Vitamin D (VDR), Pregnane X (PXR) and Constitutive Androstane (CAR) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [1,12]) are members of the NR1I family of nuclear receptors, which form heterodimers with members of the retinoid X receptor family. PXR and CAR are activated by a range of exogenous compounds, with no established endogenous physiological agonists, although high concentrations of bile acids and bile pigments activate PXR and CAR [12].

* Key recommended reading is highlighted with an asterisk

Banerjee M, Robbins D, Chen T. (2015) Targeting xenobiotic receptors PXR and CAR in human diseases. Drug Discov Today, 20 (5): 618-28. [PMID:25463033]

* Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev, 58 (4): 798-836. [PMID:17132856]

Bikle DD. (2011) Vitamin D: an ancient hormone. Exp Dermatol, 20 (1): 7-13. [PMID:21197695]

Bikle DD. (2014) Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol, 21 (3): 319-29. [PMID:24529992]

Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, Lieben L, Mathieu C, Demay M. (2008) Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev, 29 (6): 726-76. [PMID:18694980]

Campbell FC, Xu H, El-Tanani M, Crowe P, Bingham V. (2010) The yin and yang of vitamin D receptor (VDR) signaling in neoplastic progression: operational networks and tissue-specific growth control. Biochem Pharmacol, 79 (1): 1-9. [PMID:19737544]

Chen Y, Tang Y, Guo C, Wang J, Boral D, Nie D. (2012) Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters. Biochem Pharmacol, 83 (8): 1112-26. [PMID:22326308]

Cheng J, Shah YM, Gonzalez FJ. (2012) Pregnane X receptor as a target for treatment of inflammatory bowel disorders. Trends Pharmacol Sci, 33 (6): 323-30. [PMID:22609277]

Danescu LG, Levy S, Levy J. (2009) Vitamin D and diabetes mellitus. Endocrine, 35 (1): 11-7. [PMID:18979202]

Deeb KK, Trump DL, Johnson CS. (2007) Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer, 7 (9): 684-700. [PMID:17721433]

Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ. (2014) The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer, 14 (5): 342-57. [PMID:24705652]

Gerbal-Chaloin S, Iankova I, Maurel P, Daujat-Chavanieu M. (2013) Nuclear receptors in the cross-talk of drug metabolism and inflammation. Drug Metab Rev, 45 (1): 122-44. [PMID:23330545]

Gonzalez-Sanchez E, Firrincieli D, Housset C, Chignard N. (2015) Nuclear receptors in acute and chronic cholestasis. Dig Dis, 33 (3): 357-66. [PMID:26045270]

Ihunnah CA, Jiang M, Xie W. (2011) Nuclear receptor PXR, transcriptional circuits and metabolic relevance. Biochim Biophys Acta, 1812 (8): 956-63. [PMID:21295138]

Kachaylo EM, Pustylnyak VO, Lyakhovich VV, Gulyaeva LF. (2011) Constitutive androstane receptor (CAR) is a xenosensor and target for therapy. Biochemistry Mosc, 76 (10): 1087-97. [PMID:22098234]

Köhle C, Bock KW. (2009) Coordinate regulation of human drug-metabolizing enzymes, and conjugate transporters by the Ah receptor, pregnane X receptor and constitutive androstane receptor. Biochem Pharmacol, 77 (4): 689-99. [PMID:18606396]

* Long MD, Sucheston-Campbell LE, Campbell MJ. (2015) Vitamin D receptor and RXR in the post-genomic era. J Cell Physiol, 230 (4): 758-66. [PMID:25335912]

Lucock M, Jones P, Martin C, Beckett E, Yates Z, Furst J, Veysey M. (2015) Vitamin D: Beyond Metabolism. J Evid Based Complementary Altern Med, 20 (4): 310-22. [PMID:25878189]

Mani S, Dou W, Redinbo MR. (2013) PXR antagonists and implication in drug metabolism. Drug Metab Rev, 45 (1): 60-72. [PMID:23330542]

Mo L, He J. (2014) Nuclear hormone receptors PXR and CAR and metabolic diseases. Horm Mol Biol Clin Investig, 19 (2): 129-40. [PMID:25390021]

* Moore DD, Kato S, Xie W, Mangelsdorf DJ, Schmidt DR, Xiao R, Kliewer SA. (2006) 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, 58 (4): 742-59. [PMID:17132852]

Oladimeji PO, Chen T. (2018) PXR: More Than Just a Master Xenobiotic Receptor. Mol Pharmacol, 93 (2): 119-127. [PMID:29113993]

Pavek P. (2016) Pregnane X Receptor (PXR)-Mediated Gene Repression and Cross-Talk of PXR with Other Nuclear Receptors via Coactivator Interactions. Front Pharmacol, 7: 456. [PMID:27932985]

Pike JW. (2011) Genome-scale techniques highlight the epigenome and redefine fundamental principles of gene regulation. J Bone Miner Res, 26 (6): 1155-62. [PMID:21611959]

Pittas AG, Dawson-Hughes B. (2010) Vitamin D and diabetes. J Steroid Biochem Mol Biol, 121 (1-2): 425-9. [PMID:20304061]

Plum LA, DeLuca HF. (2010) Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov, 9 (12): 941-55. [PMID:21119732]

Schmuth M, Moosbrugger-Martinz V, Blunder S, Dubrac S. (2014) Role of PPAR, LXR, and PXR in epidermal homeostasis and inflammation. Biochim Biophys Acta, 1841 (3): 463-73. [PMID:24315978]

Staudinger JL, Woody S, Sun M, Cui W. (2013) Nuclear-receptor-mediated regulation of drug- and bile-acid-transporter proteins in gut and liver. Drug Metab Rev, 45 (1): 48-59. [PMID:23330541]

Suda T, Masuyama R, Bouillon R, Carmeliet G. (2015) Physiological functions of vitamin D: what we have learned from global and conditional VDR knockout mouse studies. Curr Opin Pharmacol, 22: 87-99. [PMID:25938686]

Timsit YE, Negishi M. (2007) CAR and PXR: the xenobiotic-sensing receptors. Steroids, 72 (3): 231-46. [PMID:17284330]

Urquhart BL, Tirona RG, Kim RB. (2007) Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: implications for interindividual variability in response to drugs. J Clin Pharmacol, 47 (5): 566-78. [PMID:17442683]

Wang J, Dai S, Guo Y, Xie W, Zhai Y. (2014) Biology of PXR: role in drug-hormone interactions. EXCLI J, 13: 728-39. [PMID:26417296]

Yan J, Xie W. (2016) A brief history of the discovery of PXR and CAR as xenobiotic receptors. Acta Pharm Sin B, 6 (5): 450-452. [PMID:27709013]

1. Alexander SPH, Cidlowski JA, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ et al.. (2019) THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Nuclear hormone receptors. Br J Pharmacol, 176 Suppl 1: S229-S246. [PMID:31710718]

2. Bishop JE, Collins ED, Okamura WH, Norman AW. (1994) Profile of ligand specificity of the vitamin D binding protein for 1 alpha,25-dihydroxyvitamin D3 and its analogs. J Bone Miner Res, 9 (8): 1277-88. [PMID:7976510]

3. Blumberg B, Sabbagh W, Juguilon H, Bolado J, van Meter CM, Ong ES, Evans RM. (1998) SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev, 12 (20): 3195-205. [PMID:9784494]

4. Colston KW, Mackay AG, James SY, Binderup L, Chander S, Coombes RC. (1992) EB1089: a new vitamin D analogue that inhibits the growth of breast cancer cells in vivo and in vitro. Biochem Pharmacol, 44 (12): 2273-80. [PMID:1472092]

5. Erben RG, Soegiarto DW, Weber K, Zeitz U, Lieberherr M, Gniadecki R, Möller G, Adamski J, Balling R. (2002) Deletion of deoxyribonucleic acid binding domain of the vitamin D receptor abrogates genomic and nongenomic functions of vitamin D. Mol Endocrinol, 16 (7): 1524-37. [PMID:12089348]

6. Fujishima T, Kojima Y, Azumaya I, Kittaka A, Takayama H. (2003) Design and synthesis of potent vitamin D receptor antagonists with A-ring modifications: remarkable effects of 2alpha-methyl introduction on antagonistic activity. Bioorg Med Chem, 11 (17): 3621-31. [PMID:12901907]

7. Herdick M, Steinmeyer A, Carlberg C. (2000) Carboxylic ester antagonists of 1alpha,25-dihydroxyvitamin D(3) show cell-specific actions. Chem Biol, 7 (11): 885-94. [PMID:11094341]

8. Jones SA, Moore LB, Shenk JL, Wisely GB, Hamilton GA, McKee DD, Tomkinson NC, LeCluyse EL, Lambert MH, Willson TM, Kliewer SA, Moore JT. (2000) The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol Endocrinol, 14 (1): 27-39. [PMID:10628745]

9. Kanno Y, Tanuma N, Takahashi A, Inouye Y. (2013) TO901317, a potent LXR agonist, is an inverse agonist of CAR. J Toxicol Sci, 38 (3): 309-15. [PMID:23665929]

10. Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA. (1998) The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest, 102 (5): 1016-23. [PMID:9727070]

11. 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 (19): 17277-83. [PMID:12611900]

12. Moore DD, Kato S, Xie W, Mangelsdorf DJ, Schmidt DR, Xiao R, Kliewer SA. (2006) 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, 58 (4): 742-59. [PMID:17132852]

13. Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL, Kliewer SA. (2000) St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA, 97 (13): 7500-2. [PMID:10852961]

14. Moore LB, Parks DJ, Jones SA, Bledsoe RK, Consler TG, Stimmel JB, Goodwin B, Liddle C, Blanchard SG, Willson TM, Collins JL, Kliewer SA. (2000) Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J Biol Chem, 275 (20): 15122-7. [PMID:10748001]

15. Saito N, Matsunaga T, Saito H, Anzai M, Takenouchi K, Miura D, Namekawa J, Ishizuka S, Kittaka A. (2006) Further synthetic and biological studies on vitamin D hormone antagonists based on C24-alkylation and C2alpha-functionalization of 25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactones. J Med Chem, 49 (24): 7063-75. [PMID:17125259]

16. 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 (9): 2951-8. [PMID:10757780]

17. Wentworth JM, Agostini M, Love J, Schwabe JW, Chatterjee VK. (2000) St John's wort, a herbal antidepressant, activates the steroid X receptor. J Endocrinol, 166 (3): R11-6. [PMID:10974665]

18. Wiberg K, Ljunghall S, Binderup L, Ljunggren O. (1995) Studies on two new vitamin D analogs, EB 1089 and KH 1060: effects on bone resorption and osteoclast recruitment in vitro. Bone, 17 (4): 391-5. [PMID:8573413]

Sylvia Christakos Dept. of Biochemistry and Molecular Biology Rutgers - New Jersey Medical School 185 South Orange Ave. Newark, New Jersey 07103 USA