubitemid 44427479)
44. Olinga P, Elferink MG, Draaisma AL, et al. Coordinated induction of drug transporters and phase I and II metabolism in human liver slices. Eur J Pharm Sci 2008;33:380-9
45. Chan GN, Hoque MT, Cummins CL, Bendayan R. Regulation of P-glycoprotein by orphan nuclear receptors in human brain microvessel endothelial cells. J Neurochem 2011;118:163-75
46. Geick A, Eichelbaum M, Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem 2001;276:14581-7
47. Fromm MF, Kauffmann HM, Fritz P, et al. The effect of rifampin treatment on intestinal expression of human MRP transporters. Am J Pathol 2000;157:1575-80
48. 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;277:2908-15 (Pubitemid 34953324)
49. Staudinger J, Liu Y, Madan A, et al. Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor. Drug Metab Dispos 2001;29:1467-72 (Pubitemid 33000694)
50. Shinkyo R, Guengerich FP. Cytochrome P450 7A1 cholesterol 7alphahydroxylation: individual reaction steps in the catalytic cycle and rate-limiting ferric iron reduction. J Biol Chem 2011;286:4632-43
51. 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:G74-84 (Pubitemid 39665222)
52. Hashizume T, Imaoka S, Mise M, et al. Involvement of CYP2J2 and CYP4F12 in the metabolism of ebastine in human intestinal microsomes. J Pharmacol Exp Ther 2002;300:298-304 (Pubitemid 34028540)
53. 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;37:1160-73
54. Yoshinari K, Yoda N, Toriyabe T, Yamazoe Y. Constitutive androstane receptor transcriptionally activates human CYP1A1 and CYP1A2 genes through a common regulatory element in the 5'-flanking region. Biochem Pharmacol 2010;79:261-9
55. Fang HL, Strom SC, Ellis E, et al. Positive and negative regulation of human hepatic hydroxysteroid sulfotransferase (SULT2A1) gene transcription by rifampicin: roles of hepatocyte nuclear factor 4alpha and pregnane X receptor. J Pharmacol Exp Ther 2007;323:586-98 (Pubitemid 350005130)
56. van de Kerkhof EG, de Graaf IA, Ungell AL, Groothuis GM. Induction of metabolism and transport in human intestine: validation of precision-cut slices as a tool to study induction of drug metabolism in human intestine in vitro. Drug Metab Dispos 2008;36:604-13 (Pubitemid 351397987)
57. Shelby MK, Klaassen CD. Induction of rat UDP-glucuronosyltransferases in liver and duodenum by microsomal enzyme inducers that activate various transcriptional pathways. Drug Metab Dispos 2006;34:1772-8 (Pubitemid 44427481)
58. Franke RM, Scherkenbach LA, Sparreboom A. Pharmacogenetics of the organic anion transporting polypeptide 1A2. Pharmacogenomics 2009;10:339-44
59. Meyer zu Schwabedissen HE, Tirona RG, Yip CS, et al. Interplay between the nuclear receptor pregnane X receptor and the uptake transporter organic anion transporter polypeptide 1A2 selectively enhances estrogen effects in breast cancer. Cancer Res 2008;68:9338-47
60. Veith H, Southall N, Huang R, et al. Comprehensive characterization of cytochrome P450 isozyme selectivity across chemical libraries. Nat Biotechnol 2009;27:1050-5
61. Wienkers LC, Heath TG. Predicting in vivo drug interactions from in vitro drug discovery data. Nat Rev Drug Discov 2005;4:825-33 (Pubitemid 41553963)
62. Guo GL, Moffit JS, Nicol CJ, et al. Enhanced acetaminophen toxicity by activation of the pregnane X receptor. Toxicol Sci 2004;82:374-80 (Pubitemid 39600064)
63. Wang H, Faucette S, Moore R, et al. Human constitutive androstane receptor mediates induction of CYP2B6 gene expression by phenytoin. J Biol Chem 2004;279:29295-301 (Pubitemid 38915806)
64. 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;320:72-80 (Pubitemid 46025721)
65. Haidar C, Jeha S. Drug interactions in childhood cancer. Lancet Oncol 2011;12:92-9
66. Jankovic SM, Dostic M. Choice of antiepileptic drugs for the elderly: possible drug interactions and adverse effects. Expert Opin Drug Metab Toxicol 2012;8:81-91
67. Sousa M, Pozniak A, Boffito M. Pharmacokinetics and pharmacodynamics of drug interactions involving rifampicin, rifabutin and antimalarial drugs. J Antimicrob Chemother 2008;62:872-8
68. Mai I, Bauer S, Perloff ES, et al. Hyperforin content determines the magnitude of the St John's wort-cyclosporine drug interaction. Clin Pharmacol Ther 2004;76:330-40 (Pubitemid 39313123)
69. Chen T. Overcoming drug resistance by regulating nuclear receptors. Adv Drug Deliv Rev 2010;62:1257-64
70. Zimmermann K, Wittman MD, Saulnier MG, et al. SAR of PXR transactivation in benzimidazole-based IGF-1R kinase inhibitors. Bioorg Med Chem Lett 2010;20:1744-8
71. Chen T. Nuclear receptor drug discovery. Curr Opin Chem Biol 2008;12:418-26
72. Venkatesh M, Wang H, Cayer J, et al. In vivo and in vitro characterization of a first-in-class novel azole analog that targets pregnane X receptor activation. Mol Pharmacol 2011;80:124-35
73. Synold TW, Dussault I, Forman BM. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 2001;7:584-90 (Pubitemid 32448326)
74. Huang H, Wang H, Sinz M, et al. Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. Oncogene 2007;26:258-68 (Pubitemid 46095736)
75. 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;71:220-9 (Pubitemid 46020992)
76. Healan-Greenberg C, Waring JF, Kempf DJ, et al. A human immunodeficiency virus protease inhibitor is a novel functional inhibitor of human pregnane X receptor. Drug Metab Dispos 2008;36:500-7 (Pubitemid 351397974)
77. 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;22:838-57 (Pubitemid 351482821)
78. 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;18:2402-8 (Pubitemid 39335976)
79. 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;74:443-53
80. Lau AJ, Yang G, Rajaraman G, et al. Differential effect of meclizine on the activity of human pregnane X receptor and constitutive androstane receptor. J Pharmacol Exp Ther 2011;336:816-26
81. Saradhi M, Sengupta A, Mukhopadhyay G, Tyagi RK. 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;1746:85-94
82. Moore DD, Kato S, Xie W, et al. International union of pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptor. Pharmacol Rev 2006;58:742-59 (Pubitemid 44833743)
83. Watkins RE, Davis-Searles PR, Lambert MH, Redinbo MR. Coactivator binding promotes the specific interaction between ligand and the pregnane X receptor. J Mol Biol 2003;331:815-28 (Pubitemid 36945439)
84. Xie Y, Ke S, Ouyang N, et al. Epigenetic regulation of transcriptional activity of pregnane X receptor by protein arginine methyltransferase 1. J Biol Chem 2009;284:9199-205
85. Squires EJ, Sueyoshi T, Negishi M. Cytoplasmic localization of pregnane X receptor and ligand-dependent nuclear translocation in mouse liver. J Biol Chem 2004;279:49307-14 (Pubitemid 39625817)
86. Kawana K, Ikuta T, Kobayashi Y, et al. Molecular mechanism of nuclear translocation of an orphan nuclear receptor, SXR. Mol Pharmacol 2003;63:524-31 (Pubitemid 36297321)
87. Li H, Wang H. Activation of xenobiotic receptors: driving into the nucleus. Expert Opin Drug Metab Toxicol 2010;6:409-26
88. Huang W, Zhang J, Chua SS, et al. Induction of bilirubin clearance by the constitutive androstane receptor (CAR). Proc Natl Acad Sci USA 2003;100:4156-61 (Pubitemid 36418173)
89. 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;21:2838-46 (Pubitemid 32244927)
90. di Masi A, De Marinis E, Ascenzi P, Marino M. Nuclear receptors CAR and PXR: molecular, functional, and biomedical aspects. Mol Aspects Med 2009;30:297-343
91. 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;64:1069-75 (Pubitemid 37310739)
92. 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;73:1113-21 (Pubitemid 351439193)
93. Pondugula SR, Dong H, Chen T. Phosphorylation and protein-protein interactions in PXR-mediated CYP3A repression. Expert Opin Drug Metab Toxicol 2009;5:861-73
94. 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;312:849-56 (Pubitemid 40189588)
95. Lichti-Kaiser K, Xu C, Staudinger JL. Cyclic AMP-dependent protein kinase signaling modulates pregnane x receptor activity in a species-specific manner. J Biol Chem 2009;284:6639-49
96. Lichti-Kaiser K, Brobst D, Xu C, Staudinger JL. A systematic analysis of predicted phosphorylation sites within the human pregnane X receptor protein. J Pharmacol Exp Ther 2009;331:65-76 This paper describes a systematic analysis of putative PXR phosphorylation sites (serine or threonine).
97. Pondugula SR, Brimer-Cline C, Wu J, et al. A phosphomimetic mutation at threonine-57 abolishes transactivation activity and alters nuclear localization pattern of human pregnane x receptor. Drug Metab Dispos 2009;37:719-30
98. Dong H, Lin W, Wu J, Chen T. Flavonoids activate pregnane x receptor-mediated CYP3A4 gene expression by inhibiting cyclin-dependent kinases in HepG2 liver carcinoma cells. BMC Biochem 2010;11:23
99. Lin W, Wu J, Dong H, et al. Cyclin-dependent kinase 2 negatively regulates human pregnane X receptor-mediated CYP3A4 gene expression in HepG2 liver carcinoma cells. J Biol Chem 2008;283:30650-7
100. Masuyama H, Inoshita H, Hiramatsu Y, Kudo T. Ligands have various potential effects on the degradation of pregnane X receptor by proteasome. Endocrinology 2002;143:55-61 (Pubitemid 34056403)
101. 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;19:1170-80 (Pubitemid 40594117)
102. Staudinger JL, Xu C, Biswas A, Mani S. Post-translational modification of pregnane x receptor. Pharmacol Res 2011;64:4-10 First report of the regulation of PXR stability through ubiquitination.
103. Lonard DM, O'Malley BW. Chapter 4 emerging roles of the ubiquitin proteasome system in nuclear hormone receptor signaling. Prog Mol Biol Transl Sci 2009;87:117-35
104. Biswas A, Pasquel D, Tyagi RK, Mani S. Acetylation of pregnane X receptor protein determines selective function independent of ligand activation. Biochem Biophys Res Commun 2011;406:371-6
105. 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
106. 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;548:17-20 (Pubitemid 37281243)
107. Joannard F, Rissel M, Gilot D, et al. Role for mitogen-activated protein kinases in phenobarbital-induced expression of cytochrome P450 2B in primary cultures of rat hepatocytes. Toxicol Lett 2006;161:61-72 (Pubitemid 41770877)
108. 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;70:1925-34 (Pubitemid 44771908)
109. Ingraham HA, Redinbo MR. Orphan nuclear receptors adopted by crystallography. Curr Opin Struct Biol 2005;15:708-15 (Pubitemid 41668528)
110. Nwachukwu JC, Nettles KW. The nuclear receptor signalling scaffold: insights from full-length structures. EMBO J 2012;31:251-3
111. Watkins RE, Wisely GB, Moore LB, et al. The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science 2001;292:2329-33 First reported crystal structure of the PXR LBD. (Pubitemid 32568055)
112. Suino K, Peng L, Reynolds R, et al. The nuclear xenobiotic receptor CAR: structural determinants of constitutive activation and heterodimerization. Mol Cell 2004;16:893-905 One of the first to report the crystal structure of the CAR LBD. (Pubitemid 40018400)
113. Xu RX, Lambert MH, Wisely BB, et al. A structural basis for constitutive activity in the human CAR/RXRalpha heterodimer. Mol Cell 2004;16:919-28 One of the first to report the crystal structure of the CAR LBD. (Pubitemid 40018402)
114. Shan L, Vincent J, Brunzelle JS, et al. Structure of the murine constitutive androstane receptor complexed to androstenol: a molecular basis for inverse agonism. Mol Cell 2004;16:907-17 One of the first to report the crystal structure of the CAR LBD. (Pubitemid 40018401)
115. Watkins RE, Davis-Searles PR, Lambert MH, Redinbo MR. Coactivator binding promotes the specific interaction between ligand and the pregnane X receptor. J Mol Biol 2003;331:815-28 (Pubitemid 36945439)
116. Windshugel B, Jyrkkarinne J, Vanamo J, et al. Comparison of homology models and X-ray structures of the nuclear receptor CAR: assessing the structural basis of constitutive activity. J Mol Graph Model 2007;25:644-57 (Pubitemid 46178553)
117. Moore DD. CAR: three new models for a problem child. Cell Metab 2005;1:6-8 (Pubitemid 43960590)
118. Gampe RT Jr, Montana VG, Lambert MH, et al. Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol Cell 2000;5:545-55
119. Noble SM, Carnahan VE, Moore LB, et al. Human PXR forms a tryptophan zipper-mediated homodimer. Biochemistry 2006;45:8579-89 (Pubitemid 44078878)
120. Calgaro MR, Neto Mde O, Figueira AC, et al. Orphan nuclear receptor NGFI-B forms dimers with nonclassical interface. Protein Sci 2007;16:1762-72 (Pubitemid 47195702)
121. Staudinger JL, Xu C, Cui YJ, Klaassen CD. Nuclear receptor-mediated regulation of carboxylesterase expression and activity. Expert Opin Drug Metab Toxicol 2010;6:261-71
122. Liu MJ, Takahashi Y, Wada T, et al. The aldo-keto reductase Akr1b7 gene is a common transcriptional target of xenobiotic receptors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol 2009;76:604-11
123. Shukla SJ, Sakamuru S, Huang R, et al. Identification of clinically used drugs that activate pregnane X receptors. Drug Metab Dispos 2011;39:151-9
124. 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
125. Ihunnah CA, Jiang M, Xie W. Nuclear receptor PXR, transcriptional circuits and metabolic relevance. Biochim Biophys Acta 2011;1812:956-63 A comprehensive review on PXR's functions focusing on endobiotic metabolism.
126. Ma X, Idle JR, Gonzalez FJ. The pregnane X receptor: from bench to bedside. Expert Opin Drug Metab Toxicol 2008;4:895-908 A comprehensive review on PXR's roles in human diseases.
127. Tirona RG, Lee W, Leake BF, et al. The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nat Med 2003;9:220-4 (Pubitemid 36227725)
128. Shi D, Yang D, Yan B. Dexamethasone transcriptionally increases the expression of the pregnane X receptor and synergistically enhances pyrethroid esfenvalerate in the induction of cytochrome P450 3A23. Biochem Pharmacol 2010;80:1274-83
129. Jung D, Mangelsdorf DJ, Meyer UA. Pregnane X receptor is a target of farnesoid X receptor. J Biol Chem 2006;281:19081-91 (Pubitemid 44035412)
130. Misawa A, Inoue J, Sugino Y, et al. Methylation-associated silencing of the nuclear receptor 1I2 gene in advanced-type neuroblastomas, identified by bacterial artificial chromosome array-based methylated CpG island amplification. Cancer Res 2005;65:10233-42 (Pubitemid 41743715)
131. Habano W, Gamo T, Terashima J, et al. Involvement of promoter methylation in the regulation of Pregnane X receptor in colon cancer cells. BMC Cancer 2011;11:81
132. Takagi S, Nakajima M, Mohri T, Yokoi T. Post-transcriptional regulation of human pregnane X receptor by micro-RNA affects the expression of cytochrome P450 3A4. J Biol Chem 2008;283:9674-80
133. Jyrkkarinne J, Windshugel B, Ronkko T, 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
134. Chandra V, Huang P, Hamuro Y, et al. Structure of the intact PPAR-gamma- RXR- nuclear receptor complex on DNA. Nature 2008;456:350-6
135. Orlov I, Rochel N, Moras D, Klaholz BP. Structure of the full human RXR/VDR nuclear receptor heterodimer complex with its DR3 target DNA. EMBO J 2011;31:291-300
136. Zhang J, Chalmers MJ, Stayrook KR, et al. DNA binding alters coactivator interaction surfaces of the intact VDR-RXR complex. Nat Struct Mol Biol 2011;18:556-63