PXR: A xenobiotic receptor of diverse function implicated in pharmacogenetics

Pharmacogenomics

Volumn 9, Issue 11, 2008, Pages 1695-1709

  Zhang, Bin ^a   Xie, Wen ^a   Krasowski, Matthew D ^a  

^a UNIVERSITY OF PITTSBURGH   (United States)

Author keywords

drug metabolism; genetic variants; pharmacogenetics; pregnane X receptor; splice variants

Indexed keywords

16ALPHA CYANOPREGNENOLONE; ALPHA TOCOPHEROL; CLOTRIMAZOLE; CYCLOPHOSPHAMIDE; CYCLOSPORIN A; CYPROTERONE ACETATE; DEXAMETHASONE; DOCETAXEL; FARNOQUINONE; FLAME RETARDANT; GLUTETHIMIDE; GUGGULSTERONE; HYPERICUM PERFORATUM EXTRACT; INDINAVIR; KAVA; MIFEPRISTONE; NIFEDIPINE; ORAL CONTRACEPTIVE AGENT; ORGANOCHLORINE PESTICIDE; PACLITAXEL; PHENOBARBITAL; POLYBROMINATED DIPHENYL ETHER; PREGNANE X RECEPTOR; RIFAMPICIN; RITONAVIR; SPIRONOLACTONE; TAMOXIFEN; TROGLITAZONE; UNINDEXED DRUG; WARFARIN; RETINOID X RECEPTOR; XENOBIOTIC AGENT;

BONE METABOLISM; CANCER RESISTANCE; CHOLESTASIS; COLITIS; DEPRESSION; DIET SUPPLEMENTATION; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG COMPETITION; DRUG EXCRETION; DRUG METABOLISM; ENTERITIS; GENE STRUCTURE; GENETIC ASSOCIATION; GENETIC POLYMORPHISM; GENETIC VARIABILITY; HUMAN; LIPID METABOLISM; NONHUMAN; PHARMACOGENETICS; POLLUTANT; PRIMARY SCLEROSING CHOLANGITIS; PROMOTER REGION; REVIEW; STEROID METABOLISM; ANIMAL; DRUG DETOXIFICATION; DRUG INTERACTION; GENETICS;

MAMMALIA;

ANIMALS; DRUG INTERACTIONS; HUMANS; METABOLIC DETOXICATION, DRUG; PHARMACOGENETICS; POLYMORPHISM, GENETIC; RETINOID X RECEPTORS; XENOBIOTICS;

EID: 61549104490     PISSN: 14622416     EISSN: 17448042     Source Type: Journal    
DOI: 10.2217/14622416.9.11.1695     Document Type: Review

References (113)

1. Kliewer SA, Moore JT, Wade L, et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92, 73-82 (1998). (Pubitemid 28053299)
2. Blumberg B, Sabbagh Jr W, Juguilon H, et al. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev. 12, 3195-3205 (1998). (Pubitemid 28496264)
3. 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 95, 12208-12213 (1998). (Pubitemid 28483744)
4. Carnahan VE, Redinbo MR: Structure and function of the human nuclear xenobiotic receptor PXR. Curr. Drug Metab. 6, 357-367 (2005).
5. Watkins RE, Wisely GB, Moore LB, et al. The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science 292, 2329-2333 (2001).
6. Kliewer SA, Goodwin B, Willson TM: The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr. Rev. 23, 687-702 (2002). (Pubitemid 35191629)
7. 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. 16, 977-986 (2002).
8. Xie W, Evans RM: Orphan nuclear receptors: the exotics of xenobiotics. J. Biol. Chem. 276, 37739-37742 (2001). (Pubitemid 37384015)
9. Gillam EM: The PXR ligand-binding domain: how to be picky and promiscuous at the same time. Trends Pharmacol. Sci. 22, (2001).
10. Willson TM, Kliewer SA: PXR, CAR and drug metabolism. Nat. Rev. Drug Discov. 1, 259-266 (2002).
11. Stanley LA, Horsburgh BC, Ross J, et al. PXR and CAR: nuclear receptors which play a pivotal role in drug disposition and chemical toxicity. Drug Metab. Rev. 38, 515-597 (2006). (Pubitemid 44167200)
12. Moore LB, Goodwin B, Jones SA, et al. St. Johns wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc. Natl Acad. Sci. USA 97, 7500-7502 (2000). (Pubitemid 30431492)
13. Staudinger JL, Ding X, Lichti K: Pregnane X receptor and natural products: beyond drug-drug interactions. Expert Opin. Drug Metab. Toxicol. 2, 847-857 (2006). (Pubitemid 44911536)
14. Tabb MM, Sun A, Zhou C, et al. Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor SXR. J. Biol. Chem. 278, 43919-43927 (2003). (Pubitemid 37377131)
15. Landes N, Pfluger P, Kluth D, et al. Vitamin E activates gene expression via the pregnane X receptor. Biochem. Pharmacol. 65, 269-273 (2003). (Pubitemid 36015829)
16. Pacyniak EK, Cheng X, Cunningham ML, et al. The flame retardants, polybrominated diphenyl ethers, are pregnane X receptor activators. Toxicol. Sci. 97, 94-102 (2007). (Pubitemid 47072159)
17. Coumoul X, Diry M, Barouki R: PXR-dependent induction of human CYP3A4 gene expression by organochlorine pesticides. Biochem. Pharmacol. 64, 1513-1519 (2002). (Pubitemid 35333379)
18. Mnif W, Pascussi JM, Pillon A, et al. Estrogens and antiestrogens activate hPXR. Toxicol. Lett. 170, 19-29 (2007). (Pubitemid 46509749)
19. Goodwin B, Gauthier KC, Umetani M, et al. Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor. Proc. Natl. Acad. Sci. USA 100, 223-228 (2003). (Pubitemid 36078056)
20. Xie W, Radominska-Pandya A, Shi Y, et al. An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Proc. Natl Acad. Sci. USA 98, 3375-3380 (2001). (Pubitemid 32220853)
21. Staudinger J, Liu Y, Madan A, et al. Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor. Drug Metab. Dispos. 29, 1467-1472 (2001). (Pubitemid 33000694)
22. Dussault I, Yoo HD, Lin M, et al. Identification of an endogenous ligand that activates pregnane X receptor-mediated sterol clearance. Proc. Natl Acad. Sci. USA 100, 833-838 (2003). (Pubitemid 36183916)
23. Xie W, Barwick JL, Downes M, et al. Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 406, 435-439 (2000). (Pubitemid 30625566)
24. 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. 35, 194-200 (2007). (Pubitemid 46148730)
25. Gonzalez FJ: CYP3A4 and pregnane X receptor humanized mice. J. Biochem. Mol. Toxicol. 21, 158-162 (2007).
26. Rosenfeld JM, Vargas Jr R, Xie W, Evans RM: Genetic profiling defines the xenobiotic gene network controlled by the nuclear receptor pregnane X receptor. Mol. Endocrinol. 17, 1268-1282 (2003). (Pubitemid 36819950)
27. Xie W, Uppal H, Saini SP, et al. Orphan nuclear receptor-mediated xenobiotic regulation in drug metabolism. Drug Discov. Today 9, 442-449 (2004). (Pubitemid 38510563)
28. Sonoda J, Rosenfeld JM, Xu L, et al. A nuclear receptor-mediated xenobiotic response and its implication in drug metabolism and host protection. Curr. Drug Metab. 4, 59-72 (2003). (Pubitemid 36131684)
29. Handschin C, Meyer UA: Induction of drug metabolism: the role of nuclear receptors. Pharmacol. Rev. 55, 649-673 (2003). (Pubitemid 37504978)
30. 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 a, farnesoid X receptor b, liver X receptor a, liver X receptor b, and vitamin D receptor. Pharmacol. Rev. 58, 742-759 (2006). (Pubitemid 44833743)
31. Synold TW, Dussault I, Forman BM: The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat. Med. 7, 584-590 (2001). (Pubitemid 32448326)
32. Dussault I, Lin M, Hollister K, et al. Peptide mimetic HIV protease inhibitors are ligands for the orphan receptor SXR. J. Biol. Chem. 276, 33309-33312 (2001). (Pubitemid 37384536)
33. 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. 102, 1016-1023 (1998).
34. Kliewer SA, Lehmann JM, Milburn MV, Willson TM: The PPARs and PXRs: nuclear xenobiotic receptors that define novel hormone signaling pathways. Recent Prog. Horm. Res. 54, 345-367; discussion 67-68 (1999).
35. Sinz M, Kim S, Zhu Z, et al. Evaluation of xenobiotics as transactivators of human pregnane X receptor (hPXR) and correlation to known CYP3A4 drug interactions. Curr. Drug Metab. 7, 375-388 (2006).
36. Mu Y, Zhang J, Zhang S, et al. Traditional Chinese medicines Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch) activate pregnane X receptor and increase warfarin clearance in rats. J. Pharmacol. Exp. Ther. 316, 1369-1377 (2006). (Pubitemid 43345314)
37. Goldstein JA: Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br. J. Clin. Pharmacol. 52, 349-355 (2001).
38. Tabb MM, Kholodovych V, Grun F, et al. Highly chlorinated PCBs inhibit the human xenobiotic response mediated by the steroid and xenobiotic receptor (SXR). Environ. Health Perspect. 112, 163-169 (2004). (Pubitemid 38195824)
39. Huang H, Wang H, Sinz M, et al. Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. Oncogene 26, 258-268 (2007). (Pubitemid 46095736)
40. Wang H, Huang H, Li H, et al. Activated pregnenolone X-receptor is a target for ketoconazole and its analogs. Clin. Cancer Res. 13, 2488-2495 (2007). (Pubitemid 46698601)
41. 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. 71, 220-229 (2007). (Pubitemid 46020992)
42. Wang H, Li H, Moore LB, et al. The phytoestrogen coumestrol is a naturally occurring antagonist of the human pregnane X receptor. Mol. Endocrinol. 22, 838-857 (2008). (Pubitemid 351482821)
43. 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. 36, 500-507 (2008). (Pubitemid 351397974)
44. Ekins S, Kholodovych V, Ai N, et al. Computational discovery of novel low micromolar human pregnane X receptor antagonists. Mol. Pharmacol. 74, 662-672 (2008).
45. Ekins S, Chang C, Mani S, et al. Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites. Mol. Pharmacol. 72, 592-603 (2007). (Pubitemid 47347294)
46. Gong H, Sinz MW, Feng Y, et al. Animal models of xenobiotic receptors in drug metabolism and diseases. Methods Enzymol. 400, 598-618 (2005). (Pubitemid 43052443)
47. Staudinger JL, Goodwin B, Jones SA, et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc. Natl Acad. Sci. USA 98, 3369-3374 (2001). (Pubitemid 32220852)
48. Sonoda J, Xie W, Rosenfeld JM, et al. Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR). Proc. Natl Acad. Sci. USA 99, 13801-13806 (2002). (Pubitemid 35215461)
49. Stedman CA, Liddle C, Coulter SA, et al. Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury. Proc. Natl Acad. Sci. USA 102, 2063-2068 (2005). (Pubitemid 40262012)
50. Zhang J, Huang W, Qatanani M, et al. The constitutive androstane receptor and pregnane X receptor function coordinately to prevent bile acid-induced hepatotoxicity. J. Biol. Chem. 279, 49517-49522 (2004). (Pubitemid 39625839)
51. Uppal H, Toma D, Saini SP, et al. Combined loss of orphan receptors PXR and CAR heightens sensitivity to toxic bile acids in mice. Hepatology 41, 168-176 (2005). (Pubitemid 40066395)
52. Klaassen CD, Slitt AL: Regulation of hepatic transporters by xenobiotic receptors. Curr. Drug Metab. 6, 309-328 (2005). (Pubitemid 41086765)
53. 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 100, 4150-4155 (2003). (Pubitemid 36418172)
54. Huang W, Zhang J, Moore DD: A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. J. Clin. Invest. 113, 137-143 (2004). (Pubitemid 38541640)
55. Zhai Y, Pai HV, Zhou J, et al. Activation of pregnane X receptor disrupts glucocorticoid and mineralocorticoid homeostasis. Mol. Endocrinol. 21, 138-147 (2007). (Pubitemid 46041695)
56. Zhou J, Zhai Y, Mu Y, et al. A novel pregnane X receptor-mediated and sterol regulatory element-binding proteinindependent lipogenic pathway. J. Biol. Chem. 281, 15013-15020 (2006). (Pubitemid 43855205)
57. Zhou J, Febbraio M, Wada T, et al. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARg in promoting steatosis. Gastroenterology 134, 556-567 (2008). (Pubitemid 351173049)
58. Dai G, He L, Bu P, Wan YJ: Pregnane X receptor is essential for normal progression of liver regeneration. Hepatology 47, 1277-1287 (2008). (Pubitemid 351547914)
59. Nakamura K, Moore R, Negishi M, Sueyoshi T: Nuclear pregnane X receptor cross-talk with FoxA2 to mediate druginduced regulation of lipid metabolism in fasting mouse liver. J. Biol. Chem. 282, 9768-9776 (2007). (Pubitemid 47104600)
60. Paunescu E: In vivo and in vitro suppression of humoral and cellular immunological response by rifampicin. Nature 228, 1188-1190 (1970).
61. Zhou C, Tabb MM, Nelson EL, et al. Mutual repression between steroid and xenobiotic receptor and NF-kB signaling pathways links xenobiotic metabolism and inflammation. J. Clin. Invest. 116, 2280-2289 (2006). (Pubitemid 44162338)
62. Xie W, Tian Y: Xenobiotic receptor meets NF-kB, a collision in the small bowel. Cell Metab. 4, 177-178 (2006). (Pubitemid 44283956)
63. Dring MM, Goulding CA, Trimble VI, et al. The pregnane X receptor locus is associated with susceptibility to inflammatory bowel disease. Gastroenterology 130, 341-348 (2006). (Pubitemid 43202034)
64. Langmann T, Moehle C, Mauerer R, et al. Loss of detoxification in inflammatory bowel disease: dysregulation of pregnane X receptor target genes. Gastroenterology 127, 26-40 (2004). (Pubitemid 38962271)
65. Martinez A, Marquez A, Mendoza J, et al. Role of the PXR gene locus in inflammatory bowel diseases. Inflamm. Bowel Dis. 13, 1484-1487 (2007).
66. Shah YM, Ma X, Morimura K, et al. Pregnane X receptor activation ameliorates DSS-induced inflammatory bowel disease via inhibition of NF-kB target gene expression. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G1114-G1122 (2007). (Pubitemid 46557773)
67. Chen C, Shah YM, Morimura K, et al. Metabolomics reveals that hepatic stearoyl-CoA desaturase 1 downregulation exacerbates inflammation and acute colitis. Cell Metab. 7, 135-147 (2008). (Pubitemid 351168558)
68. Pascussi JM, Robert A, Nguyen M, et al. Possible involvement of pregnane X receptorenhanced CYP24 expression in drug-induced osteomalacia. J. Clin. Invest. 115, 177-186 (2005). (Pubitemid 40385519)
69. Xu Y, Hashizume T, Shuhart MC, et al. Intestinal and hepatic CYP3A4 catalyze hydroxylation of 1a,25-dihydroxyvitamin D(3): implications for drug-induced osteomalacia. Mol. Pharmacol. 69, 56-65 (2006). (Pubitemid 43048893)
70. Wang T, Ma X, Krausz KW, et al. Role of pregnane X receptor in control of all-trans retinoic acid (ATRA) metabolism and its potential contribution to ATRA resistance. J. Pharmacol. Exp. Ther. 324, 674-684 (2008). (Pubitemid 351185843)
71. Kolars JC, Schmiedlin-Ren P, Schuetz JD, et al. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J. Clin. Invest. 90, 1871-1878 (1992).
72. Lown KS, Mayo RR, Leichtman AB, et al. Role of intestinal Pglycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin. Pharmacol. Ther. 62, 248-260 (1997).
73. Watkins PB, Murray SA, Winkelman LG, et al. Erythromycin breath test as an assay of glucocorticoid-inducible liver cytochromes P-450. Studies in rats and patients. J. Clin. Invest. 83, 688-697 (1989).
74. Perry W, Jenkins MV: Hepatic mixed function oxidase induction during rifampicin/isoniazid therapy in Indian vegetarians. Int. J. Clin. Pharmacol. Ther. Toxicol. 24, 344-348 (1986). (Pubitemid 16086834)
75. Li AP, Kaminski DL, Rasmussen A: Substrates of human hepatic cytochrome P450 3A4. Toxicology 104, 1-8 (1995). (Pubitemid 26016371)
76. Kojima K, Nagata K, Matsubara T, Yamazoe Y: Broad but distinct role of pregnane X receptor on the expression of individual cytochrome P450s in human hepatocytes. Drug Metab. Pharmacokinet. 22, 276-286 (2007).
77. 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. 7, 349-365 (2006).
78. Zhou C, Assem M, Tay JC, et al. Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. J. Clin. Invest. 116, 1703-1712 (2006). (Pubitemid 43911025)
79. 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 gluconeogenci enzymes. Mol. Cell. Biol. 24, 7931-7940 (2004). (Pubitemid 39167443)
80. Nakamura K, Moore R, Negishi M, Sueyoshi T: Nuclear pregnane X receptor cross-talk with FoxA2 to mediate druginduced regulation of lipid metabolism in fasting mouse liver. J. Biol. Chem. 282, 9768-9776 (2007). (Pubitemid 47104600)
81. Maglich JM, Caravella JA, Lambert MH, et al. The first completed genome sequence from a teleost fish (Fugu rubripes) adds significant diversity to the nuclear receptor superfamily. Nucleic Acids Res. 31, 4051-4058 (2003).
82. Zhang Z, Burch PE, Cooney AJ, et al. Genomic analysis of the nuclear receptor family: new insights into structure, regulation, and evolution from the rat genome. Genome Res. 14, 580-590 (2004). (Pubitemid 38500229)
83. 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. 19, 1720-1739 (2005). (Pubitemid 41007886)
84. Ekins S, Reschly EJ, Hagey LR, Krasowski MD: Evolution of pharmacologic specificity in the pregnane X receptor. BMC Evol. Biol. 8, 103 (2008). (Pubitemid 351652379)
85. Jones SA, Moore LB, Shenk JL, et al. The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol. Endocrinol. 14, 27-39 (2000).
86. Reschly EJ, Bainy AC, Mattos JJ, et al. Functional evolution of the vitamin D and pregnane X receptors. BMC Evol. Biol. 7, 222 (2007).
87. Iyer M, Reschly EJ, Krasowski MD: Functional evolution of the pregnane X receptor. Expert Opin. Drug Metab. Toxicol. 2, 381-397 (2006). (Pubitemid 46141405)
88. Schuetz EG, Strom S, Yasuda K, et al. Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. J. Biol. Chem. 276, 39411-39418 (2001). (Pubitemid 37371319)
89. 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. Recept. 3, 2 (2005). (Pubitemid 41522382)
90. Thompson EE, Kuttab-Boulos H, Witonsky D, et al. CYP3A variation and the evolution of salt-sensitivity variants. Am. J. Hum. Genet. 75, 1059-1069 (2004). (Pubitemid 39534403)
91. Zhang J, Kuehl P, Green ED, et al. The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. Pharmacogenetics 11, 555-572 (2001). (Pubitemid 32953582)
92. Lamba V, Yasuda K, Lamba JK, et al. PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators. Toxicol. Appl. Pharmacol. 199, 251-265 (2004). (Pubitemid 39208725)
93. Dotzlaw H, Leygue E, Watson P, Murphy LC: The human orphan receptor PXR messenger RNA is expressed in both normal and neoplastic breast tissue. Clin. Cancer Res. 5, 2103-2107 (1999). (Pubitemid 29399265)
94. Watkins RE, Maglich JM, Moore LB, et al. 2.1 Å crystal structure of human PXR in complex with the St. Johns wort compound hyperforin. Biochemistry 42, 1430-1438 (2003).
95. Hustert E, Zibat A, Presecan-Siedel E, et al. Natural protein variants of pregnane X receptor with altered transactivation activity toward CYP3A4. Drug Metab. Dispos. 29, 1454-1459 (2001). (Pubitemid 33000692)
96. 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. 32, 340-347 (2004). (Pubitemid 38263893)
97. Fukuen S, Fukuda T, Matsuda H, et al. Identification of the novel splicing variants for the hPXR in human livers. Biochem. Biophys. Res. Commun. 298, 433-438 (2002). (Pubitemid 35333725)
98. 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. 32, 149-154 (2004). (Pubitemid 38112547)
99. Koyano S, Kurose K, Ozawa S, et al. Eleven novel single nucleotide polymorphisms in the NR1I2 (PXR) gene, four of which induce non-synonymous amino acid alterations. Drug Metab. Pharmacokinet. 17, 561-565 (2002).
100. Lim YP, Liu CH, Shyu LJ, Huang JD: Functional characterization of a novel polymorphism of pregnane X receptor, Q158K, in Chinese subjects. Pharmacogenet. Genomics 15, 337-341 (2005).
101. He P, Court MH, Greenblatt DJ, von Moltke LL: Human pregnane X receptor: genetic polymorphisms, alternative mRNA splice variants, and cytochrome P450 3A metabolic activity. J. Clin. Pharmacol. 46, 1356-1369 (2006). (Pubitemid 44564365)
102. Karlsen TH, Lie BA, Frey FK, et al. Polymorphisms in the steroid and xenobiotic receptor gene influence survival in primary sclerosing cholangitis. Gastroenterology 131, 781-787 (2006).
103. Lamba J, Lamba V, Strom S, et al. Novel single nucleotide polymorphisms in the promoter and intron 1 of human PXR/NR1I2 and their association with CYP3A4 expression. Drug Metab. Dispos. 36, 169-181 (2008). (Pubitemid 351468386)
104. King CR, Xiao M, Yu J, et al. Identification of NR1I2 genetic variation using resequencing. Eur. J. Clin. Pharmacol. 63, 547-554 (2007). (Pubitemid 46684492)
105. Uno Y, Sakamoto Y, Hasegawa T, et al. Characterization of six base pair deletion in the putative HNF1-binding site of human PXR promoter. J. Hum. Genet. 48, 594-597 (2003). (Pubitemid 38017656)
106. Kamiyama Y, Matsubara T, Yoshinari K, et al. Role of human hepatocyte nuclear factor 4a in the expression of drug-metabolizing enzymes and transporters in human hepatocytes assessed by use of small interfering RNA. Drug Metab. Pharmacokinet. 22, 287-298 (2007).
107. Kyrmizi I, Hatzis P, Katrakili N, et al. Plasticity and expanding complexity of the hepatic transcription factor network during liver development. Genes Dev. 20, 2293-2305 (2006). (Pubitemid 44244529)
108. Tirona RG, Lee W, Leake BF, et al. The orphan nuclear receptor HNF4a determines PXR-and CAR-mediated xenobiotic induction of CYP3A4. Nat. Med. 9, 220-224 (2003). (Pubitemid 36227725)
109. Marek CJ, Tucker SJ, Konstantinou DK, et al. Pregnenolone-16a- carbonitrile inhibits rodent liver fibrogenesis via PXR (pregnane X receptor)-dependent and PXR-independent mechanisms. Biochem. J. 387, 601-608 (2005).
110. The Single Nucleotide Polymorphism database www.ncbi.nlm.nih.gov/ projects/SNP/
111. Sorting Intolerant From Tolerant, Fred Hutchinson Cancer Research Center. http://blocks.fhcrc.org/sift/SIFT.html
112. Polymorphism Phenotyping, Bork Group www.bork.embl-heidelberg.de/PolyPhen
113. Berkeley Drosophila Genome Project, Splice Site Prediction by Neural Network www.fruitfly.org/seq-tools/splice.html