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The AAPS Journal

, 11:590 | Cite as

Activation of Pregnane X Receptor (PXR) and Constitutive Androstane Receptor (CAR) by Herbal Medicines

  • Thomas K. H. ChangEmail author
Review Article Theme: Natural Products as Therapeutic Modulators

Abstract

Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are transcription factors that control the expression of a broad array of genes involved not only in transcellular transport and biotransformation of many drugs, other xenochemicals, and endogenous substances, such as bile acid, bilirubin, and certain vitamins, but also in various physiological/pathophysiological processes such as lipid metabolism, glucose homeostasis, and inflammation. Ligands of PXR and CAR are chemicals of diverse structures, including naturally occurring compounds present in herbal medicines. The overall aim of this article is to provide an overview of our current understanding of the role of herbal medicines as modulators of PXR and CAR.

Key words

constitutive androstane receptor herbal medicine pregnane X receptor 

Notes

Acknowledgement

This work was supported by the Canadian Institutes of Health Research (Grant MOP-84581) and Michael Smith Foundation for Health Research (a Senior Scholar Award to T.K.H.C.).

References

  1. 1.
    Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat Rev Drug Discov. 2005;4:206–20.PubMedCrossRefGoogle Scholar
  2. 2.
    Germain P, Staels B, Dacquet C, Spedding M, Laudet V. Overview of nomenclature of nuclear receptors. Pharmacol Rev. 2006;58:685–704.PubMedCrossRefGoogle Scholar
  3. 3.
    Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell. 1998;92:73–82.PubMedCrossRefGoogle Scholar
  4. 4.
    Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA. 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.PubMedCrossRefGoogle Scholar
  5. 5.
    Blumberg B, Sabbagh W Jr, Juguilon H, Bolado J Jr, van Meter CM, Ong ES, et al. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev. 1998;12:3195–205.PubMedCrossRefGoogle Scholar
  6. 6.
    Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Backman M, et al. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci USA. 1998;95:12208–13.PubMedCrossRefGoogle Scholar
  7. 7.
    Baes M, Gulick T, Choi HS, Martinoli MG, Simha D, Moore DD. 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.PubMedGoogle Scholar
  8. 8.
    Maglich JM, Stoltz CM, Goodwin B, Hawkins-Brown D, Moore JT, Kliewer SA. 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.PubMedCrossRefGoogle Scholar
  9. 9.
    Rosenfeld JM, Vargas R Jr, Xie W, Evans RM. Genetic profiling defines the xenobiotic gene network controlled by the nuclear receptor pregnane X receptor. Mol Endocrinol. 2003;17:1268–82.PubMedCrossRefGoogle Scholar
  10. 10.
    Moreau A, Vilarem MJ, Maurel P, Pascussi JM. Xenoreceptors CAR and PXR activation and consequences on lipid metabolism, glucose homeostasis, and inflammatory response. Mol Pharm. 2008;5:35–41.PubMedCrossRefGoogle Scholar
  11. 11.
    Kakizaki S, Yamazaki Y, Takizawa D, Negishi M. New insights on the xenobiotic-sensing nuclear receptors in liver diseases—CAR and PXR. Curr Drug Metab. 2008;9:614–21.PubMedCrossRefGoogle Scholar
  12. 12.
    Chang TKH, 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.PubMedCrossRefGoogle Scholar
  13. 13.
    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.PubMedCrossRefGoogle Scholar
  14. 14.
    Wentworth JM, Agostini M, Love J, Schwabe JW, Chatterjee VKK. St. John’s wort, a herbal antidepressant, activates the steroid X receptor. J Endocrinol. 2000;166:R11–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Huang W, Zhang J, Moore DD. A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. J Clin Invest. 2004;113:137–43.PubMedGoogle Scholar
  16. 16.
    Stanley LA, Horsburgh BC, Ross J, Scheer N, Wolf CR. PXR and CAR: Nuclear receptors which play a pivotal role in drug disposition and chemical toxicity. Drug Metab Rev. 2006;38:515–97.PubMedCrossRefGoogle Scholar
  17. 17.
    Timsit YE, Negishi M. CAR and PXR: the xenobiotic-sensing receptors. Steroids. 2007;72:231–46.PubMedCrossRefGoogle Scholar
  18. 18.
    Li CW, Dinh GK, Chen JD. Preferential physical and functional interaction of pregnane X receptor with the SMRTα isoform. Mol Pharmacol. 2009;75:363–73.PubMedCrossRefGoogle Scholar
  19. 19.
    Pascussi JM, Gerbal-Chaloin S, Duret C, Daujat-Chavanieu M, Vilarem MJ, Maurel P. The tangle of nuclear receptors that controls xenobiotic metabolism and transport: crosstalk and consequences. Annu Rev Pharmacol Toxicol. 2008;48:1–32.PubMedCrossRefGoogle Scholar
  20. 20.
    Zhang H, LeCluyse EL, Liu L, Hu M, Matoney L, Zhu W, et al. Rat pregnane X receptor: molecular cloning, tissue distribution, and xenobiotic regulation. Arch Biochem Biophys. 1999;368:14–22.PubMedCrossRefGoogle Scholar
  21. 21.
    Bauer B, Hartz AMS, Fricker G, Miller DS. Pregnane X receptor up-regulation of P-glycoprotein expression and transport function at the blood-brain barrier. Mol Pharmacol. 2004;66:413–9.PubMedGoogle Scholar
  22. 22.
    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. 1999;5:2103–7.PubMedGoogle Scholar
  23. 23.
    Masuyama H, Hiramatsu Y, Kodama J, Kudo T. Expression and potential roles of pregnane X receptor in endometrial cancer. J Clin Endocrinol Metab. 2003;88:4446–54.PubMedCrossRefGoogle Scholar
  24. 24.
    Ma X, Shah YM, Guo GL, Wang T, Krausz KW, Idle JR, et al. Rifaximin is a gut-specific human pregnane X receptor activator. J Pharmacol Exp Ther. 2007;322:391–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Jones SA, Moore LB, Shenk JL, Wisely GB, Hamilton GA, McKee DD, et al. The Pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol Endocrinol. 2000;14:27–39.PubMedCrossRefGoogle Scholar
  26. 26.
    Staudinger JL, Ding X, Lichti K. Pregnane X receptor and natural products: beyond drug-drug interactions. Expert Opin Drug Metab Toxicol. 2006;2:847–57.PubMedCrossRefGoogle Scholar
  27. 27.
    Ammon HP, Muller AB. Forskolin: from an Ayurvedic remedy to a modern agent. Planta Med. 1985;51:473–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Insel PA, Ostrom RS. Forskolin as a tool for examining adenylyl cyclase expression, regulation, and G protein signalling. Cell Mol Neurobiol. 2003;23:305–14.PubMedCrossRefGoogle Scholar
  29. 29.
    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.PubMedCrossRefGoogle Scholar
  30. 30.
    Dowless MS, Barbee JL, Borchert KM, Bocchinfuso WP, Houck KA. Cyclic AMP-independent activation of CYP3A4 gene expression by forskolin. Eur J Pharmacol. 2005;512:9–13.PubMedCrossRefGoogle Scholar
  31. 31.
    Sinz M, Kim S, Zhu Z, Chen T, Anthony M, Dickinson K, et al. Evaluation of 170 xenobiotics as transactivators of human pregnane X receptor (hPXR) and correlation to known CYP3A4 drug interactions. Curr Drug Metab. 2006;7:375–88.PubMedCrossRefGoogle Scholar
  32. 32.
    Satyavati GV. Gum guggul (Commiphora mukul)—the success story of an ancient insight leading to a modern discovery. Indian J Med Res. 1988;87:327–35.PubMedGoogle Scholar
  33. 33.
    Urizar NL, Moore DD. GUGULIPID: A natural cholesterol-lowering agent. Annu Rev Nutr. 2003;23:303–13.PubMedCrossRefGoogle Scholar
  34. 34.
    Wu J, Xia C, Meier J, Li S, Hu X, Lala DS. The hypolipidemic natural product guggulsterone acts as an antagonist of the bile acid receptor. Mol Endocrinol. 2002;16:1590–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Deng R, Yang D, Radke A, Yang J, Yan B. The hypolipidemic agent guggulsterone regulates the expression of human bile acid export pump: dominance of transactivation over farnesoid X-receptor-mediated antagonism. J Pharmacol Exp Ther. 2007;320:1153–62.PubMedCrossRefGoogle Scholar
  36. 36.
    Brobst DE, Ding X, Creech KL, Goodwin B, Kelley B, Staudinger JL. Guggulsterone activates multiple nuclear receptors and induces CYP3A gene expression through the pregnane X receptor. J Pharmacol Exp Ther. 2004;310:528–35.PubMedCrossRefGoogle Scholar
  37. 37.
    Ohnhaus EE, Kirchhof B, Peheim E. Effect of enzyme induction on plasma lipids using antipyrine, phenobarbital, and rifampicin. Clin Pharmacol Ther. 1979;25:591–7.PubMedGoogle Scholar
  38. 38.
    van Beek TA, Montoro P. Chemical analysis and quality control of Ginkgo biloba leaves, extracts, and phytopharmaceuticals. J Chromatogr A. 2009;1216:2002–32.PubMedCrossRefGoogle Scholar
  39. 39.
    Gohil K. Genomic responses to herbal extracts: lesson from in vitro and in vivo studies with an extract of Ginkgo biloba. Biochem Pharmacol. 2002;64:913–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Ramassamy C. Emerging role of polyphenolic compounds in the treatment of neurodegenerative diseases: a review of their intracellular targets. Eur J Pharmacol. 2006;545:51–64.PubMedCrossRefGoogle Scholar
  41. 41.
    Yeung EYH, Sueyoshi T, Negishi M, Chang TKH. Identification of Ginkgo biloba as a novel activator of pregnane X receptor. Drug Metab Dispos. 2008;36:2270–6.PubMedCrossRefGoogle Scholar
  42. 42.
    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. Pharm Res. 2009;26:872–82.PubMedCrossRefGoogle Scholar
  43. 43.
    Satsu H, Hiura Y, Mochizuki K, Hamada M, Shimizu M. Activation of pregnane X receptor and induction of MDR1 by dietary phytochemicals. J Agric Food Chem. 2008;56:5366–73.PubMedCrossRefGoogle Scholar
  44. 44.
    Zanoli P, Zavatti M. Pharmacognostic and pharmacological profile of Humulus lupulus L. J Ethnopharmacol. 2008;116:383–96.PubMedCrossRefGoogle Scholar
  45. 45.
    Chadwick LR, Pauli GF, Farnsworth NR. The pharmacognosy of Humulus lupulus L. (hops) with an emphasis on estrogenic properties. Phytomedicine. 2006;13:119–31.PubMedCrossRefGoogle Scholar
  46. 46.
    Teotico DG, Bischof JJ, Peng L, Kliewer SA, Redinbo MR. Structural basis of human pregnane X receptor activation by the hops constituent colupulone. Mol Pharmacol. 2008;74:1512–20.PubMedCrossRefGoogle Scholar
  47. 47.
    Mannering GJ, Shoeman JA, Deloria LB. Identification of the antibiotic hops component, colupulone, as an inducer of hepatic cytochrome P-450 3A in the mouse. Drug Metab Dispos. 1992;20:142–7.PubMedGoogle Scholar
  48. 48.
    Shipp EB, Mehigh CS, Helferich WG. The effect of colupulone (a hops β-acid) on hepatic cytochrome P-450 enzyme activity in the rat. Food Chem Toxicol. 1994;32:1007–14.PubMedCrossRefGoogle Scholar
  49. 49.
    Muller WE, Rolli M, Schafer C, Hafner U. Effect of hypericum extract (LI 160) in biochemical models of antidepressant activity. Pharmacopsychiatry. 1997;30:S102–7.CrossRefGoogle Scholar
  50. 50.
    Choudhuri S, Valerio LG Jr. Usefulness of studies on the molecular mechanisms of action of herbals/botanicals: the case of St. John's wort. J Biochem Mol Toxicol. 2005;19:1–11.PubMedCrossRefGoogle Scholar
  51. 51.
    Muller WE, Singer A, Wonnemann M, Hafner U, Rolli M, Schafer C. Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hypericum extract. Pharmacopsychiatry. 1998;31(Suppl. 1):16–21.PubMedCrossRefGoogle Scholar
  52. 52.
    Watkins RE, Maglich JM, Moore LB, Wisely GB, Noble SM, Davis-Searles PR, et al. 2.1 A crystal structure of human PXR in complex with the St. John's wort compound hyperforin. Biochemistry. 2003;42:1430–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Kober M, Pohl K, Efferth T. Molecular mechanisms underlying St. John's wort drug interactions. Curr Drug Metab. 2008;9:1027–37.PubMedCrossRefGoogle Scholar
  54. 54.
    Wheatley D. Medicinal plants for insomnia: a review of their pharmacology, efficacy and tolerability. J Psychopharmacol. 2005;19:414–21.PubMedCrossRefGoogle Scholar
  55. 55.
    Keledjian J, Duffield PH, Jamieson DD, Lidgaard RO, Duffield AM. Uptake into mouse brain of four compounds present in the psychoactive beverage kava. J Pharm Sci. 1988;77:1003–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Seitz U, Schule A, Gleitz J. [3H]-Monoamine uptake inhibition properties of kava pyrones. Planta Med. 1997;63:548–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Bilia AR, Scalise L, Bergonzi MC, Vincieri FF. Analysis of kavalactones from Piper methysticum (kava-kava). J Chromatogr B. 2004;812:203–14.Google Scholar
  58. 58.
    Fu PP, Xia Q, Guo L, Yu H, Chan PC. Toxicity of kava kava. J Environ Sci Health C. 2008;26:89–112.CrossRefGoogle Scholar
  59. 59.
    Raucy JL. Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Drug Metab Dispos. 2003;31:533–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Yueh MF, Kawahara M, Raucy J. High volume bioassays to assess CYP3A4-mediated drug interactions: induction and inhibition in a single cell line. Drug Metab Dispos. 2005;33:38–48.PubMedCrossRefGoogle Scholar
  61. 61.
    Ma Y, Sachdeva K, Liu J, Ford M, Yang D, Khan IA, et al. Desmethoxyyangonin and dihyromethysticin are two major pharmacological kavalactones with marked activity on the induction of CYP3A23. Drug Metab Dispos. 2004;32:1317–24.PubMedCrossRefGoogle Scholar
  62. 62.
    Li MH, Chen JM, Peng Y, Wu Q, Xiao PG. Investigation of Danshen and related medicinal plants in China. J Ethnopharmacol. 2008;120:419–26.PubMedCrossRefGoogle Scholar
  63. 63.
    Cheng TO. Cardiovascular effects of Danshen. Int J Cardiol. 2007;121:9–22.PubMedCrossRefGoogle Scholar
  64. 64.
    Wang X, Morris-Natschke SL, Lee KH. New developments in the chemistry and biology of the bioactive constituents of tanshen. Med Res Rev. 2007;27:133–48.PubMedCrossRefGoogle Scholar
  65. 65.
    Yu C, Ye S, Sun H, Liu Y, Gao L, Shen C, et al. PXR-mediated transcriptional activation of CYP3A4 by cryptotanshinone and tanshinone IIA. Chem Biol Interact. 2009;177:58–64.PubMedCrossRefGoogle Scholar
  66. 66.
    Kuo YH, Lin YL, Don MJ, Chen RM, Ueng YF. Induction of cytochrome P450-dependent monooxygenase by extracts of the medicinal herb Salvia miltiorrhiza. J Pharm Pharmacol. 2006;58:521–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Panossian A, Wikman G. Pharmacology of Schisandra chinensis Bail.: an overview of Russian research and uses in medicine. J Ethnopharmacol. 2008;118:183–212.PubMedCrossRefGoogle Scholar
  68. 68.
    Chang HF, Lin YH, Chu CC, Wu SJ, Tsai YH, Chao JCJ. Protective effects of Ginkgo biloba, Panax ginseng, and Schizandra chinensis extract on liver injury in rats. Am J Chin Med. 2007;35:995–1009.PubMedCrossRefGoogle Scholar
  69. 69.
    Halstead CW, Lee S, Khoo CS, Hennell JR, Bensoussan A. Validation of a method for the simultaneous determination of four schisandra lignans in the raw herb and commerical dried aqueous extracts of Schisandra chinensis (wu wei zi) by RP-LC with DAD. J Pharm Biomed Anal. 2007;45:30–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Mu Y, Zhang J, Zhang S, Zhou HH, Toma D, Ren S, et al. Traditional Chinese medicines Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch) activate pregnane X receptor and increases warfarin clearance in rats. J Pharmacol Exp Ther. 2006;316:1369–77.PubMedCrossRefGoogle Scholar
  71. 71.
    Sun A, Chia JS, Wang WB, Chiang CP. Immunomodulating effects of “Tien-Hsien liquid” on peripheral blood mononuclear cells and T-lymphocytes from patients with recurrent aphthous ulcerations. Am J Chin Med. 2004;32:221–4.PubMedCrossRefGoogle Scholar
  72. 72.
    Sun A, Chia JS, Chiang CP, Hsuen SP, Du JL, Wu CW, et al. The Chinese herbal medicine tien-hsien liquid inhibits cell growth and induces apoptosis in a wide variety of human cancer cells. J Altern Complement Med. 2005;11:245–56.PubMedCrossRefGoogle Scholar
  73. 73.
    Lichti-Kaiser K, Staudinger JL. The traditional Chinese herbal remedy tian xian activates pregnane X receptor and induces CYP3A gene expression in hepatocytes. Drug Metab Dispos. 2008;36:1538–45.PubMedCrossRefGoogle Scholar
  74. 74.
    van den Bout-van den Beukel CJP, Hamza OJM, Moshi JM, Matee MIN, Mikx F, Burger DM, et al. Evaluation of cytotoxic, genotoxic and CYP450 enzymatic competition effects of Tanzanian plant extracts traditionally used for treatment of fungal infections. Basic Clin Pharmacol Toxicol. 2008;102:515–26.Google Scholar
  75. 75.
    Mills E, Foster BC, van Heeswijk R, Phillips E, Wilson K, Leonard B, et al. Impact of African herbal medicines on antiretroviral metabolism. AIDS. 2005;19:95–7.PubMedCrossRefGoogle Scholar
  76. 76.
    Wei P, Zhang J, Dowhan DH, Han Y, Moore DD. Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response. Pharmacogenomics J. 2002;2:117–26.PubMedCrossRefGoogle Scholar
  77. 77.
    Faucette SR, Sueyoshi T, Smith CM, Negishi M, LeCluyse EL, Wang H. 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.PubMedCrossRefGoogle Scholar
  78. 78.
    Tien ES, Negishi M. Nuclear receptors CAR and PXR in the regulation of hepatic metabolism. Xenobiotica. 2006;36:1152–63.PubMedCrossRefGoogle Scholar
  79. 79.
    Lempiainen H, Molnar F, Gonzalez MM, Perakyla M, Carlberg C. Antagonist- and inverse agonist-driven interactions of the vitamin D receptor and the constitutive androstane receptor with corepressor protein. Mol Endocrinol. 2005;19:2258–72.PubMedCrossRefGoogle Scholar
  80. 80.
    Kodama S, Negishi M. Phenobarbital confers its diverse effects by activating the orphan nuclear receptor CAR. Drug Metab Rev. 2006;38:75–87.PubMedCrossRefGoogle Scholar
  81. 81.
    Guo D, Sarkar J, Suino-Powell K, Xu Y, Matsumoto K, Jia Y, et al. Induction of nuclear translocation of constitutive androstane receptor by peroxisome proliferator-activated receptor α synthetic ligands in mouse liver. J Biol Chem. 2007;282:36766–76.PubMedCrossRefGoogle Scholar
  82. 82.
    Iciek M, Kwiecien I, Wlodek L. Biological properties of garlic and garlic-derived organosulfur compounds. Environ Mol Mutagen. 2009;50:247–65.PubMedCrossRefGoogle Scholar
  83. 83.
    Amagase H. Clarifying the real bioactive constituents of garlic. J Nutr. 2006;136(Suppl. 3):716S–25S.PubMedGoogle Scholar
  84. 84.
    Fisher CD, Augustine LM, Maher JM, Nelson DM, Slitt AL, Klaassen CD, et al. Induction of drug-metabolizing enzymes by garlic and allyl sulfide compounds via activation of constitutive androstane receptor and nuclear factor E2-related factor 2. Drug Metab Dispos. 2007;35:995–1000.PubMedCrossRefGoogle Scholar
  85. 85.
    Yoshinari K, Sueyoshi T, Moore R, Negishi M. Nuclear receptor CAR as a regulatory factor for the sexually dimorphic induction of CYP2B1 gene by phenobarbital in rat livers. Mol Pharmacol. 2001;59:278–84.PubMedGoogle Scholar
  86. 86.
    Ding X, Staudinger JL. The ratio of constitutive androstane receptor to pregnane X receptor determines the activity of guggulsterone against the Cyp2b10 promoter. J Pharmacol Exp Ther. 2005;314:120–7.PubMedCrossRefGoogle Scholar
  87. 87.
    Chang TKH, Bandiera SM, Chen J. Constitutive androstane receptor and pregnane X receptor gene expression in human liver: Interindividual variability and correlation with CYP2B6 mRNA levels. Drug Metab Dispos. 2003;31:7–10.PubMedCrossRefGoogle Scholar
  88. 88.
    Maglich JM, Parks DJ, Moore LB, Collins JL, Goodwin B, Billin AN, 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.PubMedCrossRefGoogle Scholar
  89. 89.
    Umegaki K, Saito K, Kubota Y, Sanada H, Yamada K, Shinozuka K. Ginkgo biloba extract markedly induces pentoxyresorufin O-dealkylase activity in rats. Jpn J Pharmacol. 2002;90:345–51.PubMedCrossRefGoogle Scholar
  90. 90.
    Chen ZL, Guan WH. Approach to the effect and indication of Yin Zhi Huang to treat neonatal jaundice. J Clin Pediatr. 1985;3:302–3.Google Scholar
  91. 91.
    Yin J, Wennberg RP, Xia Y, Liu JW, Zhou H. Effect of a traditional Chinese medicine, Yin Zhi Huang, on bilirubin clearance and conjugation. Dev Pharmacol Ther. 1991;16:59–64.PubMedGoogle Scholar
  92. 92.
    Zhu Z, Kim S, Chen T, Lin JH, Bell A, Bryson J, et al. Correlation of high-throughput pregnane X receptor (PXR) transactivation and binding assays. J Biomol Screen. 2004;9:533–40.PubMedCrossRefGoogle Scholar
  93. 93.
    McGinnity DF, Zhang G, Kenny JR, Hamilton GA, Otmani S, Stams KR, et al. Evaluation of multiple in vitro systems for assessment of CYP3A4 induction in drug discovery: human hepatocytes, pregnane X receptor reporter gene, and Fa2N-4 and HepaRG cells. Drug Metab Dispos. 2009;37:1259–68.PubMedCrossRefGoogle Scholar
  94. 94.
    Kawamoto T, Sueyoshi T, Zelko I, Moore R, Washburn K, Negishi M. Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene. Mol Cell Biol. 1999;19:6318–22.PubMedGoogle Scholar
  95. 95.
    Xie W, Barwick JL, Downes M, Blumberg B, Simon CM, Nelson MC, et al. Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature. 2000;406:435–9.PubMedCrossRefGoogle Scholar
  96. 96.
    Wei P, Zhang J, Egan-Hafley M, Liang S, Moore DD. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature. 2000;407:920–3.PubMedCrossRefGoogle Scholar
  97. 97.
    Ma X, Shah Y, Cheung C, Guo GL, Feigenbaum L, Krausz KW, et al. The pregnane X receptor gene-humanized mouse: a model for investigating drug-drug interactions mediated by cytochrome P450 3A. Drug Metab Dispos. 2007;35:194–200.PubMedCrossRefGoogle Scholar
  98. 98.
    Scheer N, Ross J, Rode A, Zevnik B, Niehaves S, Faust N, 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.PubMedCrossRefGoogle Scholar
  99. 99.
    Schuetz E, Lan L, Yasuda K, Kim R, Kocarek TA, Schuetz J, et al. Development of a real-time in vivo transcription assay: application reveals pregnane X receptor-mediated induction of CYP3A4 by cancer chemotherapeutic agents. Mol Pharmacol. 2002;62:439–45.PubMedCrossRefGoogle Scholar
  100. 100.
    Wang H, Faucette S, Moore R, Sueyoshi T, Negishi M, LeCluyse E. Human constitutive androstane receptor mediates induction of CYP2B6 gene expression by phenytoin. J Biol Chem. 2004;279:29295–301.PubMedCrossRefGoogle Scholar

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© American Association of Pharmaceutical Scientists 2009

Authors and Affiliations

  1. 1.Faculty of Pharmaceutical SciencesThe University of British ColumbiaVancouverCanada

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