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Impact of Nuclear Receptors CAR, PXR, FXR, and VDR, and Their Ligands On Enzymes and Transporters

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Enzyme- and Transporter-Based Drug-Drug Interactions

Abstract

Nuclear receptors play a central role on the mechanism of induction-type drug–drug interactions by acting as xenosensing transcription factors. Together, PXR, CAR, FXR, and VDR form a core group of nuclear receptors that regulate the expression of a number of important drug-metabolizing enzymes and drug transporters. In this chapter, the molecular determinants of adaptive response to drug exposure are detailed in the context of clinical relevance and drug development.

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References

  • Acocella G (1978) Clinical pharmacokinetics of rifampicin. Clin Pharmacokinet 3:108–127.

    Article  CAS  PubMed  Google Scholar 

  • Adesnik M, Bar-Nun S, Maschio F, Zunich M, Lippman A and Bard E (1981) Mechanism of induction of cytochrome P-450 by phenobarbital. J Biol Chem 256:10340–10345.

    CAS  PubMed  Google Scholar 

  • Ananthanarayanan M, Balasubramanian N, Makishima M, Mangelsdorf DJ and Suchy FJ (2001) Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem 276:28857–28865.

    Article  CAS  PubMed  Google Scholar 

  • Aninat C, Piton A, Glaise D, Le Charpentier T, Langouet S, Morel F, Guguen-Guillouzo C and Guillouzo A (2006) Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells. Drug Metab Dispos 34:75–83.

    Article  CAS  PubMed  Google Scholar 

  • Assem M, Schuetz EG, Leggas M, Sun D, Yasuda K, Reid G, Zelcer N, Adachi M, Strom S, Evans RM, Moore DD, Borst P and Schuetz JD (2004) Interactions between hepatic Mrp4 and Sult2a as revealed by the constitutive androstane receptor and Mrp4 knockout mice. J Biol Chem 279:22250–22257.

    Article  CAS  PubMed  Google Scholar 

  • Baciewicz AM, Chrisman CR, Finch CK and Self TH (2008) Update on rifampin and rifabutin drug interactions. Am J Med Sci 335:126–136.

    Article  PubMed  Google Scholar 

  • Baes M, Gulick T, Choi HS, Martinoli MG, Simha D and Moore DD (1994) A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements. Mol Cell Biol 14:1544–1551.

    CAS  PubMed  Google Scholar 

  • Baker AR, McDonnell DP, Hughes M, Crisp TM, Mangelsdorf DJ, Haussler MR, Pike JW, Shine J and O‘Malley BW (1988) Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci U S A 85:3294–3298.

    Article  CAS  PubMed  Google Scholar 

  • Barbier O, Torra IP, Sirvent A, Claudel T, Blanquart C, Duran-Sandoval D, Kuipers F, Kosykh V, Fruchart JC and Staels B (2003) FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity. Gastroenterology 124:1926–1940.

    Article  CAS  PubMed  Google Scholar 

  • Bauer B, Hartz AM, Fricker G and Miller DS (2004) Pregnane X receptor up-regulation of P-glycoprotein expression and transport function at the blood-brain barrier. Mol Pharmacol 66:413–419.

    CAS  PubMed  Google Scholar 

  • Bauer B, Hartz AM, Lucking JR, Yang X, Pollack GM and Miller DS (2008) Coordinated nuclear receptor regulation of the efflux transporter, Mrp2, and the phase-II metabolizing enzyme, GSTpi, at the blood-brain barrier. J Cereb Blood Flow Metab 28:1222–1234.

    Article  CAS  PubMed  Google Scholar 

  • Bauer B, Yang X, Hartz AM, Olson ER, Zhao R, Kalvass JC, Pollack GM and Miller DS (2006) In vivo activation of human pregnane X receptor tightens the blood-brain barrier to methadone through P-glycoprotein up-regulation. Mol Pharmacol 70:1212–1219.

    Article  CAS  PubMed  Google Scholar 

  • Beischlag TV, Luis Morales J, Hollingshead BD and Perdew GH (2008) The aryl hydrocarbon receptor complex and the control of gene expression. Crit Rev Eukaryot Gene Expr 18:207–250.

    CAS  PubMed  Google Scholar 

  • Benedetti MS (2000) Enzyme induction and inhibition by new antiepileptic drugs: a review of human studies. Fundam Clin Pharmacol 14:301–319.

    Article  CAS  PubMed  Google Scholar 

  • Bertilsson G, Berkenstam A and Blomquist P (2001) Functionally conserved xenobiotic responsive enhancer in cytochrome P450 3A7. Biochem Biophys Res Commun 280:139–144.

    Article  CAS  PubMed  Google Scholar 

  • Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Backman M, Ohlsson R, Postlind H, Blomquist P and Berkenstam A (1998) Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci U S A 95:12208–12213.

    Article  CAS  PubMed  Google Scholar 

  • Bertilsson L, Hojer B, Tybring G, Osterloh J and Rane A (1980) Autoinduction of carbamazepine metabolism in children examined by a stable isotope technique. Clin Pharmacol Ther 27:83–88.

    Article  CAS  PubMed  Google Scholar 

  • Blumberg B, Sabbagh W, Jr., Juguilon H, Bolado J, Jr., van Meter CM, Ong ES and Evans RM (1998) SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev 12:3195–3205.

    Article  CAS  PubMed  Google Scholar 

  • Boyer JL, Trauner M, Mennone A, Soroka CJ, Cai SY, Moustafa T, Zollner G, Lee JY and Ballatori N (2006) Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTalpha-OSTbeta in cholestasis in humans and rodents. Am J Physiol 290:G1124–G1130.

    CAS  Google Scholar 

  • Briz O, Romero MR, Martinez-Becerra P, Macias RI, Perez MJ, Jimenez F, San Martin FG and Marin JJ (2006) Oatp8/1B3-mediated cotransport of bile acids and glutathione. An export pathway for organic anions from hepatocytes?. J Biol Chem 281:30326–30335.

    Article  CAS  PubMed  Google Scholar 

  • Burbach KM, Poland A and Bradfield CA (1992) Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proc Natl Acad Sci USA 89:8185–8189.

    Article  CAS  PubMed  Google Scholar 

  • Burk O, Arnold KA, Nussler AK, Schaeffeler E, Efimova E, Avery BA, Avery MA, Fromm MF and Eichelbaum M (2005) Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol 67:1954–1965.

    Article  CAS  PubMed  Google Scholar 

  • Carter BA, Taylor OA, Prendergast DR, Zimmerman TL, Von Furstenberg R, Moore DD and Karpen SJ (2007) Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR. Pediatr Res 62:301–306.

    Article  CAS  PubMed  Google Scholar 

  • Castro-Gago M, Novo-Rodriguez MI, Gomez-Lado C, Rodriguez-Garcia J, Rodriguez-Segade S and Eiris-Punal J (2007) Evolution of subclinical hypothyroidism in children treated with antiepileptic drugs. Pediatr Neurol 37:426–430.

    Article  PubMed  Google Scholar 

  • Chawla A, Repa JJ, Evans RM and Mangelsdorf DJ (2001) Nuclear receptors and lipid physiology: opening the X-files. Science 294:1866–1870.

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Ferguson SS, Negishi M and Goldstein JA (2003) Identification of constitutive androstane receptor and glucocorticoid receptor binding sites in the CYP2C19 promoter. Mol Pharmacol 64:316–324.

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Ferguson SS, Negishi M and Goldstein JA (2004) Induction of human CYP2C9 by rifampicin, hyperforin, and phenobarbital is mediated by the pregnane X receptor. J Pharmacol Exp Ther 308:495–501.

    Article  CAS  PubMed  Google Scholar 

  • Conney AH, Davison C, Gastel R and Burns JJ (1960) Adaptive increases in drug-metabolizing enzymes induced by phenobarbital and other drugs. J Pharmacol Exp Ther 130:1–8.

    CAS  PubMed  Google Scholar 

  • Conney AH, Jacobson M, Schneidman K and Kuntzman R (1965) Induction of liver microsomal cortisol 6beta-hydroxylase by diphenylhydantoin or phenobarbital: an explanation for the increased excretion of 6-hydroxycortisol in humans treated with these drugs. Life Sci 4:1091–1098.

    Article  CAS  PubMed  Google Scholar 

  • Cucinell SA, Koster R, Conney AH and Burns JJ (1963) Stimulatory Effect Of Phenobarbital On The Metabolism Of Diphenylhydantoin. J Pharmacol Exp Ther 141:157–160.

    CAS  PubMed  Google Scholar 

  • Curran PG and DeGroot LJ (1991) The effect of hepatic enzyme-inducing drugs on thyroid hormones and the thyroid gland. Endocr Rev 12:135–150.

    Article  CAS  PubMed  Google Scholar 

  • de Haan W, de Vries-van der Weij J, Mol IM, Hoekstra M, Romijn JA, Jukema JW, Havekes LM, Princen HM and Rensen PC (2009) PXR agonism decreases plasma HDL levels in ApoE3-Leiden.CETP mice. Biochim Biophys Acta 1791:191–197.

    PubMed  Google Scholar 

  • Dekeyser JG, Stagliano MC, Auerbach SS, Prabu KS, Jones AD and Omiecinski CJ (2009) Di(2-ethylhexyl) phthalate is a highly potent agonist for the human constitutive androstane receptor splice variant, CAR2. Mol Pharmacol 75:1003–1013.

    Article  CAS  Google Scholar 

  • Denson LA, Sturm E, Echevarria W, Zimmerman TL, Makishima M, Mangelsdorf DJ and Karpen SJ (2001) The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology 121:140–147.

    Article  CAS  PubMed  Google Scholar 

  • DeVane CL (2003) Pharmacokinetics, drug interactions, and tolerability of valproate. Psychopharmacol Bull 37 Suppl 2:25–42.

    PubMed  Google Scholar 

  • Ding X, Lichti K and Staudinger JL (2006) The mycoestrogen zearalenone induces CYP3A through activation of the pregnane X receptor. Toxicol Sci 91:448–455.

    Article  CAS  PubMed  Google Scholar 

  • Ding X and Staudinger JL (2005a) 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 312:849–856.

    Article  CAS  PubMed  Google Scholar 

  • Ding X and Staudinger JL (2005b) Repression of PXR-mediated induction of hepatic CYP3A gene expression by protein kinase C. Biochem Pharmacol 69:867–873.

    Article  CAS  PubMed  Google Scholar 

  • Dresser GK, Schwarz UI, Wilkinson GR and Kim RB (2003) Coordinate induction of both cytochrome P4503A and MDR1 by St John’s wort in healthy subjects. Clin Pharmacol Ther 73:41–50.

    Article  CAS  PubMed  Google Scholar 

  • Dring MM, Goulding CA, Trimble VI, Keegan D, Ryan AW, Brophy KM, Smyth CM, Keeling PW, O‘Donoghue D, O‘Sullivan M, O‘Morain C, Mahmud N, Wikstrom AC, Kelleher D and McManus R (2006) The pregnane X receptor locus is associated with susceptibility to inflammatory bowel disease. Gastroenterology 130:341–348 quiz 592.

    Article  CAS  PubMed  Google Scholar 

  • Drocourt L, Ourlin JC, Pascussi JM, Maurel P and Vilarem MJ (2002) Expression of CYP3A4, CYP2B6, and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes. J Biol Chem 277:25125–25132.

    Article  CAS  PubMed  Google Scholar 

  • Drocourt L, Pascussi JM, Assenat E, Fabre JM, Maurel P and Vilarem MJ (2001) Calcium channel modulators of the dihydropyridine family are human pregnane X receptor activators and inducers of CYP3A, CYP2B, and CYP2C in human hepatocytes. Drug Metab Dispos 29:1325–1331.

    CAS  PubMed  Google Scholar 

  • Durr D, Stieger B, Kullak-Ublick GA, Rentsch KM, Steinert HC, Meier PJ and Fattinger K (2000) St John’s Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin Pharmacol Ther 68:598–604.

    Article  CAS  PubMed  Google Scholar 

  • Dussault I, Beard R, Lin M, Hollister K, Chen J, Xiao JH, Chandraratna R and Forman BM (2003a) Identification of gene-selective modulators of the bile acid receptor FXR. J Biol Chem 278:7027–7033.

    Article  CAS  PubMed  Google Scholar 

  • Dussault I, Yoo HD, Lin M, Wang E, Fan M, Batta AK, Salen G, Erickson SK and Forman BM (2003b) Identification of an endogenous ligand that activates pregnane X receptor-mediated sterol clearance. Proc Natl Acad Sci USA 100:833–838.

    Article  CAS  PubMed  Google Scholar 

  • Echchgadda I, Song CS, Oh T, Ahmed M, De La Cruz IJ and Chatterjee B (2007) The xenobiotic-sensing nuclear receptors pregnane X receptor, constitutive androstane receptor, and orphan nuclear receptor hepatocyte nuclear factor 4 in the regulation of human steroid-/bile acid-sulfotransferase. Mol Endocrinol 21:2099–2111.

    Article  CAS  PubMed  Google Scholar 

  • Echchgadda I, Song CS, Roy AK and Chatterjee B (2004) Dehydroepiandrosterone sulfotransferase is a target for transcriptional induction by the vitamin D receptor. Mol Pharmacol 65:720–729.

    Article  CAS  PubMed  Google Scholar 

  • Eiris-Punal J, Del Rio-Garma M, Del Rio-Garma MC, Lojo-Rocamonde S, Novo-Rodriguez I and Castro-Gago M (1999) Long-term treatment of children with epilepsy with valproate or carbamazepine may cause subclinical hypothyroidism. Epilepsia 40:1761–1766.

    Article  CAS  PubMed  Google Scholar 

  • Evans MJ, Mahaney PE, Borges-Marcucci L, Lai K, Wang S, Krueger JA, Gardell SJ, Huard C, Martinez R, Vlasuk GP and Harnish DC (2009) A synthetic farnesoid X receptor (FXR) agonist promotes cholesterol lowering in models of dyslipidemia. Am J Physiol 296:G543–G552.

    CAS  Google Scholar 

  • Fang HL, Strom SC, Ellis E, Duanmu Z, Fu J, Duniec-Dmuchowski Z, Falany CN, Falany JL, Kocarek TA and Runge-Morris M (2007) Positive and Negative Regulation of Human Hepatic Hydroxysteroid Sulfotransferase (SULT2A1) Gene Transcription by Rifampicin: Roles of Hepatocyte Nuclear Factor 4? and Pregnane X Receptor. J Pharmacol Exp Ther 323:586–590.

    Article  CAS  PubMed  Google Scholar 

  • Ferguson SS, LeCluyse EL, Negishi M and Goldstein JA (2002) Regulation of human CYP2C9 by the constitutive androstane receptor: discovery of a new distal binding site. Mol Pharmacol 62:737–746.

    Article  CAS  PubMed  Google Scholar 

  • Figge A, Lammert F, Paigen B, Henkel A, Matern S, Korstanje R, Shneider BL, Chen F, Stoltenberg E, Spatz K, Hoda F, Cohen DE and Green RM (2004) Hepatic overexpression of murine Abcb11 increases hepatobiliary lipid secretion and reduces hepatic steatosis. J Biol Chem 279:2790–2799.

    Article  CAS  PubMed  Google Scholar 

  • Finch CK, Chrisman CR, Baciewicz AM and Self TH (2002) Rifampin and rifabutin drug interactions: an update. Arch Intern Med 162:985–992.

    Article  CAS  PubMed  Google Scholar 

  • Finkelstein D, Lamba V, Assem M, Rengelshausen J, Yasuda K, Strom S and Schuetz E (2006) ADME transcriptome in Hispanic versus White donor livers: evidence of a globally enhanced NR1I3 (CAR, constitutive androstane receptor) gene signature in Hispanics. Xenobiotica 36:989–1012.

    Article  CAS  PubMed  Google Scholar 

  • Finn RD, Henderson CJ, Scott CL and Wolf CR (2009) Unsaturated fatty acid regulation of cytochrome P450 expression via a CAR-dependent pathway. Biochem J 417:43–54.

    Article  CAS  PubMed  Google Scholar 

  • Flatt B, Martin R, Wang TL, Mahaney P, Murphy B, Gu XH, Foster P, Li J, Pircher P, Petrowski M, Schulman I, Westin S, Wrobel J, Yan G, Bischoff E, Daige C and Mohan R (2009) Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR). J Med Chem Jan 21. [Epub ahead of print].

    Google Scholar 

  • Forman BM, Tzameli I, Choi HS, Chen J, Simha D, Seol W, Evans RM and Moore DD (1998) Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta. Nature 395:612–615.

    Article  CAS  PubMed  Google Scholar 

  • Frankenberg T, Miloh T, Chen FY, Ananthanarayanan M, Sun AQ, Balasubramaniyan N, Arias I, Setchell KD, Suchy FJ and Shneider BL (2008) The membrane protein ATPase class I type 8B member 1 signals through protein kinase C zeta to activate the farnesoid X receptor. Hepatology 48:1896–1905.

    Article  CAS  PubMed  Google Scholar 

  • Fromm MF, Kauffmann HM, Fritz P, Burk O, Kroemer HK, Warzok RW, Eichelbaum M, Siegmund W and Schrenk D (2000) The effect of rifampin treatment on intestinal expression of human MRP transporters. Am J Pathol 157:1575–1580.

    CAS  PubMed  Google Scholar 

  • Frye RF, Fitzgerald SM, Lagattuta TF, Hruska MW and Egorin MJ (2004) Effect of St John’s wort on imatinib mesylate pharmacokinetics. Clin Pharmacol Ther 76:323–329.

    Article  CAS  PubMed  Google Scholar 

  • Gallicano KD, Sahai J, Shukla VK, Seguin I, Pakuts A, Kwok D, Foster BC and Cameron DW (1999) Induction of zidovudine glucuronidation and amination pathways by rifampicin in HIV-infected patients. Br J Clin Pharmacol 48:168–179.

    Article  CAS  PubMed  Google Scholar 

  • Gardner-Stephen D, Heydel JM, Goyal A, Lu Y, Xie W, Lindblom T, Mackenzie P and Radominska-Pandya A (2004) Human PXR variants and their differential effects on the regulation of human UDP-glucuronosyltransferase gene expression. Drug Metab Dispos 32:340–347.

    Article  CAS  PubMed  Google Scholar 

  • Geick A, Eichelbaum M and Burk O (2001) Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem 276:14581–14587.

    Article  CAS  PubMed  Google Scholar 

  • Gerbal-Chaloin S, Daujat M, Pascussi JM, Pichard-Garcia L, Vilarem MJ and Maurel P (2002) Transcriptional regulation of CYP2C9 gene. Role of glucocorticoid receptor and constitutive androstane receptor. J Biol Chem 277:209–217.

    Article  CAS  PubMed  Google Scholar 

  • Gerbal-Chaloin S, Pascussi JM, Pichard-Garcia L, Daujat M, Waechter F, Fabre JM, Carrere N and Maurel P (2001) Induction of CYP2C genes in human hepatocytes in primary culture. Drug Metab Dispos 29:242–251.

    CAS  PubMed  Google Scholar 

  • Gineste R, Sirvent A, Paumelle R, Helleboid S, Aquilina A, Darteil R, Hum DW, Fruchart JC and Staels B (2008) Phosphorylation of farnesoid X receptor by protein kinase C promotes its transcriptional activity. Mol Endocrinol 22:2433–2447.

    Article  CAS  PubMed  Google Scholar 

  • Gnerre C, Blattler S, Kaufmann MR, Looser R and Meyer UA (2004) Regulation of CYP3A4 by the bile acid receptor FXR: evidence for functional binding sites in the CYP3A4 gene. Pharmacogenetics 14:635–645.

    Article  CAS  PubMed  Google Scholar 

  • Goodwin B, Hodgson E and Liddle C (1999) The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Mol Pharmacol 56:1329–1339.

    CAS  PubMed  Google Scholar 

  • Goodwin B, Moore LB, Stoltz CM, McKee DD and Kliewer SA (2001) Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor. Mol Pharmacol 60:427–431.

    CAS  PubMed  Google Scholar 

  • Gorski JC, Huang SM, Pinto A, Hamman MA, Hilligoss JK, Zaheer NA, Desai M, Miller M and Hall SD (2004) The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo. Clin Pharmacol Ther 75:89–100.

    Article  PubMed  Google Scholar 

  • Greiner B, Eichelbaum M, Fritz P, Kreichgauer HP, von Richter O, Zundler J and Kroemer HK (1999) The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Invest 104:147–153.

    Article  CAS  PubMed  Google Scholar 

  • Hariparsad N, Carr BA, Evers R and Chu X (2008) Comparison of immortalized Fa2N-4 cells and human hepatocytes as in vitro models for cytochrome P450 induction. Drug Metab Dispos 36:1046–1055.

    Article  CAS  PubMed  Google Scholar 

  • Hartman HB, Gardell SJ, Petucci CJ, Wang S, Krueger JA and Evans MJ (2009) Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR-/- and apoE-/- mice. J Lipid Res Jan 27. [Epub ahead of print].

    Google Scholar 

  • Hayashi A, Suzuki H, Itoh K, Yamamoto M and Sugiyama Y (2003) Transcription factor Nrf2 is required for the constitutive and inducible expression of multidrug resistance-associated protein 1 in mouse embryo fibroblasts. Biochem Biophys Res Commun 310:824–829.

    Article  CAS  PubMed  Google Scholar 

  • Healan-Greenberg C, Waring JF, Kempf DJ, Blomme EA, Tirona RG and Kim RB (2008) A human immunodeficiency virus protease inhibitor is a novel functional inhibitor of human pregnane X receptor. Drug Metab Dispos 36:500–507.

    Article  CAS  PubMed  Google Scholar 

  • Hendrix CW, Wakeford J, Wire MB, Lou Y, Bigelow GE, Martinez E, Christopher J, Fuchs EJ and Snidow JW (2004) Pharmacokinetics and pharmacodynamics of methadone enantiomers after coadministration with amprenavir in opioid-dependent subjects. Pharmacotherapy 24:1110–1121.

    Article  CAS  PubMed  Google Scholar 

  • Hoekstra M, Lammers B, Out R, Li Z, Van Eck M and Van Berkel TJ (2009) Activation of the nuclear receptor PXR decreases plasma LDL-cholesterol levels and induces hepatic steatosis in LDL receptor knockout mice. Mol Pharm 6:182–189.

    Article  CAS  PubMed  Google Scholar 

  • Hoffman EC, Reyes H, Chu FF, Sander F, Conley LH, Brooks BA and Hankinson O (1991) Cloning of a factor required for activity of the Ah (dioxin) receptor. Science 252:954–958.

    Article  CAS  PubMed  Google Scholar 

  • Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M and Brinkmann U (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97:3473–3478.

    Article  CAS  PubMed  Google Scholar 

  • Honkakoski P, Zelko I, Sueyoshi T and Negishi M (1998) The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol Cell Biol 18:5652–5658.

    CAS  PubMed  Google Scholar 

  • Hosseinpour F, Timsit Y, Koike C, Matsui K, Yamamoto Y, Moore R and Negishi M (2007) Overexpression of the Rho-guanine nucleotide exchange factor ECT2 inhibits nuclear translocation of nuclear receptor CAR in the mouse liver. FEBS Lett 581:4937–4942.

    Article  CAS  PubMed  Google Scholar 

  • Huang H, Wang H, Sinz M, Zoeckler M, Staudinger J, Redinbo MR, Teotico DG, Locker J, Kalpana GV and Mani S (2007) Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. Oncogene 26:258–268.

    Article  PubMed  CAS  Google Scholar 

  • Huang W, Zhang J, Chua SS, Qatanani M, Han Y, Granata R and Moore DD (2003) Induction of bilirubin clearance by the constitutive androstane receptor (CAR). Proc Natl Acad Sci USA 100:4156–4161.

    Article  CAS  PubMed  Google Scholar 

  • Huang W, Zhang J and Moore DD (2004) A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. J Clin Invest 113:137–143.

    CAS  PubMed  Google Scholar 

  • Hustert E, Zibat A, Presecan-Siedel E, Eiselt R, Mueller R, Fuss C, Brehm I, Brinkmann U, Eichelbaum M, Wojnowski L and Burk O (2001) Natural protein variants of pregnane X receptor with altered transactivation activity toward CYP3A4. Drug Metab Dispos 29:1454–1459.

    CAS  PubMed  Google Scholar 

  • Huwyler J, Wright MB, Gutmann H and Drewe J (2006) Induction of cytochrome P450 3A4 and P-glycoprotein by the isoxazolyl-penicillin antibiotic flucloxacillin. Curr Drug Metab 7:119–126.

    Article  CAS  PubMed  Google Scholar 

  • Inoue K and Negishi M (2008) Nuclear receptor CAR requires early growth response 1 to activate the human cytochrome P450 2B6 gene. J Biol Chem 283:10425–10432.

    Article  CAS  PubMed  Google Scholar 

  • Itoh M, Nakajima M, Higashi E, Yoshida R, Nagata K, Yamazoe Y and Yokoi T (2006) Induction of human CYP2A6 is mediated by the pregnane X receptor with peroxisome proliferator-activated receptor-gamma coactivator 1alpha. J Pharmacol Exp Ther 319:693–702.

    Article  CAS  PubMed  Google Scholar 

  • Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M and Roots I (1999) Pharmacokinetic interaction of digoxin with an herbal extract from St John’s wort (Hypericum perforatum). Clin Pharmacol Ther 66:338–345.

    Article  CAS  PubMed  Google Scholar 

  • Jung D, Elferink MG, Stellaard F and Groothuis GM (2007) Analysis of bile acid-induced regulation of FXR target genes in human liver slices. Liver Int 27:137–144.

    Article  CAS  PubMed  Google Scholar 

  • Jung D, Mangelsdorf DJ and Meyer UA (2006) Pregnane X receptor is a target of farnesoid X receptor. J Biol Chem 281:19081–19091.

    Article  CAS  PubMed  Google Scholar 

  • Jung D, Podvinec M, Meyer UA, Mangelsdorf DJ, Fried M, Meier PJ and Kullak-Ublick GA (2002) Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptor. Gastroenterology 122:1954–1966.

    Article  CAS  PubMed  Google Scholar 

  • Justesen US, Klitgaard NA, Brosen K and Pedersen C (2003) Pharmacokinetic interaction between amprenavir and delavirdine after multiple-dose administration in healthy volunteers. Br J Clin Pharmacol 55:100–106.

    Article  CAS  PubMed  Google Scholar 

  • Kaeding J, Bouchaert E, Belanger J, Caron P, Chouinard S, Verreault M, Larouche O, Pelletier G, Staels B, Belanger A and Barbier O (2008) Activators of the farnesoid X receptor negatively regulate androgen glucuronidation in human prostate cancer LNCAP cells. Biochem J 410:245–253.

    Article  CAS  PubMed  Google Scholar 

  • Kanebratt KP and Andersson TB (2008) HepaRG cells as an in vitro model for evaluation of cytochrome P450 induction in humans. Drug Metab Dispos 36:137–145.

    Article  CAS  PubMed  Google Scholar 

  • Kang MI, Kobayashi A, Wakabayashi N, Kim SG and Yamamoto M (2004) Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. Proc Natl Acad Sci USA 101:2046–2051.

    Article  CAS  PubMed  Google Scholar 

  • Kast HR, Goodwin B, Tarr PT, Jones SA, Anisfeld AM, Stoltz CM, Tontonoz P, Kliewer S, Willson TM and Edwards PA (2002) Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J Biol Chem 277:2908–2915.

    Article  CAS  PubMed  Google Scholar 

  • Kawaguchi A, Ohmori M, Tsuruoka S, Nishiki K, Harada K, Miyamori I, Yano R, Nakamura T, Masada M and Fujimura A (2004) Drug interaction between St John’s Wort and quazepam. Br J Clin Pharmacol 58:403–410.

    Article  CAS  PubMed  Google Scholar 

  • Kawamoto T, Sueyoshi T, Zelko I, Moore R, Washburn K and Negishi M (1999) Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene. Mol Cell Biol 19:6318–6322.

    CAS  PubMed  Google Scholar 

  • Kennedy J, Wang CC and Wu CH (2008) Patient disclosure about herb and supplement use among adults in the US. Evid Based Complement Alternat Med 5:451–456.

    Article  PubMed  Google Scholar 

  • Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, Taylor A, Xie HG, McKinsey J, Zhou S, Lan LB, Schuetz JD, Schuetz EG and Wilkinson GR (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70:189–199.

    Article  CAS  PubMed  Google Scholar 

  • Kim DL, Song KH, Lee JH, Lee KY and Kim SK (2007) Rifampin-induced hypothyroidism without underlying thyroid disease. Thyroid 17:793–795.

    Article  PubMed  CAS  Google Scholar 

  • King JR and Acosta EP (2006) Tipranavir: a novel nonpeptidic protease inhibitor of HIV. Clin Pharmacokinet 45:665–682.

    Article  CAS  PubMed  Google Scholar 

  • Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, McKee DD, Oliver BB, Willson TM, Zetterstrom RH, Perlmann T and Lehmann JM (1998) An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92:73–82.

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi K, Yamanaka Y, Iwazaki N, Nakajo I, Hosokawa M, Negishi M and Chiba K (2005) Identification of HMG-CoA reductase inhibitors as activators for human, mouse and rat constitutive androstane receptor. Drug Metab Dispos 33:924–929.

    Article  CAS  PubMed  Google Scholar 

  • Kocarek TA, Schuetz EG, Strom SC, Fisher RA and Guzelian PS (1995) Comparative analysis of cytochrome P4503A induction in primary cultures of rat, rabbit, and human hepatocytes. Drug Metab Dispos 23:415–421.

    CAS  PubMed  Google Scholar 

  • Kodama S, Tanaka K, Konishi H, Momota K, Nakasako H, Nakayama S, Yagi J and Koderazawa K (1989) Supplementary thyroxine therapy in patients with hypothyroidism induced by long-term anticonvulsant therapy. Acta Paediatr Jpn 31:555–562.

    CAS  PubMed  Google Scholar 

  • Kohler GI, Bode-Boger SM, Busse R, Hoopmann M, Welte T and Boger RH (2000) Drug–drug interactions in medical patients: effects of in-hospital treatment and relation to multiple drug use. Int J Clin Pharmacol Ther 38:504–513.

    CAS  PubMed  Google Scholar 

  • Kong B, Luyendyk JP, Tawfik O and Guo GL (2009) Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet. J Pharmacol Exp Ther 328:116–122.

    Article  CAS  PubMed  Google Scholar 

  • Kovacs P, Kress R, Rocha J, Kurtz U, Miquel JF, Nervi F, Mendez-Sanchez N, Uribe M, Bock HH, Schirin-Sokhan R, Stumvoll M, Mossner J, Lammert F and Wittenburg H (2008) Variation of the gene encoding the nuclear bile salt receptor FXR and gallstone susceptibility in mice and humans. J Hepatol 48:116–124.

    Article  CAS  PubMed  Google Scholar 

  • Koyano S, Kurose K, Ozawa S, Saeki M, Nakajima Y, Hasegawa R, Komamura K, Ueno K, Kamakura S, Nakajima T, Saito H, Kimura H, Goto Y, Saitoh O, Katoh M, Ohnuma T, Kawai M, Sugai K, Ohtsuki T, Suzuki C, Minami N, Saito Y and Sawada J (2002) 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.

    Article  PubMed  Google Scholar 

  • Kwak MK, Wakabayashi N, Itoh K, Motohashi H, Yamamoto M and Kensler TW (2003) Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J Biol Chem 278:8135–8145.

    Article  CAS  PubMed  Google Scholar 

  • Lamba J, Lamba V, Strom S, Venkataramanan R and Schuetz E (2008) Novel single nucleotide polymorphisms in the promoter and intron 1 of human pregnane X receptor/NR1I2 and their association with CYP3A4 expression. Drug Metab Dispos 36:169–181.

    Article  CAS  PubMed  Google Scholar 

  • Lamba JK, Lin YS, Schuetz EG and Thummel KE (2002) Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 54:1271–1294.

    Article  CAS  PubMed  Google Scholar 

  • Lamba V, Yasuda K, Lamba JK, Assem M, Davila J, Strom S and Schuetz EG (2004) PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators. Toxicol Appl Pharmacol 199:251–265.

    Article  CAS  PubMed  Google Scholar 

  • Lambert CB, Spire C, Claude N and Guillouzo A (2009a) Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol 234:345–360.

    Article  CAS  PubMed  Google Scholar 

  • Lambert CB, Spire C, Renaud MP, Claude N and Guillouzo A (2009b) Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro 23:466–475.

    Article  CAS  PubMed  Google Scholar 

  • Landrier JF, Eloranta JJ, Vavricka SR and Kullak-Ublick GA (2006) The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-alpha and -beta genes. Am J Physiol Gastrointest Liver Physiol 290:G476–G485.

    Article  CAS  PubMed  Google Scholar 

  • Langmade SJ, Gale SE, Frolov A, Mohri I, Suzuki K, Mellon SH, Walkley SU, Covey DF, Schaffer JE and Ory DS (2006) Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann-Pick C disease. Proc Natl Acad Sci USA 103:13807–13812.

    Article  CAS  PubMed  Google Scholar 

  • Langmann T, Moehle C, Mauerer R, Scharl M, Liebisch G, Zahn A, Stremmel W and Schmitz G (2004) Loss of detoxification in inflammatory bowel disease: dysregulation of pregnane X receptor target genes. Gastroenterology 127:26–40.

    Article  CAS  PubMed  Google Scholar 

  • Lazarou J, Pomeranz BH and Corey PN (1998) Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. J Am Med Assoc 279:1200–1205.

    Article  CAS  Google Scholar 

  • Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT and 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 102:1016–1023.

    Article  CAS  PubMed  Google Scholar 

  • Li L, Chen T, Stanton JD, Sueyoshi T, Negishi M and Wang H (2008) The peripheral benzodiazepine receptor ligand 1-(2-chlorophenyl-methylpropyl)-3-isoquinoline-carboxamide is a novel antagonist of human constitutive androstane receptor. Mol Pharmacol 74:443–453.

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Ross-Viola JS, Shay NF, Moore DD and Ricketts ML (2009b) Human CYP3A4 and murine Cyp3A11 are regulated by equol and genistein via the pregnane X receptor in a species-specific manner. J Nutr 139::898–904.

    Article  CAS  Google Scholar 

  • Li L, Stanton JD, Tolson AH, Luo Y and Wang H (2009a) 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 26:872–882.

    Article  CAS  PubMed  Google Scholar 

  • Li YT, Swales KE, Thomas GJ, Warner TD and Bishop-Bailey D (2007) Farnesoid X receptor ligands inhibit vascular smooth muscle cell inflammation and migration. Arterioscler Thromb Vasc Biol 27:2606–2611.

    Article  PubMed  CAS  Google Scholar 

  • Lim YP, Liu CH, Shyu LJ and Huang JD (2005) Functional characterization of a novel polymorphism of pregnane X receptor, Q158K, in Chinese subjects. Pharmacogenet Genomics 15:337–341.

    Article  CAS  PubMed  Google Scholar 

  • Lloyd P, Flesch G and Dieterle W (1994) Clinical pharmacology and pharmacokinetics of oxcarbazepine. Epilepsia 35 Suppl 3:S10–S13.

    Article  CAS  PubMed  Google Scholar 

  • Luo G, Cunningham M, Kim S, Burn T, Lin J, Sinz M, Hamilton G, Rizzo C, Jolley S, Gilbert D, Downey A, Mudra D, Graham R, Carroll K, Xie J, Madan A, Parkinson A, Christ D, Selling B, LeCluyse E and Gan LS (2002) CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab Dispos 30:795–804.

    Article  CAS  PubMed  Google Scholar 

  • Ma X, Cheung C, Krausz KW, Shah YM, Wang T, Idle JR and Gonzalez FJ (2008) A double transgenic mouse model expressing human pregnane X receptor and cytochrome P450 3A4. Drug Metab Dispos 36:2506–2512.

    Article  CAS  PubMed  Google Scholar 

  • Ma X, Shah YM, Guo GL, Wang T, Krausz KW, Idle JR and Gonzalez FJ (2007) Rifaximin is a gut-specific human pregnane X receptor activator. J Pharmacol Exp Ther 322:391–398.

    Article  CAS  PubMed  Google Scholar 

  • Maglich JM, Lobe DC and Moore JT (2009) The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress. J Lipid Res 50:439–445.

    Article  CAS  PubMed  Google Scholar 

  • Maglich JM, Parks DJ, Moore LB, Collins JL, Goodwin B, Billin AN, Stoltz CA, Kliewer SA, Lambert MH, Willson TM and 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 278:17277–17283.

    Article  CAS  PubMed  Google Scholar 

  • Maglich JM, Stoltz CM, Goodwin B, Hawkins-Brown D, Moore JT and Kliewer SA (2002) Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol Pharmacol 62:638–646.

    Article  CAS  PubMed  Google Scholar 

  • Mai I, Stormer E, Bauer S, Kruger H, Budde K and Roots I (2003) Impact of St John’s wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal transplant patients. Nephrol Dial Transplant 18:819–822.

    Article  CAS  PubMed  Google Scholar 

  • Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H, Evans RM, Haussler MR and Mangelsdorf DJ (2002) Vitamin D receptor as an intestinal bile acid sensor. Science 296:1313–1316.

    Article  CAS  PubMed  Google Scholar 

  • Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ and Shan B (1999) Identification of a nuclear receptor for bile acids. Science 284:1362–1365.

    Article  CAS  PubMed  Google Scholar 

  • Mangelsdorf DJ and Evans RM (1995) The RXR heterodimers and orphan receptors. Cell 83:841–850.

    Article  CAS  PubMed  Google Scholar 

  • Mani S, Huang H, Sundarababu S, Liu W, Kalpana G, Smith AB and Horwitz SB (2005) Activation of the steroid and xenobiotic receptor (human pregnane X receptor) by nontaxane microtubule-stabilizing agents. Clin Cancer Res 11:6359–6369.

    Article  CAS  PubMed  Google Scholar 

  • Markowitz JS, Donovan JL, DeVane CL, Taylor RM, Ruan Y, Wang JS and Chavin KD (2003) Effect of St John’s wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. J Am Med Assoc 290:1500–1504.

    Article  CAS  Google Scholar 

  • Marzolini C, Tirona RG, Gervasini G, Poonkuzhali B, Assem M, Lee W, Leake BF, Schuetz JD, Schuetz EG and Kim RB (2007) A common polymorphism in the bile acid receptor farnesoid X receptor is associated with decreased hepatic target gene expression. Mol Endocrinol 21:1769–1780.

    Article  CAS  PubMed  Google Scholar 

  • Masson D, Lagrost L, Athias A, Gambert P, Brimer-Cline C, Lan L, Schuetz JD, Schuetz EG and Assem M (2005) Expression of the pregnane X receptor in mice antagonizes the cholic acid-mediated changes in plasma lipoprotein profile. Arterioscler Thromb Vasc Biol 25:2164–2169.

    Article  CAS  PubMed  Google Scholar 

  • Mathijssen RH, Verweij J, de Bruijn P, Loos WJ and Sparreboom A (2002) Effects of St. John’s wort on irinotecan metabolism. J Natl Cancer Inst 94:1247–1249.

    CAS  PubMed  Google Scholar 

  • McCance-Katz EF, Rainey PM, Friedland G and Jatlow P (2003) The protease inhibitor lopinavir-ritonavir may produce opiate withdrawal in methadone-maintained patients. Clin Infect Dis 37:476–482.

    Article  CAS  PubMed  Google Scholar 

  • McCarthy TC, Li X and Sinal CJ (2005) Vitamin D receptor-dependent regulation of colon multidrug resistance-associated protein 3 gene expression by bile acids. J Biol Chem 280:23232–23242.

    Article  CAS  PubMed  Google Scholar 

  • McGinnity DF, Zhang G, Kenny J, Hamilton G, Otmani S, Stams K, Haney S, Brassil P, Stresser DM and Riley RJ (2009) Evaluation of multiple in vitro systems for assessment of CYP3A4 induction in drug discovery: human hepatocytes, PXR reporter gene, Fa2N-4 and HepaRG cells. Drug Metab Dispos Mar 23. [Epub ahead of print].

    Google Scholar 

  • Mencarelli A, Renga B, Distrutti E and Fiorucci S (2009) Antiatherosclerotic effect of farnesoid X receptor. Am J Physiol Heart Circ Physiol 296:H272–H281.

    Article  CAS  PubMed  Google Scholar 

  • Merrell MD, Jackson JP, Augustine LM, Fisher CD, Slitt AL, Maher JM, Huang W, Moore DD, Zhang Y, Klaassen CD and Cherrington NJ (2008) The Nrf2 activator oltipraz also activates the constitutive androstane receptor. Drug Metab Dispos 36:1716–1721.

    Article  CAS  PubMed  Google Scholar 

  • Meyer zu Schwabedissen HE, Tirona RG, Yip CS, Ho RH and Kim RB (2008) Interplay between the nuclear receptor pregnane X receptor and the uptake transporter organic anion transporter polypeptide 1A2 selectively enhances estrogen effects in breast cancer. Cancer Res 68:9338–9347.

    Article  CAS  PubMed  Google Scholar 

  • Miki Y, Suzuki T, Kitada K, Yabuki N, Shibuya R, Moriya T, Ishida T, Ohuchi N, Blumberg B and Sasano H (2006) Expression of the steroid and xenobiotic receptor and its possible target gene, organic anion transporting polypeptide-A, in human breast carcinoma. Cancer Res 66:535–542.

    Article  CAS  PubMed  Google Scholar 

  • Mills JB, Rose KA, Sadagopan N, Sahi J and de Morais SM (2004) Induction of drug metabolism enzymes and MDR1 using a novel human hepatocyte cell line. J Pharmacol Exp Ther 309:303–309.

    Article  CAS  PubMed  Google Scholar 

  • Miyata M, Matsuda Y, Tsuchiya H, Kitada H, Akase T, Shimada M, Nagata K, Gonzalez FJ and Yamazoe Y (2006) Chenodeoxycholic acid-mediated activation of the farnesoid X receptor negatively regulates hydroxysteroid sulfotransferase. Drug Metab Pharmacokinet 21:315–323.

    Article  CAS  PubMed  Google Scholar 

  • Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL and Kliewer SA (2000a) St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 97:7500–7502.

    Article  CAS  PubMed  Google Scholar 

  • Moore LB, Parks DJ, Jones SA, Bledsoe RK, Consler TG, Stimmel JB, Goodwin B, Liddle C, Blanchard SG, Willson TM, Collins JL and Kliewer SA (2000b) Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J Biol Chem 275:15122–15127.

    Article  CAS  PubMed  Google Scholar 

  • Moreno-Torres A, Domingo P, Pujol J, Blanco-Vaca F, Arroyo JA and Sambeat MA (2007) Liver triglyceride content in HIV-1-infected patients on combination antiretroviral therapy studied with 1H-MR spectroscopy. Antivir Ther 12:195–203.

    CAS  PubMed  Google Scholar 

  • Moschetta A, Bookout AL and Mangelsdorf DJ (2004) Prevention of cholesterol gallstone disease by FXR agonists in a mouse model. Nat Med 10:1352–1358.

    Article  CAS  PubMed  Google Scholar 

  • Mouly S, Lown KS, Kornhauser D, Joseph JL, Fiske WD, Benedek IH and Watkins PB (2002) Hepatic but not intestinal CYP3A4 displays dose-dependent induction by efavirenz in humans. Clin Pharmacol Ther 72:1–9.

    Article  CAS  PubMed  Google Scholar 

  • Murphy RL, Sommadossi JP, Lamson M, Hall DB, Myers M and Dusek A (1999) Antiviral effect and pharmacokinetic interaction between nevirapine and indinavir in persons infected with human immunodeficiency virus type 1. J Infect Dis 179:1116–1123.

    Article  CAS  PubMed  Google Scholar 

  • Narang VS, Fraga C, Kumar N, Shen J, Throm S, Stewart CF and Waters CM (2008) Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier. Am J Physiol Cell Physiol 295:C440–C450.

    Article  CAS  PubMed  Google Scholar 

  • Nebel A, Schneider BJ, Baker RK and Kroll DJ (1999) Potential metabolic interaction between St. John’s wort and theophylline. Ann Pharmacother 33:502.

    Article  CAS  PubMed  Google Scholar 

  • Nguyen T, Huang HC and Pickett CB (2000) Transcriptional regulation of the antioxidant response element. Activation by Nrf2 and repression by MafK. J Biol Chem 275:15466–15473.

    Article  CAS  PubMed  Google Scholar 

  • Ohtsuka H, Abe T, Onogawa T, Kondo N, Sato T, Oshio H, Mizutamari H, Mikkaichi T, Oikawa M, Rikiyama T, Katayose Y and Unno M (2006) Farnesoid X receptor, hepatocyte nuclear factors 1alpha and 3beta are essential for transcriptional activation of the liver-specific organic anion transporter-2 gene. J Gastroenterol 41:369–377.

    Article  CAS  PubMed  Google Scholar 

  • Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD and Lehmann JM (1999) Bile acids: natural ligands for an orphan nuclear receptor. Science 284:1365–1368.

    Article  CAS  PubMed  Google Scholar 

  • Pascussi JM, Drocourt L, Gerbal-Chaloin S, Fabre JM, Maurel P and Vilarem MJ (2001) Dual effect of dexamethasone on CYP3A4 gene expression in human hepatocytes. Sequential role of glucocorticoid receptor and pregnane X receptor. Eur J Biochem 268:6346–6358.

    Article  CAS  PubMed  Google Scholar 

  • Pascussi JM, Jounaidi Y, Drocourt L, Domergue J, Balabaud C, Maurel P and Vilarem MJ (1999) Evidence for the presence of a functional pregnane X receptor response element in the CYP3A7 promoter gene. Biochem Biophys Res Commun 260:377–381.

    Article  CAS  PubMed  Google Scholar 

  • Pascussi JM, Robert A, Nguyen M, Walrant-Debray O, Garabedian M, Martin P, Pineau T, Saric J, Navarro F, Maurel P and Vilarem MJ (2005) Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia. J Clin Invest 115:177–186.

    CAS  PubMed  Google Scholar 

  • Peng CC, Glassman PA, Trilli LE, Hayes-Hunter J and Good CB (2004) Incidence and severity of potential drug-dietary supplement interactions in primary care patients: an exploratory study of 2 outpatient practices. Arch Intern Med 164:630–636.

    Article  PubMed  Google Scholar 

  • Pentikis HS, Connolly M, Trapnell CB, Forbes WP and Bettenhausen DK (2007) The effect of multiple-dose, oral rifaximin on the pharmacokinetics of intravenous and oral midazolam in healthy volunteers. Pharmacotherapy 27:1361–1369.

    Article  CAS  PubMed  Google Scholar 

  • Perloff ES, Duan SX, Skolnik PR, Greenblatt DJ and von Moltke LL (2005) Atazanavir: effects on P-glycoprotein transport and CYP3A metabolism in vitro. Drug Metab Dispos 33:764–770.

    Article  CAS  PubMed  Google Scholar 

  • Pickett CBPD, Nguyen T and Nioi P (2009) The Nrf2-ARE signaling pathway and its activation by oxidative stress. J Biol Chem Jan 30. [Epub ahead of print].

    Google Scholar 

  • Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM and Falloon J (2000) Indinavir concentrations and St John’s wort. Lancet 355:547–548.

    Article  CAS  PubMed  Google Scholar 

  • Piscitelli SC, Burstein AH, Welden N, Gallicano KD and Falloon J (2002) The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis 34:234–238.

    Article  PubMed  Google Scholar 

  • Plass JR, Mol O, Heegsma J, Geuken M, Faber KN, Jansen PL and Muller M (2002) Farnesoid X receptor and bile salts are involved in transcriptional regulation of the gene encoding the human bile salt export pump. Hepatology 35:589–596.

    Article  CAS  PubMed  Google Scholar 

  • Poland A, Glover E and Kende AS (1976) Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J Biol Chem 251:4936–4946.

    CAS  PubMed  Google Scholar 

  • Pondugula SR, Brimer-Cline C, Wu J, Schuetz EG, Tyagi RK and Chen T (2009) A phosphomimetic mutation at threonine-57 abolishes transactivation activity and alters nuclear localization pattern of human pregnane x receptor. Drug Metab Dispos 37:719–730.

    Article  CAS  PubMed  Google Scholar 

  • Portoles A, Terleira A, Calvo A, Martinez I and Resplandy G (2006) Effects of Hypericum perforatum on ivabradine pharmacokinetics in healthy volunteers: an open-label, pharmacokinetic interaction clinical trial. J Clin Pharmacol 46:1188–1194.

    Article  CAS  PubMed  Google Scholar 

  • Qatanani M, Zhang J and Moore DD (2005) Role of the constitutive androstane receptor in xenobiotic-induced thyroid hormone metabolism. Endocrinology 146:995–1002.

    Article  CAS  PubMed  Google Scholar 

  • Qureshi GD, Reinders TP, Somori GJ and Evans HJ (1984) Warfarin resistance with nafcillin therapy. Ann Intern Med 100:527–529.

    CAS  PubMed  Google Scholar 

  • Raucy J, Warfe L, Yueh MF and Allen SW (2002) A cell-based reporter gene assay for determining induction of CYP3A4 in a high-volume system. J Pharmacol Exp Ther 303:412–423.

    Article  CAS  PubMed  Google Scholar 

  • Remmer H, Schoene B and Fleischmann RA (1973) Induction of the unspecific microsomal hydroxylase in the human liver. Drug Metab Dispos 1:224–230.

    CAS  PubMed  Google Scholar 

  • Ricketts ML, Boekschoten MV, Kreeft AJ, Hooiveld GJ, Moen CJ, Muller M, Frants RR, Kasanmoentalib S, Post SM, Princen HM, Porter JG, Katan MB, Hofker MH and Moore DD (2007) The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors. Mol Endocrinol 21:1603–1616.

    Article  CAS  PubMed  Google Scholar 

  • Riddle TM, Kuhel DG, Woollett LA, Fichtenbaum CJ and Hui DY (2001) HIV protease inhibitor induces fatty acid and sterol biosynthesis in liver and adipose tissues due to the accumulation of activated sterol regulatory element-binding proteins in the nucleus. J Biol Chem 276:37514–37519.

    Article  CAS  PubMed  Google Scholar 

  • Ripp SL, Mills JB, Fahmi OA, Trevena KA, Liras JL, Maurer TS and de Morais SM (2006) Use of immortalized human hepatocytes to predict the magnitude of clinical drug–drug interactions caused by CYP3A4 induction. Drug Metab Dispos 34:1742–1748.

    Article  CAS  PubMed  Google Scholar 

  • Rizzo G, Renga B, Antonelli E, Passeri D, Pellicciari R and Fiorucci S (2005) The methyl transferase PRMT1 functions as co-activator of farnesoid X receptor (FXR)/9-cis retinoid X receptor and regulates transcription of FXR responsive genes. Mol Pharmacol 68:551–558.

    Article  CAS  PubMed  Google Scholar 

  • Robertson SM, Davey RT, Voell J, Formentini E, Alfaro RM and Penzak SR (2008) Effect of Ginkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects. Curr Med Res Opin 24:591–599.

    Article  CAS  PubMed  Google Scholar 

  • Ruschitzka F, Meier PJ, Turina M, Luscher TF and Noll G (2000) Acute heart transplant rejection due to Saint John’s wort. Lancet 355:548–549.

    Article  CAS  PubMed  Google Scholar 

  • Saeki M, Kurose K, Tohkin M and Hasegawa R (2008) Identification of the functional vitamin D response elements in the human MDR1 gene. Biochem Pharmacol 76:531–542.

    Article  CAS  PubMed  Google Scholar 

  • Sandanaraj E, Lal S, Selvarajan V, Ooi LL, Wong ZW, Wong NS, Ang PC, Lee EJ and Chowbay B (2008) PXR pharmacogenetics: association of haplotypes with hepatic CYP3A4 and ABCB1 messenger RNA expression and doxorubicin clearance in Asian breast cancer patients. Clin Cancer Res 14:7116–7126.

    Article  CAS  PubMed  Google Scholar 

  • Scheer N, Ross J, Rode A, Zevnik B, Niehaves S, Faust N and Wolf CR (2008) 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 118:3228–3239.

    Article  CAS  PubMed  Google Scholar 

  • Schmiedlin-Ren P, Thummel KE, Fisher JM, Paine MF, Lown KS and Watkins PB (1997) Expression of enzymatically active CYP3A4 by Caco-2 cells grown on extracellular matrix-coated permeable supports in the presence of 1?,25-dihydroxyvitamin D3. Mol Pharmacol 51:741–754.

    CAS  PubMed  Google Scholar 

  • Schoene B, Fleischmann RA, Remmer H and von Oldershausen HF (1972) Determination of drug metabolizing enzymes in needle biopsies of human liver. Eur J Clin Pharmacol 4:65–73.

    Article  CAS  PubMed  Google Scholar 

  • Schuetz E, Lan L, Yasuda K, Kim R, Kocarek TA, Schuetz J and Strom S (2002) development of a real-time in vivo transcription assay: application reveals pregnane X receptor-mediated induction of CYP3A4 by cancer chemotherapeutic agents. Mol Pharmacol 62:439–445.

    Article  CAS  PubMed  Google Scholar 

  • Schuetz EG, Schinkel AH, Relling MV and Schuetz JD (1996) P-glycoprotein: a major determinant of rifampicin-inducible expression of cytochrome P4503A in mice and humans. Proc Natl Acad Sci USA 93:4001–4005.

    Article  CAS  PubMed  Google Scholar 

  • Schuetz EG, Strom S, Yasuda K, Lecureur V, Assem M, Brimer C, Lamba J, Kim RB, Ramachandran V, Komoroski BJ, Venkataramanan R, Cai H, Sinal CJ, Gonzalez FJ and Schuetz JD (2001) Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. J Biol Chem 276:39411–39418.

    Article  CAS  PubMed  Google Scholar 

  • Schwarz UI, Buschel B and Kirch W (2003) Unwanted pregnancy on self-medication with St John’s wort despite hormonal contraception. Br J Clin Pharmacol 55:112–113.

    Article  PubMed  Google Scholar 

  • Schwarz UI, Hanso H, Oertel R, Miehlke S, Kuhlisch E, Glaeser H, Hitzl M, Dresser GK, Kim RB and Kirch W (2007) Induction of intestinal P-glycoprotein by St John’s wort reduces the oral bioavailability of talinolol. Clin Pharmacol Ther 81:669–678.

    Article  CAS  PubMed  Google Scholar 

  • Shah YM, Ma X, Morimura K, Kim I and Gonzalez FJ (2007) Pregnane X receptor activation ameliorates DSS-induced inflammatory bowel disease via inhibition of NF-kappaB target gene expression. Am J Physiol 292:G1114–G1122.

    CAS  Google Scholar 

  • Shah SC, Sharma RK, Hemangini and Chitle AR (1981) Rifampicin induced osteomalacia. Tubercle 62:207–209.

    Article  CAS  PubMed  Google Scholar 

  • Shulman AI, Larson C, Mangelsdorf DJ and Ranganathan R (2004) Structural determinants of allosteric ligand activation in RXR heterodimers. Cell 116:417–429.

    Article  CAS  PubMed  Google Scholar 

  • Siccardi M, D‘Avolio A, Baietto L, Gibbons S, Sciandra M, Colucci D, Bonora S, Khoo S, Back DJ, Di Perri G and Owen A (2008) Association of a single-nucleotide polymorphism in the pregnane X receptor (PXR 63396–->T) with reduced concentrations of unboosted atazanavir. Clin Infect Dis 47:1222–1225.

    Article  CAS  PubMed  Google Scholar 

  • Sonoda J, Xie W, Rosenfeld JM, Barwick JL, Guzelian PS and Evans RM (2002) Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR). Proc Natl Acad Sci USA 99:13801–13806.

    Article  CAS  PubMed  Google Scholar 

  • Sporstol M, Tapia G, Malerod L, Mousavi SA and Berg T (2005) Pregnane X receptor-agonists down-regulate hepatic ATP-binding cassette transporter A1 and scavenger receptor class B type I. Biochem Biophys Res Commun 331:1533–1541.

    Article  CAS  PubMed  Google Scholar 

  • Sueyoshi T, Kawamoto T, Zelko I, Honkakoski P and Negishi M (1999) The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene. J Biol Chem 274:6043–6046.

    Article  CAS  PubMed  Google Scholar 

  • Sueyoshi T, Moore R, Sugatani J, Matsumura Y and Negishi M (2008) PPP1R16A, the membrane subunit of protein phosphatase 1beta, signals nuclear translocation of the nuclear receptor constitutive active/androstane receptor. Mol Pharmacol 73:1113–1121.

    Article  CAS  PubMed  Google Scholar 

  • Sugatani J, Kojima H, Ueda A, Kakizaki S, Yoshinari K, Gong QH, Owens IS, Negishi M and Sueyoshi T (2001) The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology 33:1232–1238.

    Article  CAS  PubMed  Google Scholar 

  • Sugatani J, Yamakawa K, Tonda E, Nishitani S, Yoshinari K, Degawa M, Abe I, Noguchi H and Miwa M (2004) The induction of human UDP-glucuronosyltransferase 1A1 mediated through a distal enhancer module by flavonoids and xenobiotics. Biochem Pharmacol 67:989–1000.

    Article  CAS  PubMed  Google Scholar 

  • Suino K, Peng L, Reynolds R, Li Y, Cha JY, Repa JJ, Kliewer SA and Xu HE (2004) The nuclear xenobiotic receptor CAR: structural determinants of constitutive activation and heterodimerization. Mol Cell 16:893–905.

    CAS  PubMed  Google Scholar 

  • Sulkowski MS, Mehta SH, Torbenson M, Afdhal NH, Mirel L, Moore RD and Thomas DL (2005) Hepatic steatosis and antiretroviral drug use among adults coinfected with HIV and hepatitis C virus. Aids 19:585–592.

    Article  PubMed  Google Scholar 

  • Synold TW, Dussault I and Forman BM (2001) The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 7:584–590.

    Article  CAS  PubMed  Google Scholar 

  • Takagi S, Nakajima M, Mohri T and Yokoi T (2008) Post-transcriptional regulation of human pregnane X receptor by micro-RNA affects the expression of cytochrome P450 3A4. J Biol Chem 283:9674–9680.

    Article  CAS  PubMed  Google Scholar 

  • Teotico DG, Bischof JJ, Peng L, Kliewer SA and Redinbo MR (2008) Structural basis of human pregnane X receptor activation by the hops constituent colupulone. Mol Pharmacol 74:1512–1520.

    Article  CAS  PubMed  Google Scholar 

  • Terzolo M, Borretta G, Ali A, Cesario F, Magro G, Boccuzzi A, Reimondo G and Angeli A (1995) Misdiagnosis of Cushing’s syndrome in a patient receiving rifampicin therapy for tuberculosis. Horm Metab Res 27:148–150.

    Article  CAS  PubMed  Google Scholar 

  • Thummel KE, Brimer C, Yasuda K, Thottassery J, Senn T, Lin Y, Ishizuka H, Kharasch E, Schuetz J and Schuetz E (2001) Transcriptional control of intestinal cytochrome P-4503A by 1α,25-dihydroxyvitamin D3. Mol Pharmacol 60:1399–1406.

    CAS  PubMed  Google Scholar 

  • Tirona RG and Kim RB (2009) Nuclear receptors and drug–drug interactions with prescription and herbal medicines, in Nuclear Receptors in Drug Metabolism (Xie W ed) pp. 211–239, Wiley, Hoboken, NJ.

    Google Scholar 

  • Tirona RG, Leake BF, Podust LM and Kim RB (2004) Identification of amino acids in rat pregnane X receptor that determine species-specific activation. Mol Pharmacol 65:36–44.

    Article  CAS  PubMed  Google Scholar 

  • Tirona RG, Leake BF, Wolkoff AW and Kim RB (2003) Human organic anion transporting polypeptide-C (SLC21A6) is a major determinant of rifampin-mediated pregnane X receptor activation. J Pharmacol Exp Ther 304:223–228.

    Article  CAS  PubMed  Google Scholar 

  • Tran JQ, Kovacs SJ, McIntosh TS, Davis HM and Martin DE (1999) Morning spot and 24-hour urinary 6 beta-hydroxycortisol to cortisol ratios: intraindividual variability and correlation under basal conditions and conditions of CYP 3A4 induction. J Clin Pharmacol 39:487–494.

    CAS  PubMed  Google Scholar 

  • Trapnell CB, Connolly M, Pentikis H, Forbes WP and Bettenhausen DK (2007) Absence of effect of oral rifaximin on the pharmacokinetics of ethinyl estradiol/norgestimate in healthy females. Ann Pharmacother 41:222–228.

    Article  CAS  PubMed  Google Scholar 

  • Trubetskoy O, Marks B, Zielinski T, Yueh MF and Raucy J (2005) A simultaneous assessment of CYP3A4 metabolism and induction in the DPX-2 cell line. Aaps J 7:E6–E13.

    Article  PubMed  Google Scholar 

  • Urizar NL, Liverman AB, Dodds DT, Silva FV, Ordentlich P, Yan Y, Gonzalez FJ, Heyman RA, Mangelsdorf DJ and Moore DD (2002) A natural product that lowers cholesterol as an antagonist ligand for FXR. Science 296:1703–1706.

    Article  CAS  PubMed  Google Scholar 

  • van Giersbergen PL, Gnerre C, Treiber A, Dingemanse J and Meyer UA (2002) Bosentan, a dual endothelin receptor antagonist, activates the pregnane X nuclear receptor. Eur J Pharmacol 450:115–121.

    Article  PubMed  Google Scholar 

  • Van Mil SW, Milona A, Dixon PH, Mullenbach R, Geenes VL, Chambers J, Shevchuk V, Moore GE, Lammert F, Glantz AG, Mattsson LA, Whittaker J, Parker MG, White R and Williamson C (2007) Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy. Gastroenterology 133:507–516.

    Article  PubMed  CAS  Google Scholar 

  • Venugopal R and Jaiswal AK (1996) Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proc Natl Acad Sci U S A 93:14960–14965.

    Article  CAS  PubMed  Google Scholar 

  • Wakabayashi N, Dinkova-Kostova AT, Holtzclaw WD, Kang MI, Kobayashi A, Yamamoto M, Kensler TW and Talalay P (2004) Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers. Proc Natl Acad Sci USA 101:2040–2045.

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Chen J, Hollister K, Sowers LC and Forman BM (1999) Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 3:543–553.

    Article  CAS  PubMed  Google Scholar 

  • Wang YD, Chen WD, Wang M, Yu D, Forman BM and Huang W (2008b) Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 48:1632–1643.

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Faucette SR, Moore R, Sueyoshi T, Negishi M and LeCluyse EL (2004a) Human constitutive androstane receptor mediates induction of CYP2B6 gene expression by phenytoin. J Biol Chem 279:29295–29301.

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Faucette S, Sueyoshi T, Moore R, Ferguson S, Negishi M and LeCluyse EL (2003) A novel distal enhancer module regulated by pregnane X receptor/constitutive androstane receptor is essential for the maximal induction of CYP2B6 gene expression. J Biol Chem 278:14146–14152.

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Huang H, Li H, Teotico DG, Sinz M, Baker SD, Staudinger J, Kalpana G, Redinbo MR and Mani S (2007) Activated pregnenolone X-receptor is a target for ketoconazole and its analogs. Clin Cancer Res 13:2488–2495.

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Li H, Moore LB, Johnson MD, Maglich JM, Goodwin B, Ittoop OR, Wisely B, Creech K, Parks DJ, Collins JL, Willson TM, Kalpana GV, Venkatesh M, Xie W, Cho SY, Roboz J, Redinbo M, Moore JT and Mani S (2008a) The phytoestrogen coumestrol is a naturally occurring antagonist of the human pregnane X receptor. Mol Endocrinol 22:838–857.

    Article  CAS  PubMed  Google Scholar 

  • Wang XD, Li JL, Su QB, Guan S, Chen J, Du J, He YW, Zeng J, Zhang JX, Chen X, Huang M and Zhou SF (2009) Impact of the haplotypes of the human pregnane X receptor gene on the basal and St John’s wort-induced activity of cytochrome P450 3A4 enzyme. Br J Clin Pharmacol 67:255–261.

    Article  CAS  PubMed  Google Scholar 

  • Wang LS, Zhou G, Zhu B, Wu J, Wang JG, Abd El-Aty AM, Li T, Liu J, Yang TL, Wang D, Zhong XY and Zhou HH (2004b) St John’s wort induces both cytochrome P450 3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole. Clin Pharmacol Ther 75:191–197.

    Article  CAS  PubMed  Google Scholar 

  • Watkins RE, Davis-Searles PR, Lambert MH and Redinbo MR (2003a) Coactivator binding promotes the specific interaction between ligand and the pregnane X receptor. J Mol Biol 331:815–828.

    Article  CAS  PubMed  Google Scholar 

  • Watkins RE, Maglich JM, Moore LB, Wisely GB, Noble SM, Davis-Searles PR, Lambert MH, Kliewer SA and Redinbo MR (2003b) 2.1 A crystal structure of human PXR in complex with the St. John’s wort compound hyperforin. Biochemistry 42:1430–1438.

    Article  CAS  PubMed  Google Scholar 

  • Watkins RE, Wisely GB, Moore LB, Collins JL, Lambert MH, Williams SP, Willson TM, Kliewer SA and Redinbo MR (2001) The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science 292:2329–2333.

    Article  CAS  PubMed  Google Scholar 

  • Wong H, Lehman-McKeeman LD, Grubb MF, Grossman SJ, Bhaskaran VM, Solon EG, Shen HS, Gerson RJ, Car BD, Zhao B and Gemzik B (2005) Increased hepatobiliary clearance of unconjugated thyroxine determines DMP 904-induced alterations in thyroid hormone homeostasis in rats. Toxicol Sci 84:232–242.

    Article  CAS  PubMed  Google Scholar 

  • Xie W, Barwick JL, Downes M, Blumberg B, Simon CM, Nelson MC, Neuschwander-Tetri BA, Brunt EM, Guzelian PS and Evans RM (2000) Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 406:435–439.

    Article  CAS  PubMed  Google Scholar 

  • Xie Y, Ke S, Ouyang N, He J, Xie W, Bedford MT and Tian Y (2009) Epigenetic regulation of transcriptional activity of pregnane X receptor by protein arginine methyltransferase 1. J Biol Chem 284:9199–9205.

    Article  CAS  PubMed  Google Scholar 

  • Xu RX, Lambert MH, Wisely BB, Warren EN, Weinert EE, Waitt GM, Williams JD, Collins JL, Moore LB, Willson TM and Moore JT (2004) A structural basis for constitutive activity in the human CAR/RXRalpha heterodimer. Mol Cell 16:919–928.

    Article  CAS  PubMed  Google Scholar 

  • Yamazaki Y, Kakizaki S, Horiguchi N, Sohara N, Sato K, Takagi H, Mori M and Negishi M (2007) The role of the nuclear receptor constitutive androstane receptor in the pathogenesis of non-alcoholic steatohepatitis. Gut 56:565–574.

    Article  CAS  PubMed  Google Scholar 

  • Yang D, Wang X, Chen YT, Deng R and Yan B (2009) Pyrethroid insecticides: Isoform-dependent hydrolysis, induction of cytochrome P450 3A4 and evidence on the involvement of the pregnane X receptor. Toxicol Appl Pharmacol Feb 26. [Epub ahead of print].

    Google Scholar 

  • Yang J and Yan B (2007) Photochemotherapeutic agent 8-methoxypsoralen induces cytochrome P450 3A4 and carboxylesterase HCE2: evidence on an involvement of the pregnane X receptor. Toxicol Sci 95:13–22.

    Article  CAS  PubMed  Google Scholar 

  • Yasuda K, Ranade A, Venkataramanan R, Strom S, Chupka J, Ekins S, Schuetz E and Bachmann K (2008) A comprehensive in vitro and in silico analysis of antibiotics that activate pregnane X receptor and induce CYP3A4 in liver and intestine. Drug Metab Dispos 36:1689–1697.

    Article  CAS  PubMed  Google Scholar 

  • Yeung EY, Sueyoshi T, Negishi M and Chang TK (2008) Identification of Ginkgo biloba as a novel activator of pregnane X receptor. Drug Metab Dispos 36:2270–2276.

    Article  CAS  PubMed  Google Scholar 

  • Yin OQ, Tomlinson B, Waye MM, Chow AH and Chow MS (2004) Pharmacogenetics and herb–drug interactions: experience with Ginkgo biloba and omeprazole. Pharmacogenetics 14:841–850.

    Article  PubMed  Google Scholar 

  • Yuan CS, Wei G, Dey L, Karrison T, Nahlik L, Maleckar S, Kasza K, Ang-Lee M and Moss J (2004) Brief communication: American ginseng reduces warfarin’s effect in healthy patients: a randomized, controlled trial. Ann Intern Med 141:23–27.

    CAS  PubMed  Google Scholar 

  • Yue QY, Bergquist C and Gerden B (2000) Safety of St John’s wort (Hypericum perforatum). Lancet 355:576–577.

    Article  CAS  PubMed  Google Scholar 

  • Zastre JA, Chan GN, Ronaldson PT, Ramaswamy M, Couraud PO, Romero IA, Weksler B, Bendayan M and Bendayan R (2009) Up-regulation of P-glycoprotein by HIV protease inhibitors in a human brain microvessel endothelial cell line. J Neurosci Res 87:1023–1036.

    Article  CAS  PubMed  Google Scholar 

  • Zhai Y, Pai HV, Zhou J, Amico JA, Vollmer RR and Xie W (2007) Activation of pregnane X receptor disrupts glucocorticoid and mineralocorticoid homeostasis. Mol Endocrinol 21:138–147.

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Kuehl P, Green ED, Touchman JW, Watkins PB, Daly A, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Wrighton SA, Hancock M, Kim RB, Strom S, Thummel K, Russell CG, Hudson JR, Jr., Schuetz EG and Boguski MS (2001) The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. Pharmacogenetics 11:555–572.

    Article  CAS  PubMed  Google Scholar 

  • Zhang S, Liu Q, Wang J and Harnish DC (2009) Suppression of interleukin-6-induced C-reactive protein expression by FXR agonists. Biochem Biophys Res Commun 379:476–479.

    Article  CAS  PubMed  Google Scholar 

  • Zhou C, Assem M, Tay JC, Watkins PB, Blumberg B, Schuetz EG and Thummel KE (2006a) Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. J Clin Invest 116:1703–1712.

    Article  CAS  PubMed  Google Scholar 

  • Zhou J, Febbraio M, Wada T, Zhai Y, Kuruba R, He J, Lee JH, Khadem S, Ren S, Li S, Silverstein RL and Xie W (2008a) Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 134:556–567.

    Article  CAS  PubMed  Google Scholar 

  • Zhou J, Liu M, Zhai Y and Xie W (2008b) The antiapoptotic role of pregnane X receptor in human colon cancer cells. Mol Endocrinol 22:868–880.

    Article  CAS  PubMed  Google Scholar 

  • Zhou C, Poulton EJ, Grun F, Bammler TK, Blumberg B, Thummel KE and Eaton DL (2007) The dietary isothiocyanate sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor. Mol Pharmacol 71:220–229.

    Article  CAS  PubMed  Google Scholar 

  • Zhou C, Tabb MM, Nelson EL, Grun F, Verma S, Sadatrafiei A, Lin M, Mallick S, Forman BM, Thummel KE and Blumberg B (2006b) Mutual repression between steroid and xenobiotic receptor and NF-kappaB signaling pathways links xenobiotic metabolism and inflammation. J Clin Invest 116:2280–2289.

    Article  CAS  PubMed  Google Scholar 

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  1. Division of Clinical Pharmacology, Department of Medicine, Department of Physiology & Pharmacology, Schulich School of Medicine and Dentisity, University of Western Ontario, London Health Sciences Centre - University Hospital, London, Ontario, Canada

    Rommel G. Tirona

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  3. AstraZeneca UK, Alderley Park, Macclesfield, Cheshire, SK10 4TF, United Kingdom

    Raimund M. Peter

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Tirona, R.G. (2010). Impact of Nuclear Receptors CAR, PXR, FXR, and VDR, and Their Ligands On Enzymes and Transporters. In: Pang , K., Rodrigues, A., Peter, R. (eds) Enzyme- and Transporter-Based Drug-Drug Interactions. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0840-7_4

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