Abstract
Pregnane X receptor (PXR), a ligand-activated nuclear receptor, was originally identified as a regulator of drug and bile acid metabolism. Studies in experimental animals and humans within the last decade have revealed PXR as a regulator of energy metabolism repressing gluconeogenesis and hepatic lipid oxidation. The most recent in vivo studies demonstrate that PXR activation has a detrimental role in the regulation of glucose metabolism. The prevalence of many PXR agonists in low concentrations in our environments as well as the PXR-activating properties of numerous commonly used medications and herbal remedies may have unanticipated health effects. It could be speculated that, due to its dual role as a xenosensor and a regulator of energy metabolism, PXR, in concert with a mixture of PXR agonists in the environment, contributes to the present-day type 2 diabetes epidemic. With this hypothesis in mind, we review the current literature on PXR as a regulator of glucose and hepatic lipid metabolism and the association of exposure to PXR agonists with diabetes susceptibility.
References
1. Ihunnah CA, Jiang M, Xie W. Nuclear receptor PXR, transcriptional circuits and metabolic relevance. Biochim Biophys Acta 2011;1812:956–63.10.1016/j.bbadis.2011.01.014Search in Google Scholar PubMed PubMed Central
2. Song X, Xie M, Zhang H, Li Y, Sachdeva K, Yan B. The pregnane X receptor binds to response elements in a genomic context-dependent manner, and PXR activator rifampicin selectively alters the binding among target genes. Drug Metab Dispos 2004;32:35–42.10.1124/dmd.32.1.35Search in Google Scholar PubMed
3. 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 2007;22:276–86.10.2133/dmpk.22.276Search in Google Scholar PubMed
4. Zollner G, Marschall HU, Wagner M, Trauner M. Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Mol Pharmacol 2006;3:231–51.10.1021/mp060010sSearch in Google Scholar PubMed
5. Miki Y, Suzuki T, Tazawa C, Blumberg B, Sasano H. Steroid and xenobiotic receptor (SXR), cytochrome P450 3A4 and multidrug resistance gene 1 in human adult and fetal tissues. Mol Cell Endocrinol 2005;231:75–85.10.1016/j.mce.2004.12.005Search in Google Scholar PubMed
6. 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: 51–73.10.1080/03602530600569828Search in Google Scholar PubMed
7. Kojima H, Sata F, Takeuchi S, Sueyoshi T, Nagai T. Comparative study of human and mouse pregnane X receptor agonistic activity in 200 pesticides using in vitro reporter gene assays. Toxicology 2011;280:77–87.10.1016/j.tox.2010.11.008Search in Google Scholar PubMed
8. Hukkanen J. Induction of CYP enzymes: a view on human in vivo findings. Expert Rev Clin Pharmacol 2012;5:569–85.10.1586/ecp.12.39Search in Google Scholar PubMed
9. Johnson DR, Li CW, Chen LY, Ghosh JC, Chen JD. Regulation and binding of pregnane X receptor by nuclear receptor corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT). Mol Pharmacol 2006;69:99–108.10.1124/mol.105.013375Search in Google Scholar PubMed
10. Kodama S, Negishi M. PXR cross-talks with internal and external signals in physiological and pathophysiological responses. Drug Metab Rev 2013;5:300–10.10.3109/03602532.2013.795585Search in Google Scholar PubMed
11. Konno Y, Negishi M, Kodama S. The roles of nuclear receptors CAR and PXR in hepatic energy metabolism. Drug Metab Pharmacokinet 2008;23:8–13.10.2133/dmpk.23.8Search in Google Scholar PubMed
12. Gao J, Xie W. Targeting xenobiotic receptors PXR and CAR for metabolic diseases. Trends Pharmacol Sci 2012;33:552–8.10.1016/j.tips.2012.07.003Search in Google Scholar PubMed PubMed Central
13. Federation ID. IDF Diabetes atlas, 5th ed. Brussels: International Diabetes Federation, 2011.Search in Google Scholar
14. Wild SH, Byrne CD. ABC of obesity. Risk factors for diabetes and coronary heart disease. Br Med J 2006;333:1009–11.10.1136/bmj.39024.568738.43Search in Google Scholar PubMed PubMed Central
15. Neel BA, Sargis RM. The paradox of progress: environmental disruption of metabolism and the diabetes epidemic. Diabetes 2011;60:1838–48.10.2337/db11-0153Search in Google Scholar PubMed PubMed Central
16. Hectors TL, Vanparys C, van der Ven K, Martens GA, Jorens PG, Van Gaal LF, et al. Environmental pollutants and type 2 diabetes: a review of mechanisms that can disrupt beta cell function. Diabetologia 2011;54:1273–90.10.1007/s00125-011-2109-5Search in Google Scholar PubMed
17. Baillie-Hamilton PF. Chemical toxins: a hypothesis to explain the global obesity epidemic. J Altern Complement Med 2002;8: 185–92.10.1089/107555302317371479Search in Google Scholar PubMed
18. Grun F, Blumberg B. Endocrine disrupters as obesogens. Mol Cell Endocrinol 2009;304:19–29.10.1016/j.mce.2009.02.018Search in Google Scholar PubMed PubMed Central
19. Bhalla S, Ozalp C, Fang S, Xiang L, Kemper JK. 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;279:45139–47.10.1074/jbc.M405423200Search in Google Scholar PubMed
20. Kodama S, Moore R, Yamamoto Y, Negishi M. Human nuclear pregnane X receptor cross-talk with CREB to repress cAMP activation of the glucose-6-phosphatase gene. Biochem J 2007;407:373–81.10.1042/BJ20070481Search in Google Scholar PubMed PubMed Central
21. 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 gluconeogenic enzymes. Mol Cell Biol 2004;24:7931–40.10.1128/MCB.24.18.7931-7940.2004Search in Google Scholar PubMed PubMed Central
22. Zhou J, Zhai Y, Mu Y, Gong H, Uppal H, Toma D, et al. A novel pregnane X receptor-mediated and sterol regulatory element-binding protein-independent lipogenic pathway. J Biol Chem 2006;281:15013–20.10.1074/jbc.M511116200Search in Google Scholar
23. Ma Y, Liu D. Activation of pregnane X receptor by pregnenolone 16 alpha-carbonitrile prevents high-fat diet-induced obesity in AKR/J mice. PLoS One 2012;7:e38734.10.1371/journal.pone.0038734Search in Google Scholar
24. Rysa J, Buler M, Savolainen MJ, Ruskoaho H, Hakkola J, Hukkanen J. Pregnane X receptor agonists impair postprandial glucose tolerance. Clin Pharmacol Ther 2013;93:556–63.10.1038/clpt.2013.48Search in Google Scholar
25. Nakamura K, Moore R, Negishi M, Sueyoshi T. Nuclear pregnane X receptor cross-talk with FoxA2 to mediate drug-induced regulation of lipid metabolism in fasting mouse liver. J Biol Chem 2007;282:9768–76.10.1074/jbc.M610072200Search in Google Scholar
26. Tuchweber B, Solymoss B, Khandekar JD, Kovacs K, Garg BD, Zsigmond G, et al. Effect of pregnenolone-16-carbonitrile on the hepatic ultrastructure, glycogen content and ethylmorphine N-demethylase activity in pregnant, fetal, and newborn rats. Exp Mol Pathol 1972;17:281–95.10.1016/0014-4800(72)90041-XSearch in Google Scholar
27. Kourounakis P, Szabo S, Selye H. Effect of pregnenolone-16alpha-carbonitrile on the rat liver. Arzneimittelforschung 1976;26:74–5.Search in Google Scholar
28. He J, Gao J, Xu M, Ren S, Stefanovic-Racic M, O’Doherty RM, et al. PXR ablation alleviates diet-induced and genetic obesity and insulin resistance in mice. Diabetes 2013;62:1876–87.10.2337/db12-1039Search in Google Scholar PubMed PubMed Central
29. Takasu N, Yamada T, Miura H, Sakamoto S, Korenaga M, Nakajima K, et al. Rifampicin-induced early phase hyperglycemia in humans. Am Rev Respir Dis 1982;125:23–7.Search in Google Scholar
30. Purohit SD, Gupta PR, Agarwal KC, Sharma TN, Durlabhji P, Sharma RK. Glucose tolerance during rifampicin therapy. Ind J Tuberc 1984;31:3–5.Search in Google Scholar
31. Sharma TN, Agarwal KC, Gupta PR, Purohit SD, Sharma VK, Mathur BB. Further experience on glucose tolerance test during rifampicin therapy. J Assoc Phys India 1986;34:131–3.Search in Google Scholar
32. Gao J, He J, Zhai Y, Wada T, Xie W. The constitutive androstane receptor is an anti-obesity nuclear receptor that improves insulin sensitivity. J Biol Chem 2009;284:25984–92.10.1074/jbc.M109.016808Search in Google Scholar PubMed PubMed Central
33. Dong B, Saha PK, Huang W, Chen W, Abu-Elheiga LA, Wakil SJ, et al. Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease. Proc Natl Acad Sci USA 2009;106:18831–6.10.1073/pnas.0909731106Search in Google Scholar PubMed PubMed Central
34. Rezen T, Tamasi V, Lovgren-Sandblom A, Bjorkhem I, Meyer UA, Rozman D. Effect of CAR activation on selected metabolic pathways in normal and hyperlipidemic mouse livers. BMC Genomics 2009;10:384.10.1186/1471-2164-10-384Search in Google Scholar PubMed PubMed Central
35. Buler M, Aatsinki SM, Skoumal R, Komka Z, Toth M, Kerkela R, et al. Energy-sensing factors coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) and AMP-activated protein kinase control expression of inflammatory mediators in liver: induction of interleukin 1 receptor antagonist. J Biol Chem 2012;287: 1847–60.10.1074/jbc.M111.302356Search in Google Scholar PubMed PubMed Central
36. Cheng J, Krausz KW, Tanaka N, Gonzalez FJ. Chronic exposure to rifaximin causes hepatic steatosis in pregnane X receptor-humanized mice. Toxicol Sci 2012;129:456–68.10.1093/toxsci/kfs211Search in Google Scholar PubMed PubMed Central
37. Hoekstra M, Lammers B, Out R, Li Z, Van Eck M, Van Berkel TJ. Activation of the nuclear receptor PXR decreases plasma LDL-cholesterol levels and induces hepatic steatosis in LDL receptor knockout mice. Mol Pharmacol 2009;6:182–9.10.1021/mp800131dSearch in Google Scholar PubMed
38. Zhou J, Febbraio M, Wada T, Zhai Y, Kuruba R, He J, et al. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 2008;134:556–67.10.1053/j.gastro.2007.11.037Search in Google Scholar PubMed
39. Moreau A, Teruel C, Beylot M, Albalea V, Tamasi V, Umbdenstock T, et al. A novel pregnane X receptor and S14-mediated lipogenic pathway in human hepatocyte. Hepatology 2009;49:2068–79.10.1002/hep.22907Search in Google Scholar PubMed
40. Shibata M, Kihara Y, Taguchi M, Tashiro M, Otsuki M. Nonalcoholic fatty liver disease is a risk factor for type 2 diabetes in middle-aged Japanese men. Diabetes Care 2007;30:2940–4.10.2337/dc07-0792Search in Google Scholar PubMed
41. Fan JG, Li F, Cai XB, Peng YD, Ao QH, Gao Y. Effects of nonalcoholic fatty liver disease on the development of metabolic disorders. J Gastroenterol Hepatol 2007;22:1086–91.10.1111/j.1440-1746.2006.04781.xSearch in Google Scholar PubMed
42. Kim CH, Park JY, Lee KU, Kim JH, Kim HK. Fatty liver is an independent risk factor for the development of type 2 diabetes in Korean adults. Diabetes Med 2008;25:476–81.10.1111/j.1464-5491.2008.02410.xSearch in Google Scholar PubMed
43. Anderson GW, Zhu Q, Metkowski J, Stack MJ, Gopinath S, Mariash CN. The Thrsp null mouse (Thrsp(tm1cnm)) and diet-induced obesity. Mol Cell Endocrinol 2009;302:99–107.10.1016/j.mce.2009.01.005Search in Google Scholar PubMed PubMed Central
44. Matsuzaka T, Shimano H, Yahagi N, Kato T, Atsumi A, Yamamoto T, et al. Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance. Nat Med 2007;13:1193–202.10.1038/nm1662Search in Google Scholar PubMed
45. Targher G, Byrne CD. Clinical review: nonalcoholic fatty liver disease: a novel cardiometabolic risk factor for type 2 diabetes and its complications. J Clin Endocrinol Metab 2013;98:483–95.10.1210/jc.2012-3093Search in Google Scholar PubMed
46. Fahmi OA, Kish M, Boldt S, Obach RS. Cytochrome P450 3A4 mRNA is a more reliable marker than CYP3A4 activity for detecting pregnane X receptor-activated induction of drug-metabolizing enzymes. Drug Metab Dispos 2010;38: 1605–11.10.1124/dmd.110.033126Search in Google Scholar
47. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735–42.10.1016/S0140-6736(09)61965-6Search in Google Scholar
48. Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. J Am Med Assoc 2011;305:2556–64.10.1001/jama.2011.860Search in Google Scholar PubMed
49. Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM. Risk of incident diabetes among patients treated with statins: population based study. Br Med J 2013;346:f2610.10.1136/bmj.f2610Search in Google Scholar PubMed PubMed Central
50. Zaharan NL, Williams D, Bennett K. Statins and risk of treated incident diabetes in a primary care population. Br J Clin Pharmacol 2013;75:1118–24.10.1111/j.1365-2125.2012.04403.xSearch in Google Scholar PubMed PubMed Central
51. Culver AL, Ockene IS, Balasubramanian R, Olendzki BC, Sepavich DM, Wactawski-Wende J, et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s Health Initiative. Arch Intern Med 2012;172:144–52.10.1001/archinternmed.2011.625Search in Google Scholar PubMed
52. El-Sankary W, Gibson GG, Ayrton A, Plant N. Use of a reporter gene assay to predict and rank the potency and efficacy of CYP3A4 inducers. Drug Metab Dispos 2001;29:1499–504.Search in Google Scholar
53. Howe K, Sanat F, Thumser AE, Coleman T, Plant N. The statin class of HMG-CoA reductase inhibitors demonstrate differential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes. Xenobiotica 2011;41:519–29.10.3109/00498254.2011.569773Search in Google Scholar PubMed
54. Monostory K, Pascussi JM, Szabo P, Temesvari M, Kohalmy K, Acimovic J, et al. Drug interaction potential of 2-((3,4-dichlorophenethyl)(propyl)amino)-1-(pyridin-3-yl)ethanol (LK-935), the novel nonstatin-type cholesterol-lowering agent. Drug Metab Dispos 2009;37:375–85.10.1124/dmd.108.023887Search in Google Scholar PubMed
55. Feidt DM, Klein K, Hofmann U, Riedmaier S, Knobeloch D, Thasler WE, et al. Profiling induction of cytochrome P450 enzyme activity by statins using a new liquid chromatography-tandem mass spectrometry cocktail assay in human hepatocytes. Drug Metab Dispos 2010;38:1589–97.10.1124/dmd.110.033886Search in Google Scholar PubMed
56. Horsmans Y, Desager JP, van den Berge V, Abrassart M, Harvengt C. Effects of simvastatin and pravastatin on 6beta-hydroxycortisol excretion, a potential marker of cytochrome P-450 3A. Pharmacol Res 1993;28:243–8.10.1006/phrs.1993.1127Search in Google Scholar PubMed
57. Karayalcin U, Takeda Y, Miyamori I, Morise T, Takeda R. Effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin on urinary 6beta-hydroxycortisol excretion: a preliminary study. Steroids 1991;56:598–600.10.1016/0039-128X(91)90023-OSearch in Google Scholar
58. Simonson SG, Martin PD, Warwick MJ, Mitchell PD, Schneck DW. The effect of rosuvastatin on oestrogen & progestin pharmacokinetics in healthy women taking an oral contraceptive. Br J Clin Pharmacol 2004;57:279–86.10.1046/j.1365-2125.2003.02015.xSearch in Google Scholar PubMed PubMed Central
59. Willrich MA, Rodrigues AC, Cerda A, Genvigir FD, Arazi SS, Dorea EL, et al. Effects of atorvastatin on CYP3A4 and CYP3A5 mRNA expression in mononuclear cells and CYP3A activity in hypercholeresterolemic patients. Clin Chim Acta 2013;421: 157–63.10.1016/j.cca.2013.03.007Search in Google Scholar PubMed
60. Watanabe H, Kosuge K, Nishio S, Yamada H, Uchida S, Satoh H, et al. Pharmacokinetic and pharmacodynamic interactions between simvastatin and diltiazem in patients with hypercholesterolemia and hypertension. Life Sci 2004;76:281–92.10.1016/j.lfs.2004.06.022Search in Google Scholar PubMed
61. Luna B, Feinglos MN. Drug-induced hyperglycemia. J Am Med Assoc 2001;286:1945–8.10.1001/jama.286.16.1945Search in Google Scholar PubMed
62. Kalra S, Agrawal N. Diabetes and HIV: current understanding and future perspectives. Curr Diabetes Rep 2013;13:419–27.10.1007/s11892-013-0369-9Search in Google Scholar PubMed
63. Butt AA, McGinnis K, Rodriguez-Barradas MC, Crystal S, Simberkoff M, Goetz MB, et al. HIV infection and the risk of diabetes mellitus. AIDS 2009;23:1227–34.10.1097/QAD.0b013e32832bd7afSearch in Google Scholar PubMed PubMed Central
64. Bigoloni A, Gianotti N, Spagnuolo V, Galli L, Nozza S, Cossarini F, et al. Long-term glucose tolerance in highly experienced HIV-infected patients receiving nucleoside analogue-sparing regimens. AIDS 2012;26:1837–40.10.1097/QAD.0b013e32835705ddSearch in Google Scholar PubMed
65. Dussault I, Lin M, Hollister K, Wang EH, Synold TW, Forman BM. Peptide mimetic HIV protease inhibitors are ligands for the orphan receptor SXR. J Biol Chem 2001;276:33309–12.10.1074/jbc.C100375200Search in Google Scholar PubMed
66. Gupta A, Mugundu GM, Desai PB, Thummel KE, Unadkat JD. Intestinal human colon adenocarcinoma cell line LS180 is an excellent model to study pregnane X receptor, but not constitutive androstane receptor, mediated CYP3A4 and multidrug resistance transporter 1 induction: studies with anti-human immunodeficiency virus protease inhibitors. Drug Metab Dispos 2008;36:1172–80.10.1124/dmd.107.018689Search in Google Scholar PubMed
67. Svard J, Spiers JP, Mulcahy F, Hennessy M. Nuclear receptor-mediated induction of CYP450 by antiretrovirals: functional consequences of NR1I2 (PXR) polymorphisms and differential prevalence in whites and sub-Saharan Africans. J Acquir Immune Defic Syndr 2010;55:536–49.10.1097/QAI.0b013e3181f52f0cSearch in Google Scholar PubMed
68. Sharma D, Lau AJ, Sherman MA, Chang TK. Agonism of human pregnane X receptor by rilpivirine and etravirine: Comparison with first generation non-nucleoside reverse transcriptase inhibitors. Biochem Pharmacol 2013;85:1700–11.10.1016/j.bcp.2013.04.002Search in Google Scholar PubMed
69. Weiss J, Haefeli WE. Potential of the novel antiretroviral drug rilpivirine to modulate the expression and function of drug transporters and drug-metabolising enzymes in vitro. Int J Antimicrob Agents 2013;41:484–7.10.1016/j.ijantimicag.2013.01.004Search in Google Scholar PubMed
70. Faucette SR, Zhang TC, Moore R, Sueyoshi T, Omiecinski CJ, LeCluyse EL, 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;320:72–80.10.1124/jpet.106.112136Search in Google Scholar PubMed PubMed Central
71. Sahi J, Shord SS, Lindley C, Ferguson S, LeCluyse EL. Regulation of cytochrome P450 2C9 expression in primary cultures of human hepatocytes. J Biochem Mol Toxicol 2009;23:43–58.10.1002/jbt.20264Search in Google Scholar PubMed
72. Sotaniemi EA, Arranto AJ, Sutinen S, Stengard JH. Treatment of noninsulin-dependent diabetes mellitus with enzyme inducers. Clin Pharmacol Ther 1983;33:826–35.10.1038/clpt.1983.113Search in Google Scholar PubMed
73. Lahtela JT, Arranto AJ, Sotaniemi EA. Enzyme inducers improve insulin sensitivity in non-insulin-dependent diabetic subjects. Diabetes 1985;34:911–6.10.2337/diab.34.9.911Search in Google Scholar PubMed
74. Lahtela JT, Sarkka P, Sotaniemi EA. Phenobarbital treatment enhances insulin mediated glucose metabolism in man. Res Commun Chem Pathol Pharmacol 1984;44:215–26.Search in Google Scholar
75. Lahtela JT, Gachalyi B, Eksyma S, Hamalainen A, Sotaniemi EA. The effect of liver microsomal enzyme inducing and inhibiting drugs on insulin mediated glucose metabolism in man. Br J Clin Pharmacol 1986;21:19–26.10.1111/j.1365-2125.1986.tb02818.xSearch in Google Scholar PubMed PubMed Central
76. Korhonen T, Uusitupa M, Voutilainen E, Sarlund H, Laakso M, Laitinen M, et al. Lack of effect of hepatic enzyme induction on metabolic control in patients with type 2 (non-insulin-dependent) diabetes. Clin Pharmacol Ther 1987;41:633–8.10.1038/clpt.1987.88Search in Google Scholar PubMed
77. Haspel HC, Stephenson KN, Davies-Hill T, El-Barbary A, Lobo JF, Croxen RL, et al. Effects of barbiturates on facilitative glucose transporters are pharmacologically specific and isoform selective. J Membr Biol 1999;169:45–53.10.1007/PL00005900Search in Google Scholar PubMed
78. Honkanen RA, McBath H, Kushmerick C, Callender GE, Scarlata SF, Fenstermacher JD, et al. Barbiturates inhibit hexose transport in cultured mammalian cells and human erythrocytes and interact directly with purified GLUT-1. Biochemistry 1995;34:535–44.10.1021/bi00002a019Search in Google Scholar PubMed
79. Chaudhry AS, Urban TJ, Lamba JK, Birnbaum AK, Remmel RP, Subramanian M, et al. CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose. J Pharmacol Exp Ther 2010;332:599–611.10.1124/jpet.109.161026Search in Google Scholar PubMed PubMed Central
80. Phabphal K, Limapichat K, Sathirapanya P, Setthawatcharawanich S, Geater A. Characterization of glucose homeostasis and lipid profile in adult, seizure-free, epileptic patients in Asian population. Eur J Neurol 2012;19:1228–34.10.1111/j.1468-1331.2012.03708.xSearch in Google Scholar PubMed
81. Draznin B, Ayalon D, Hoerer E, Oberman Z, Harell A, Ravid R, et al. Effect of diphenylhydantoin on patterns of insulin secretion in obese subjects. Acta Diabetol Lat 1977;14:51–61.10.1007/BF02624663Search in Google Scholar PubMed
82. Malherbe C, Burrill KC, Levin SR, Karam JH, Forsham PH. Effect of diphenylhydantoin on insulin secretion in man. N Engl J Med 1972;286:339–42.10.1056/NEJM197202172860702Search in Google Scholar PubMed
83. Levin SR, Reed JW, Ching KN, Davis JW, Blum MR, Forsham PH. Diphenylhydantoin. Its use in detecting early insulin secretory defects in patients with mild glucose intolerance. Diabetes 1973;22:194–201.10.2337/diab.22.3.194Search in Google Scholar PubMed
84. Perry-Keene DA, Larkins RG, Heyma P, Peter CT, Ross D, Sloman JG. The effect of long-term diphenylhydantoin therapy on glucose tolerance and insulin secretion: a controlled trial. Clin Endocrinol (Oxf) 1980;12:575–80.10.1111/j.1365-2265.1980.tb01378.xSearch in Google Scholar PubMed
85. Siegel EG, Janjic D, Wollheim CB. Phenytoin inhibition of insulin release. Studies on the involvement of Ca2+ fluxes in rat pancreatic islets. Diabetes 1982;31:265–9.10.2337/diab.31.3.265Search in Google Scholar PubMed
86. Li L, Stanton JD, Tolson AH, Luo Y, Wang H. Bioactive terpenoids and flavonoids from Ginkgo biloba extract induce the expression of hepatic drug-metabolizing enzymes through pregnane X receptor, constitutive androstane receptor, and aryl hydrocarbon receptor-mediated pathways. Pharmacol Res 2009;26:872–82.10.1007/s11095-008-9788-8Search in Google Scholar PubMed PubMed Central
87. Kudolo GB. The effect of 3-month ingestion of Ginkgo biloba extract on pancreatic beta-cell function in response to glucose loading in normal glucose tolerant individuals. J Clin Pharmacol 2000;40:647–54.10.1002/j.1552-4604.2000.tb05991.xSearch in Google Scholar
88. Kudolo GB. The effect of 3-month ingestion of Ginkgo biloba extract (EGb 761) on pancreatic beta-cell function in response to glucose loading in individuals with non-insulin-dependent diabetes mellitus. J Clin Pharmacol 2001;41:600–11.10.1177/00912700122010483Search in Google Scholar
89. Kudolo GB, Dorsey S, Blodgett J. Effect of the ingestion of Ginkgo biloba extract on platelet aggregation and urinary prostanoid excretion in healthy and type 2 diabetic subjects. Thromb Res 2002;108:151–60.10.1016/S0049-3848(02)00394-8Search in Google Scholar
90. Kudolo GB, Wang W, Elrod R, Barrientos J, Haase A, Blodgett J. Short-term ingestion of Ginkgo biloba extract does not alter whole body insulin sensitivity in non-diabetic, pre-diabetic or type 2 diabetic subjects – a randomized double-blind placebo-controlled crossover study. Clin Nutr 2006;25:123–34.10.1016/j.clnu.2005.10.001Search in Google Scholar PubMed
91. Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, et al. St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 2000;97:7500–2.10.1073/pnas.130155097Search in Google Scholar PubMed PubMed Central
92. Krausova L, Stejskalova L, Wang H, Vrzal R, Dvorak Z, Mani S, et al. Metformin suppresses pregnane X receptor (PXR)-regulated transactivation of CYP3A4 gene. Biochem Pharmacol 2011;82:1771–80.10.1016/j.bcp.2011.08.023Search in Google Scholar PubMed PubMed Central
93. Thayer KA, Heindel JJ, Bucher JR, Gallo MA. Role of environmental chemicals in diabetes and obesity: a National Toxicology Program workshop review. Environ Health Perspect 2012;120:779–89.10.1289/ehp.1104597Search in Google Scholar PubMed PubMed Central
94. Taylor KW, Novak RF, Anderson HA, Birnbaum LS, Blystone C, Devito M, et al. Evaluation of the association between persistent organic pollutants (POPs) and diabetes in epidemiological studies: a National Toxicology Program workshop review. Environ Health Perspect 2013;21:774–83.10.1289/ehp.1205502Search in Google Scholar PubMed PubMed Central
95. Hernandez JP, Mota LC, Baldwin WS. Activation of CAR and PXR by dietary, environmental and occupational chemicals alters drug metabolism, intermediary metabolism, and cell proliferation. Curr Pharmacogenomics Person Med 2009;7:81–105.10.2174/187569209788654005Search in Google Scholar PubMed PubMed Central
96. Abass K, Lamsa V, Reponen P, Kublbeck J, Honkakoski P, Mattila S, et al. Characterization of human cytochrome P450 induction by pesticides. Toxicology 2012;294:17–26.10.1016/j.tox.2012.01.010Search in Google Scholar PubMed
97. Al-Salman F, Plant N. Non-coplanar polychlorinated biphenyls (PCBs) are direct agonists for the human pregnane-X receptor and constitutive androstane receptor, and activate target gene expression in a tissue-specific manner. Toxicol Appl Pharmacol 2012;263:7–13.10.1016/j.taap.2012.05.016Search in Google Scholar PubMed
98. Kretschmer XC, Baldwin WS. CAR and PXR: xenosensors of endocrine disrupters? Chem Biol Interact 2005;155:111–28.10.1016/j.cbi.2005.06.003Search in Google Scholar PubMed
99. Lemaire G, Mnif W, Pascussi JM, Pillon A, Rabenoelina F, Fenet H, et al. Identification of new human pregnane X receptor ligands among pesticides using a stable reporter cell system. Toxicol Sci 2006;91:501–9.10.1093/toxsci/kfj173Search in Google Scholar PubMed
100. Montgomery MP, Kamel F, Saldana TM, Alavanja MC, Sandler DP. Incident diabetes and pesticide exposure among licensed pesticide applicators: Agricultural Health Study, 1993–2003. Am J Epidemiol 2008;167:1235–46.10.1093/aje/kwn028Search in Google Scholar PubMed PubMed Central
101. Patel CJ, Bhattacharya J, Butte AJ. An Environment-Wide Association Study (EWAS) on type 2 diabetes mellitus. PLoS One 2010;5:e10746.10.1371/journal.pone.0010746Search in Google Scholar PubMed PubMed Central
102. Son HK, Kim SA, Kang JH, Chang YS, Park SK, Lee SK, et al. Strong associations between low-dose organochlorine pesticides and type 2 diabetes in Korea. Environ Int 2010;36:410–4.10.1016/j.envint.2010.02.012Search in Google Scholar PubMed
103. Lee DH, Lee IK, Song K, Steffes M, Toscano W, Baker BA, et al. A strong dose-response relation between serum concentrations of persistent organic pollutants and diabetes: results from the National Health and Examination Survey 1999–2002. Diabetes Care 2006;29:1638–44.10.2337/dc06-0543Search in Google Scholar PubMed
104. Lee DH, Lind PM, Jacobs DR Jr, Salihovic S, van Bavel B, Lind L. Polychlorinated biphenyls and organochlorine pesticides in plasma predict development of type 2 diabetes in the elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Diabetes Care 2011;34:1778–84.10.2337/dc10-2116Search in Google Scholar PubMed PubMed Central
105. Codru N, Schymura MJ, Negoita S, Rej R, Carpenter DO. Diabetes in relation to serum levels of polychlorinated biphenyls and chlorinated pesticides in adult Native Americans. Environ Health Perspect 2007;115:1442–7.10.1289/ehp.10315Search in Google Scholar PubMed PubMed Central
106. Cox S, Niskar AS, Narayan KM, Marcus M. Prevalence of self-reported diabetes and exposure to organochlorine pesticides among Mexican Americans: Hispanic Health and nutrition examination survey, 1982–1984. Environ Health Perspect 2007;115:1747–52.10.1289/ehp.10258Search in Google Scholar PubMed PubMed Central
107. Philibert A, Schwartz H, Mergler D. An exploratory study of diabetes in a First Nation community with respect to serum concentrations of p,p′-DDE and PCBs and fish consumption. Int J Environ Res Public Health 2009;6:3179–89.10.3390/ijerph6123179Search in Google Scholar PubMed PubMed Central
108. Rignell-Hydbom A, Rylander L, Hagmar L. Exposure to persistent organochlorine pollutants and type 2 diabetes mellitus. Hum Exp Toxicol 2007;26:447–52.10.1177/0960327107076886Search in Google Scholar PubMed
109. Rignell-Hydbom A, Lidfeldt J, Kiviranta H, Rantakokko P, Samsioe G, Agardh CD, et al. Exposure to p,p′-DDE: a risk factor for type 2 diabetes. PLoS One 2009;4:e7503.10.1371/journal.pone.0007503Search in Google Scholar PubMed PubMed Central
110. Rylander L, Rignell-Hydbom A, Hagmar L. A cross-sectional study of the association between persistent organochlorine pollutants and diabetes. Environ Health 2005;4:28.10.1186/1476-069X-4-28Search in Google Scholar PubMed PubMed Central
111. Turyk M, Anderson H, Knobeloch L, Imm P, Persky V. Organochlorine exposure and incidence of diabetes in a cohort of Great Lakes sport fish consumers. Environ Health Perspect 2009;117:1076–82.10.1289/ehp.0800281Search in Google Scholar PubMed PubMed Central
112. Airaksinen R, Rantakokko P, Eriksson JG, Blomstedt P, Kajantie E, Kiviranta H. Association between type 2 diabetes and exposure to persistent organic pollutants. Diabetes Care 2011;34:1972–9.10.2337/dc10-2303Search in Google Scholar PubMed PubMed Central
113. Everett CJ, Frithsen IL, Diaz VA, Koopman RJ, Simpson WM Jr, Mainous AG 3rd. Association of a polychlorinated dibenzo-p-dioxin, a polychlorinated biphenyl, and DDT with diabetes in the 1999–2002 National Health and Nutrition Examination Survey. Environ Res 2007;103:413–8.10.1016/j.envres.2006.11.002Search in Google Scholar PubMed
114. Lee DH, Lee IK, Steffes M, Jacobs DR Jr. Extended analyses of the association between serum concentrations of persistent organic pollutants and diabetes. Diabetes Care 2007;30:1596–8.10.2337/dc07-0072Search in Google Scholar PubMed
115. Jacobs MN, Nolan GT, Hood SR. Lignans, bacteriocides and organochlorine compounds activate the human pregnane X receptor (PXR). Toxicol Appl Pharmacol 2005;209:123–33.10.1016/j.taap.2005.03.015Search in Google Scholar PubMed
116. Lee DH, Steffes MW, Sjodin A, Jones RS, Needham LL, Jacobs DR Jr. Low dose of some persistent organic pollutants predicts type 2 diabetes: a nested case-control study. Environ Health Perspect 2010;118:1235–42.10.1289/ehp.0901480Search in Google Scholar PubMed PubMed Central
117. Hurst CH, Waxman DJ. Environmental phthalate monoesters activate pregnane X receptor-mediated transcription. Toxicol Appl Pharmacol 2004;199:266–74.10.1016/j.taap.2003.11.028Search in Google Scholar PubMed
118. James-Todd T, Stahlhut R, Meeker JD, Powell SG, Hauser R, Huang T, et al. Urinary phthalate metabolite concentrations and diabetes among women in the National Health and Nutrition Examination Survey (NHANES) 2001–2008. Environ Health Perspect 2012;120:1307–13.10.1289/ehp.1104717Search in Google Scholar PubMed PubMed Central
119. Takeshita A, Koibuchi N, Oka J, Taguchi M, Shishiba Y, Ozawa Y. Bisphenol-A, an environmental estrogen, activates the human orphan nuclear receptor, steroid and xenobiotic receptor-mediated transcription. Eur J Endocrinol 2001;145:513–7.10.1530/eje.0.1450513Search in Google Scholar PubMed
120. Lang IA, Galloway TS, Scarlett A, Henley WE, Depledge M, Wallace RB, et al. Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. J Am Med Assoc 2008;300:1303–10.10.1001/jama.300.11.1303Search in Google Scholar PubMed
121. Sui Y, Ai N, Park SH, Rios-Pilier J, Perkins JT, Welsh WJ, et al. Bisphenol A and its analogues activate human pregnane X receptor. Environ Health Perspect 2012;120:399–405.10.1289/ehp.1104426Search in Google Scholar PubMed PubMed Central
122. Melzer D, Rice NE, Lewis C, Henley WE, Galloway TS. Association of urinary bisphenol a concentration with heart disease: evidence from NHANES 2003/06. PLoS One 2010;5:e8673.10.1371/journal.pone.0008673Search in Google Scholar PubMed PubMed Central
123. Fierens S, Mairesse H, Heilier JF, De Burbure C, Focant JF, Eppe G, et al. Dioxin/polychlorinated biphenyl body burden, diabetes and endometriosis: findings in a population-based study in Belgium. Biomarkers 2003;8:529–34.10.1080/1354750032000158420Search in Google Scholar PubMed
124. Vasiliu O, Cameron L, Gardiner J, Deguire P, Karmaus W. Polybrominated biphenyls, polychlorinated biphenyls, body weight, and incidence of adult-onset diabetes mellitus. Epidemiology 2006;17:352–9.10.1097/01.ede.0000220553.84350.c5Search in Google Scholar PubMed
125. Uemura H, Arisawa K, Hiyoshi M, Satoh H, Sumiyoshi Y, Morinaga K, et al. Associations of environmental exposure to dioxins with prevalent diabetes among general inhabitants in Japan. Environ Res 2008;108:63–8.10.1016/j.envres.2008.06.002Search in Google Scholar PubMed
126. Wang SL, Tsai PC, Yang CY, Guo YL. Increased risk of diabetes and polychlorinated biphenyls and dioxins: a 24-year follow-up study of the Yucheng cohort. Diabetes Care 2008;31:1574–9.10.2337/dc07-2449Search in Google Scholar PubMed PubMed Central
127. Turyk M, Anderson HA, Knobeloch L, Imm P, Persky VW. Prevalence of diabetes and body burdens of polychlorinated biphenyls, polybrominated diphenyl ethers, and p,p′-diphenyldichloroethene in Great Lakes sport fish consumers. Chemosphere 2009;75:674–9.10.1016/j.chemosphere.2008.12.035Search in Google Scholar PubMed
128. Ukropec J, Radikova Z, Huckova M, Koska J, Kocan A, Sebokova E, et al. High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail. Diabetologia 2010;53:899–906.10.1007/s00125-010-1683-2Search in Google Scholar PubMed
129. Grandjean P, Henriksen JE, Choi AL, Petersen MS, Dalgard C, Nielsen F, et al. Marine food pollutants as a risk factor for hypoinsulinemia and type 2 diabetes. Epidemiology 2011;22:410–7.10.1097/EDE.0b013e318212fab9Search in Google Scholar PubMed PubMed Central
130. Persky V, Piorkowski J, Turyk M, Freels S, Chatterton R Jr, Dimos J, et al. Associations of polychlorinated biphenyl exposure and endogenous hormones with diabetes in post-menopausal women previously employed at a capacitor manufacturing plant. Environ Res 2011;111:817–24.10.1016/j.envres.2011.05.012Search in Google Scholar PubMed
131. Persky V, Piorkowski J, Turyk M, Freels S, Chatterton R Jr, Dimos J, et al. Polychlorinated biphenyl exposure, diabetes and endogenous hormones: a cross-sectional study in men previously employed at a capacitor manufacturing plant. Environ Health 2012;11:57.10.1186/1476-069X-11-57Search in Google Scholar PubMed PubMed Central
132. Silverstone AE, Rosenbaum PF, Weinstock RS, Bartell SM, Foushee HR, Shelton C, et al. Polychlorinated biphenyl (PCB) exposure and diabetes: results from the Anniston Community Health Survey. Environ Health Perspect 2012;120:727–32.10.1289/ehp.1104247Search in Google Scholar PubMed PubMed Central
133. Everett CJ, Thompson OM. Associations of dioxins, furans and dioxin-like PCBs with diabetes and pre-diabetes: is the toxic equivalency approach useful? Environ Res 2012;118:107–11.10.1016/j.envres.2012.06.012Search in Google Scholar PubMed
134. Tanaka T, Morita A, Kato M, Hirai T, Mizoue T, Terauchi Y, et al. Congener-specific polychlorinated biphenyls and the prevalence of diabetes in the Saku Control Obesity Program (SCOP). Endocr J 2011;58:589–96.10.1507/endocrj.K10E-361Search in Google Scholar PubMed
135. Poland A, Smith D, Kuntzman R, Jacobson M, Conney AH. Effect of intensive occupational exposure to DDT on phenylbutazone and cortisol metabolism in human subjects. Clin Pharmacol Ther 1970;11:724–32.10.1002/cpt1970115724Search in Google Scholar PubMed
136. Lee DH, Steffes MW, Sjodin A, Jones RS, Needham LL, Jacobs DR Jr. Low dose organochlorine pesticides and polychlorinated biphenyls predict obesity, dyslipidemia, and insulin resistance among people free of diabetes. PLoS One 2011;6:e15977.10.1371/journal.pone.0015977Search in Google Scholar PubMed PubMed Central
137. Kolodkin A, Sahin N, Phillips A, Hood SR, Bruggeman FJ, Westerhoff HV, et al. Optimization of stress response through the nuclear receptor-mediated cortisol signalling network. Nat Commun 2013;4:1792.10.1038/ncomms2799Search in Google Scholar PubMed PubMed Central
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