Induction of phase I, II and III drug metabolism/transport by xenobiotics

  • Changjiang Xu
  • Christina Yong-Tao Li
  • Ah-Ng Tony Kong


Drug metabolizing enzymes (DMEs) play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body. Most of the tissues and organs in our body are well equipped with diverse and various DMEs including phase I, phase II metabolizing enzymes and phase III transporters, which are present in abundance either at the basal unstimulated level, and/or are inducible at elevated level after exposure to xenobiotics. Recently, many important advances have been made in the mechanisms that regulate the expression of these drug metabolism genes. Various nuclear receptors including the aryl hydrocarbon receptor (AhR), orphan nuclear receptors, and nuclear factor-erythoroid 2 p45-related factor 2 (Nrf2) have been shown to be the key mediators of drug-induced changes in phase I, phase II metabolizing enzymes as well as phase III transporters involved in efflux mechanisms. For instance, the expression of CYP1 genes can be induced by AhR, which dimerizes with the AhR nuclear translocator (Arnt), in response to many polycyclic aromatic hydrocarbon (PAHs). Similarly, the steroid family of orphan nuclear receptors, the constitutive androstane receptor (CAR) and pregnane X receptor (PXR), both heterodimerize with the retinoid X receptor (RXR), are shown to transcriptionally activate the promoters of CYP2B and CYP3A gene expression by xenobiotics such as phenobarbital-like compounds (CAR) and dexamethasone and rifampin-type of agents (PXR). The peroxisome proliferator activated receptor (PPAR), which is one of the first characterized members of the nuclear hormone receptor, also dimerizes with RXR and has been shown to be activated by lipid lowering agent fibrate-type of compounds leading to transcriptional activation of the promoters on CYP4A gene. CYP7A was recognized as the first target gene of the liver X receptor (LXR), in which the elimination of cholesterol depends on CYP7A. Farnesoid X receptor (FXR) was identified as a bile acid receptor, and its activation results in the inhibition of hepatic acid biosynthesis and increased transport of bile acids from intestinal lumen to the liver, and CYP7A is one of its target genes. The transcriptional activation by these receptors upon binding to the promoters located at the 5-flanking region of these CYP genes generally leads to the induction of their mRNA gene expression. The physiological and the pharmacological implications of common partner of RXR for CAR, PXR, PPAR, LXR and FXR receptors largely remain unknown and are under intense investigations. For the phase II DMEs, phase II gene inducers such as the phenolic compounds butylated hydroxyanisol (BHA),tert-butylhydroquinone (tBHQ), green tea polyphenol (GTP), (-)-epigallocatechin-3-gallate (EGCG) and the isothiocyanates (PEITC, sulforaphane) generally appear to be electrophiles. They generally possess electrophilic-mediated stress response, resulting in the activation of bZIP transcription factors Nrf2 which dimerizes with Mafs and binds to the antioxidant/electrophile response element (ARE/EpRE) promoter, which is located in many phase II DMEs as well as many cellular defensive enzymes such as heme oxygenase-1 (HO-1), with the subsequent induction of the expression of these genes. Phase III transporters, for example, P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs), and organic anion transporting polypeptide 2 (OATP2) are expressed in many tissues such as the liver, intestine, kidney, and brain, and play crucial roles in drug absorption, distribution, and excretion. The orphan nuclear receptors PXR and CAR have been shown to be involved in the regulation of these transporters. Along with phase I and phase II enzyme induction, pretreatment with several kinds of inducers has been shown to alter the expression of phase III transporters, and alter the excretion of xenobiotics, which implies that phase III transporters may also be similarly regulated in a coordinated fashion, and provides an important mean to protect the body from xenobiotics insults. It appears that in general, exposure to phase I, phase II and phase III gene inducers may trigger cellular “stress” response leading to the increase in their gene expression, which ultimately enhance the elimination and clearance of these xenobiotics and/or other “cellular stresses” including harmful reactive intermediates such as reactive oxygen species (ROS), so that the body will remove the “stress” expeditiously. Consequently, this homeostatic response of the body plays a central role in the protection of the body against “environmental” insults such as those elicited by exposure to xenobiotics.

Key words

Phase I metabolizing enzymes, Phase II metabolizing enzymes P-Glycoprotein Multidrug resistance-associated protein, Organic anion transporting polypeptide 2 Aryl hydrocarbon receptor Pregnane X receptor Constitutive androstane receptor Peroxisome proliferator activated receptor Liver X receptor Farnesoid X receptor Retinoid X receptor Nuclear factor-erythoroid 2 p45-related factor 2 


  1. Alam, J., Killeen, E., Gong, P., Naquin, R., Hu, B., Stewart, D., Ingelfinger, J. R., and Nath, K. A., Heme activates the heme oxygenase-1 gene in renal epithelial cells by stabilizing Nrf2.Am. J. Physiol. Renal. Physiol., 284, F743–752 (2003).PubMedGoogle Scholar
  2. Anakk, S., Kalsotra, A., Kikuta, Y., Huang, W., Zhang, J., Staudinger, J. L., Moore, D. D., and Strobel, H. W., CAR/PXR provide directives for Cyp3a41 gene regulation differently from Cyp3a11.Pharmacogenomics J., 4, 91–101 (2004).PubMedCrossRefGoogle Scholar
  3. Bae, Y., Kemper, J. K., and Kemper, B., Repression of CAR-mediated transactivation of CYP2B genes by the orphan nuclear receptor, short heterodimer partner (SHP).DNA Cell Biol., 23, 81–91 (2004).PubMedCrossRefGoogle Scholar
  4. Baes, M., Gulick, T., Choi, H. S., Martinoli, M. G., Simha, D., and Moore, D. D., A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements.Mol. Cell Biol., 14, 1544–1552 (1994).PubMedGoogle Scholar
  5. Banoglu, E., Current status of the cytosolic suIfotransferases in the metabolic activation of promutagens and procarcinogens.Curr. Drug Metab., 1, 1–30 (2000).PubMedCrossRefGoogle Scholar
  6. Beigneux, A. P., Moser, A. H., Shigenaga, J. K., Grunfeld, C., and Feingold, K. R., Reduction in cytochrome P-450 enzyme expression is associated with repression of CAR (constitutive androstane receptor) and PXR (pregnane X receptor) in mouse liver during the acute phase response.Biochem. Biophys. Res. Commun., 293, 145–149 (2002).PubMedCrossRefGoogle Scholar
  7. Bock, K. W., Gschaidmeier, H., Heel, H., Lehmkoster, T., Munzel, P. A., Raschko, F., and Bock-Hennig, B., AH receptor-controlled transcriptional regulation and function of rat and human UDP-glucuronosyltransferase isoforms.Adv. Enzyme Regul., 38, 207–222 (1998).PubMedCrossRefGoogle Scholar
  8. Bolton, J. L. and Chang, M., Quinoids as reactive intermediates in estrogen carcinogenesis.Adv. Exp. Med. Biol., 500, 497–507 (2001).PubMedGoogle Scholar
  9. Bolton, J. L., Trush, M. A., Penning, T. M., Dryhurst, G., and Monks, T. J., Role of quinones in toxicology.Chem. Res. Toxicol., 13, 135–160 (2000).PubMedCrossRefGoogle Scholar
  10. Brinkmann, U. and Eichelbaum, M., Polymorphisms in the ABC drug transporter gene MDR1.Pharmacogenomics J., 1, 59–64 (2001).PubMedGoogle Scholar
  11. Chan, K. and Kan, Y. W., Nrf2 is essential for protection against acute pulmonary injury in mice.Proc. Natl. Acad. Sci. U.S.A., 96, 12731–12736 (1999).PubMedCrossRefGoogle Scholar
  12. Chan, L. M., Lowes, S., and Hirst, B. H., The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability.Eur. J. Pharm. Sci., 21, 25–51 (2004).PubMedCrossRefGoogle Scholar
  13. Chandra, P. and Brouwer, K. L., The complexities of hepatic drug transport: current knowledge and emerging concepts.Pharm. Res., 21, 719–735 (2004).PubMedCrossRefGoogle Scholar
  14. Chen, C., Yu, R., Owuor, E. D., and Kong, A. N., Activation of antioxidant-response element (ARE), mitogen-activated protein kinases (MAPKs) and caspases by major green tea polyphenol components during cell survival and death.Arch. Pharm. Res., 23, 605–612 (2000).PubMedCrossRefGoogle Scholar
  15. Cherrington, N. J., Hartley, D. P., Li, N., Johnson, D. R., and Klaassen, C. D., Organ distribution of multidrug resistance proteins 1, 2, and 3 (Mrp1, 2, and 3) mRNA and hepatic induction of Mrp3 by constitutive androstane receptor activators in rats.J. Pharmacol. Exp. Ther., 300, 97–104 (2002).PubMedCrossRefGoogle Scholar
  16. Coles, B. R., Chen, G., Kadlubar, F. R., and Radominska-Pandya, A., Interindividual variation and organ-specific patterns of glutathione S-transferase alpha, mu, and pi expression in gastrointestinal tract mucosa of normal individuals.Arch. Biochem. Biophys., 403, 270–276 (2002).PubMedCrossRefGoogle Scholar
  17. Coumoul, X., Diry, M., and Barouki, R., PXR-dependent induction of human CYP3A4 gene expression by organochlorine pesticides.Biochem. Pharmacol., 64, 1513–1519 (2002).PubMedCrossRefGoogle Scholar
  18. Cullinan, S. B. and Diehl, J. A., PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress.J. Biol. Chem., 279, 20108–20117 (2004).PubMedCrossRefGoogle Scholar
  19. Cullinan, S. B., Zhang, D., Hannink, M., Arvisais, E., Kaufman, R. J., and Diehl, J. A., Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival.Mol. Cell Biol., 23, 7198–7209 (2003).PubMedCrossRefGoogle Scholar
  20. Dean, M., Hamon, Y., and Chimini, G., The human ATP-binding cassette (ABC) transporter superfamily.J. Lipid Res., 42, 1007–1017 (2001).PubMedGoogle Scholar
  21. del Castillo-Olivares, A. and Gil, G., Role of FXR and FTF in bile acid-mediated suppression of cholesterol 7alpha-hydroxylase transcription.Nucleic Acids Res., 28, 3587–3593 (2000).PubMedCrossRefGoogle Scholar
  22. Denson, L. A., Sturm, E., Echevarria, W., Zimmerman, T. L., Makishima, M., Mangelsdorf, D. J., and Karpen, S. J., The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp.Gastroenterology., 121, 140–147 (2001).PubMedCrossRefGoogle Scholar
  23. Dinkova-Kostova, A. T., Protection against cancer by plant phenylpropenoids: induction of mammalian anticarcinogenic enzymes.Mini Rev. Med. Chem., 2, 595–610 (2002a).PubMedCrossRefGoogle Scholar
  24. Dinkova-Kostova, A. T., Holtzclaw, W. D., Cole, R. N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., and Talalay, P., Direct evidence that sulfhydryl groups of Keapl are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants.Proc. Natl. Acad. Sci. U.S.A., 99, 11908–11913 (2002b).PubMedCrossRefGoogle Scholar
  25. Dinkova-Kostova, A. T., Massiah, M. A., Bozak, R. E., Hicks, R. J., and Talalay, P., Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups.Proc. Natl. Acad. Sci. U.S.A., 98, 3404–3409 (2001).PubMedCrossRefGoogle Scholar
  26. Dussault, I. and Forman, B. M., The nuclear receptor PXR: a master regulator of “homeland” defense.Crit. Rev. Eukaryot. Gene Expr., 12, 53–64 (2002).PubMedCrossRefGoogle Scholar
  27. Elferink, C. J., Aryl hydrocarbon receptor-mediated cell cycle control.Prog. Cell Cycle Res., 5, 261–267 (2003).PubMedGoogle Scholar
  28. Fardel, O., Lecureur, V., Corlu, A., and Guillouzo, A., P-glycoprotein induction in rat liver epithelial cells in response to acute 3-methylcholanthrene treatment.Biochem. Pharmacol., 51, 1427–1436 (1996).PubMedCrossRefGoogle Scholar
  29. Ferguson, S. S., LeCluyse, E. L., Negishi, M., and Goldstein, J. A., Regulation of human CYP2C9 by the constitutive androstane receptor: discovery of a new distal binding site.Mol. Pharmacol., 62, 737–746 (2002).PubMedCrossRefGoogle Scholar
  30. Fraser, D. J., Zumsteg, A., and Meyer, U. A., Nuclear receptors constitutive androstane receptor and pregnane X receptor activate a drug-responsive enhancer of the murine 5-aminolevulinic acid synthase gene.J. Biol. Chem., 278, 39392–39401 (2003).PubMedCrossRefGoogle Scholar
  31. Gao, B., Wenzel, A., Grimm, C., Vavricka, S. R., Benke, D., Meier, P. J., and Reme, C. E., Localization of organic anion transport protein 2 in the apical region of rat retinal pigment epithelium.Invest. Ophthalmol. Vis. Sci., 43, 510–514 (2002).PubMedGoogle Scholar
  32. Geick, A., Eichelbaum, M., and Burk, O., Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin.J. Biol. Chem., 276, 14581–14587 (2001).PubMedCrossRefGoogle Scholar
  33. Gervois, P., Torra, I. P., Fruchart, J. C., and Staels, B., Regulation of lipid and lipoprotein metabolism by PPAR activators.Clin. Chem. Lab. Med., 38, 3–11 (2000).PubMedCrossRefGoogle Scholar
  34. Gilde, A. J., van der Lee, K. A., Willemsen, P. H., Chinetti, G., van der Leij, F. R., van der Vusse, G. J., Staels, B., and van Bilsen, M., Peroxisome proliferator-activated receptor (PPAR) alpha and PPARbeta/delta, but not PPARgamma, modulate the expression of genes involved in cardiac lipid metabolism.Circ. Res., 92, 518–524 (2003).PubMedCrossRefGoogle Scholar
  35. Gonzalez, F. J. and Fernandez-Salguero, P., The aryl hydrocarbon receptor: studies using the AHR-null mice.Drug Metab. Dispos., 26, 1194–1198 (1998).PubMedGoogle Scholar
  36. Gonzalez, F. J. and Nebert, D. W., Evolution of the P450 gene superfamily: animal-plant ‘warfare’, molecular drive and human genetic differences in drug oxidation.Trends Genet., 6, 182–186 (1990).PubMedCrossRefGoogle Scholar
  37. Goodwin, B., Hodgson, E., D’Costa, D. J., Robertson, G. R., and Liddle, C., Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor.Mol. Pharmacol., 62, 359–365 (2002).PubMedCrossRefGoogle Scholar
  38. Guengerich, F. P., Cytochromes p450, drugs, and diseases.Mol. Intervent., 3, 194–204 (2003).CrossRefGoogle Scholar
  39. Guenthner, T. M., Qato, M., Whalen, R., and Glomb, S., Similarities between catalase and cytosolic epoxide hydrolase.Drug Metab. Rev., 20, 733–748 (1989).PubMedCrossRefGoogle Scholar
  40. Guo, G. L., Choudhuri, S., and Klaassen, C. D., Induction profile of rat organic anion transporting polypeptide 2 (oatp2) by prototypical drug-metabolizing enzyme inducers that activate gene expression through ligand-activated transcription factor pathways.J. Pharmacol. Exp. Ther., 300, 206–212 (2002a).PubMedCrossRefGoogle Scholar
  41. Guo, G. L., Staudinger, J., Ogura, K., and Klaassen, C. D., Induction of rat organic anion transporting polypeptide 2 by pregnenolone-16alpha-carbonitrile is via interaction with pregnane X receptor.Mol. Pharmacol., 61, 832–839 (2002b).PubMedCrossRefGoogle Scholar
  42. Hahn, M. E., Aryl hydrocarbon receptors: diversity and evolution.Chem. Biol. Interact., 141, 131–160 (2002).PubMedCrossRefGoogle Scholar
  43. Heid, S. E., Pollenz, R. S., and Swanson, H. I., Role of heat shock protein 90 dissociation in mediating agonist-induced activation of the aryl hydrocarbon receptor.Mol. Pharmacol., 57, 82–92 (2000).PubMedGoogle Scholar
  44. Hinson, J. A. and Forkert, P. G., Phase II enzymes and bioactivation.Can. J. Physiol. Pharmacol., 73, 1407–1413 (1995).PubMedGoogle Scholar
  45. Hirohashi, T., Suzuki, H., Ito, K., Ogawa, K., Kume, K., Shimizu, T., and Sugiyama, Y., Hepatic expression of multidrug resistance-associated protein-like proteins maintained in eisai hyperbilirubinemic rats.Mol. Pharmacol., 53, 1068–1075 (1998).PubMedGoogle Scholar
  46. Honkakoski, P., Moore, R., Washburn, K. A., and Negishi, M., Activation by diverse xenochemicals of the 51-base pair phenobarbital-responsive enhancer module in the CYP2B10 gene.Mol. Pharmacol., 53, 597–601 (1998a).PubMedGoogle Scholar
  47. Honkakoski, P. and Negishi, M., Characterization of a phenobarbital-responsive enhancer module in mouse P450 Cyp2b10 gene.J. Biol. Chem., 272, 14943–14949 (1997).PubMedCrossRefGoogle Scholar
  48. Honkakoski, P., Sueyoshi, T., and Negishi, M., Drug-activated nuclear receptors CAR and PXR.Ann. Med., 35, 172–182 (2003).PubMedCrossRefGoogle Scholar
  49. Honkakoski, P., Zelko, I., Sueyoshi, T., and Negishi, M., 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 (1998b).PubMedGoogle Scholar
  50. Hu, R., Hebbar, V., Kim, B. R., Chen, C., Winnik, B., Buckley, B., Soteropoulos, P., Tolias, P., Hart, R. P., and Kong, A. N., In vivo pharmacokinetics and regulation of gene expression profiles by isothiocyanate sulforaphane in the rat.J. Pharmacol. Exp. Ther., (2004).Google Scholar
  51. Huang, H. C., Nguyen, T., and Pickett, C. B., Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2.Proc. Natl. Acad. Sci. U.S.A., 97, 12475–12480 (2000).PubMedCrossRefGoogle Scholar
  52. Huang, H. C., Nguyen, T., and Pickett, C. B., Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription.J. Biol. Chem., 277, 42769–42774 (2002).PubMedCrossRefGoogle Scholar
  53. Huang, X., Powell-Coffman, J. A., and Jin, Y., The AHR-1 aryl hydrocarbon receptor and its co-factor the AHA-1 aryl hydrocarbon receptor nuclear translocator specify GABAergic neuron cell fate in C. elegans.Development, 131, 819–828 (2004).PubMedCrossRefGoogle Scholar
  54. Innocenti, F., Grimsley, C., Das, S., Ramirez, J., Cheng, C., Kuttab-Boulos, H., Ratain, M. J., and Di Rienzo, A., Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups.Pharmacogenetics, 12, 725–733 (2002).PubMedCrossRefGoogle Scholar
  55. Inokuchi, A., Hinoshita, E., Iwamoto, Y., Kohno, K., Kuwano, M., and Uchiumi, T., Enhanced expression of the human multidrug resistance protein 3 by bile salt in human enterocytes. A transcriptional control of a plausible bile acid transporter.J. Biol. Chem., 276, 46822–46829 (2001).PubMedCrossRefGoogle Scholar
  56. Issemann, I. and Green, S., Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators.Nature, 347, 645–650 (1990).PubMedCrossRefGoogle Scholar
  57. Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., Oyake, T., Hayashi, N., Satoh, K., Hatayama, I., Yamamoto, M., and Nabeshima, Y., An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements.Biochem. Biophys. Res. Commun., 236, 313–322 (1997).PubMedCrossRefGoogle Scholar
  58. Jaiswal, A. K., Jun and Fos regulation of NAD(P)H: quinone oxidoreductase gene expression.Pharmacogenetics, 4, 1–10 (1994).PubMedCrossRefGoogle Scholar
  59. Jelinek, D. R., Andersson, S., Slaughter, C. A., and Russell, D. W., Cloning and regulation of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis.J. Biol. Chem., 265, 8190–8197 (1990).PubMedGoogle Scholar
  60. Jelinek, D. F. and Russell, D. W., Structure of the rat gene encoding cholesterol 7 alpha-hydroxylase.Biochemistry, 29, 7781–7785(1990).PubMedCrossRefGoogle Scholar
  61. Johnson, B. M., Charman, W. N., and Porter, C. J., Application of compartmental modeling to an examination ofin vitro intestinal permeability data: assessing the impact of tissue uptake, P-glycoprotein, and CYP3A.Drug Metab. Dispos., 31, 1151–1160 (2003).PubMedCrossRefGoogle Scholar
  62. Jones, S. A., Moore, L. B., Shenk, J. L., Wisely, G. B., Hamilton, G. A., McKee, D. D., Tomkinson, N. C., LeCluyse, E. L., Lambert, M. H., Willson, T. M., Kliewer, S. A., and Moore, J. T., The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution.Mol. Endocrinol., 14, 27–39 (2000).PubMedCrossRefGoogle Scholar
  63. Kang, K. W., Lee, S. J., Park, J. W., and Kim, S. G., Phosphatidylinositol 3-kinase regulates nuclear translocation of NF-E2-related factor 2 through actin rearrangement in response to oxidative stress.Mol. Pharmacol., 62, 1001–1010 (2002).PubMedCrossRefGoogle Scholar
  64. Kast, H. R., Goodwin, B., Tarr, P. T., Jones, S. A., Anisfeld, A. M., Stoltz, C. M., Tontonoz, P., Kliewer, S., Willson, T. M., and Edwards, P. A., 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 (2002).PubMedCrossRefGoogle Scholar
  65. Kawamoto, T., Sueyoshi, T., Zelko, I., Moore, R., Washburn, K., and Negishi, M., Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene.Mol. Cell Biol., 19, 6318–6322 (1999).PubMedGoogle Scholar
  66. Kerb, R., Hoffmeyer, S., and Brinkmann, U., ABC drug transporters: hereditary polymorphisms and pharmacological impact in MDR1, MRP1 and MRP2.Pharmacogenomics, 2, 51–64 (2001).PubMedCrossRefGoogle Scholar
  67. Keum, Y. S., Owuor, E. D., Kim, B. R., Hu, R., and Kong, A. N., Involvement of Nrf2 and JNK1 in the activation of antioxidant responsive element (ARE) by chemopreventive agent phenethyl isothiocyanate (PEITC).Pharm. Res., 20, 1351–1356 (2003).PubMedCrossRefGoogle Scholar
  68. Khan, S. A. and Vanden Heuvel, J. P., Role of nuclear receptors in the regulation of gene expression by dietary fatty acids (review).J. Nutr. Biochem., 14, 554–567 (2003).PubMedCrossRefGoogle Scholar
  69. Kikuchi, Y., Ohsawa, S., Mimura, J., Ema, M., Takasaki, C., Sogawa, K., and Fujii-Kuriyama, Y., Heterodimers of bHLH-PAS protein fragments derived from AhR, AhRR, and Arnt prepared by co-expression in Escherichia coli: characterization of their DNA binding activity and preparation of a DNA complex.J. Biochem. (Tokyo), 134, 83–90 (2003).Google Scholar
  70. Kim, R. B., Organic anion-transporting polypeptide (OATP) transporter family and drug disposition.Eur. J. Clin. Invest., 33Suppl 2, 1–5(2003).PubMedCrossRefGoogle Scholar
  71. King, C. D., Rios, G. R., Green, M. D., and Tephly, T. R., UDP-glucuronosyltransferases.Curr. Drug Metab., 1, 143–161 (2000).PubMedCrossRefGoogle Scholar
  72. Kliewer, S. A., Moore, J. T., Wade, L., Staudinger, J. L., Watson, M. A., Jones, S. A., McKee, D. D., Oliver, B. B., Willson, T. M., Zetterstrom, R. H., Perlmann, T., and Lehmann, J. M., An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway.Cell, 92, 73–82 (1998).PubMedCrossRefGoogle Scholar
  73. Kong, A. N. T., Owuor, E., Yu, R., Hebbar, V., Chen, C., Hu, R., and Mandlekar, S., Induction of xenobiotic enzymes by the MAP kinase pathway and the antioxidant or electrophile response element (ARE/EpRE).Drug Metab. Rev., 33, 255–271 (2001a).PubMedCrossRefGoogle Scholar
  74. Kong, A. N. T., Yu, R., Chen, C., Mandlekar, S., and Primiano, T., Signal transduction events elicited by natural products: role of MAPK and caspase pathways in homeostatic response and induction of apoptosis.Arch. Pharm. Res., 23, 1–16 (2000).PubMedCrossRefGoogle Scholar
  75. Kong, A. N. T., Yu, R., Hebbar, V., Chen, C., Owuor, E., Hu, R., Ee, R., and Mandlekar, S., Signal transduction events elicited by cancer prevention compounds.Mutat. Res., 480-481, 231–241 (2001b).PubMedGoogle Scholar
  76. Konig, J., Nies, A. T., Cui, Y., Leier, I., and Keppler, D., Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance.Biochim. Biophys. Acta, 1461, 377–394 (1999a).PubMedCrossRefGoogle Scholar
  77. Konig, J., Rost, D., Cui, Y., and Keppler, D., Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane.Hepatology, 29, 1156–1163 (1999b).PubMedCrossRefGoogle Scholar
  78. Kullak-Ublick, G. A. and Becker, M. B., Regulation of drug and bile salt transporters in liver and intestine.Drug Metab. Rev., 35, 305–317 (2003).PubMedCrossRefGoogle Scholar
  79. Kullak-Ublick, G. A., Stieger, B., and Meier, P. J., Enterohepatic bile salt transporters in normal physiology and liver disease.Gastroenterology, 126, 322–342 (2004).PubMedCrossRefGoogle Scholar
  80. Kumar, R.and Thompson, E. B., The structure of the nuclear hormone receptors.Steroids, 64, 310–319 (1999).PubMedCrossRefGoogle Scholar
  81. Kwak, M. K., Itoh, K., Yamamoto, M., and Kensler, T. W., Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter.Mol. Cell Biol., 22, 2883–2892 (2002).PubMedCrossRefGoogle Scholar
  82. Kwak, M. K., Itoh, K., Yamamoto, M., Sutter, T. R., and Kensler, T. W., Role of transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymesin vivo by the cancer chemoprotective agent, 3H-1, 2-dimethiole-3-thione.Mol. Med., 7, 135–145 (2001).PubMedGoogle Scholar
  83. Lambe, K. G. and Tugwood, J. D., A human peroxisome-proliferator-activated receptor-gamma is activated by inducers of adipogenesis, including thiazolidinedione drugs.Eur. J. Biochem., 239, 1–7 (1996).PubMedCrossRefGoogle Scholar
  84. Lee, J. M., Hanson, J. M., Chu, W. A., and Johnson, J. A., Phosphatidylinositol 3-kinase, not extracellular signal-regulated kinase, regulates activation of the antioxidant-responsive element in IMR-32 human neuroblastoma cells.J. Biol. Chem., 276, 20011–20016 (2001).PubMedCrossRefGoogle Scholar
  85. Lehmann, J. M., Kliewer, S. A., Moore, L. B., Smith-Oliver, T. A., Oliver, B. B., Su, J. L, Sundseth, S. S., Winegar, D. A., Blanchard, D. E., Spencer, T. A., and Willson, T. M., Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway.J. Biol. Chem., 272, 3137–3140(1997).PubMedCrossRefGoogle Scholar
  86. Lehmann, J. M., McKee, D. D., Watson, M. A., Willson, T. M., Moore, J. T., and Kliewer, S. A., The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.J. Clin. Invest., 102, 1016–1023 (1998).PubMedCrossRefGoogle Scholar
  87. Levine, S. L. and Perdew, G. H., Aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) activity is unaltered by phosphorylation of a periodicity/ARNT/single-minded (PAS)-region serine residue.Mol. Pharmacol., 59, 557–566 (2001).PubMedGoogle Scholar
  88. Lewis, D. E., P450 structures and oxidative metabolism of xenobiotics.Pharmacogenomics, 4, 387–395 (2003).PubMedCrossRefGoogle Scholar
  89. Li, W., Harper, P. A., Tang, B. K., and Okey, A. B., Regulation of cytochrome P450 enzymes by aryl hydrocarbon receptor in human cells: CYP1A2 expression in the LS180 colon carcinoma cell line after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin or 3-methylcholanthrene.Biochem. Pharmacol., 56, 599–612 (1998).PubMedCrossRefGoogle Scholar
  90. Mackenzie, P. I., Owens, I. S., Burchell, B., Bock, K. W., Bairoch, A., Belanger, A., Fournel-Gigleux, S., Green, M., Hum, D. W., lyanagi, T, Lancet, D., Louisot, P., Magdalou, J., Chowdhury, J. R., Ritter, J. K., Schachter, H., Tephly, T. R., Tipton, K. E., and Nebert, D. W., The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence.Pharmacogenetics, 7, 255–269 (1997).PubMedCrossRefGoogle Scholar
  91. Maglich, J. M., Stoltz, C. M., Goodwin, B., Hawkins-Brown, D., Moore, J. T., and Kliewer, S. A., Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification.Mol. Pharmacol., 62,638–646 (2002).PubMedCrossRefGoogle Scholar
  92. Maheo, K., Antras-Ferry, J., Morel, E, Langouet, S., and Guillouzo, A., Modulation of glutathione S-transferase subunits A2, M1, and P1 expression by interleukin-1beta in rat hepatocytes in primary culture.J. Biol. Chem., 272, 16125–16132 (1997).PubMedCrossRefGoogle Scholar
  93. Makishima, M., Okamoto, A. Y, Repa, J. J., Tu, H., Learned, R. M., Luk, A., Hull, M. V., Lustig, K. D., Mangelsdorf, D. J., and Shan, B., Identification of a nuclear receptor for bile acids.Science, 284, 1362–1365 (1999).PubMedCrossRefGoogle Scholar
  94. Mangelsdorf, D. J., Borgmeyer, U., Heyman, R. A., Zhou, J. Y., Ong, E. S., Oro, A. E., Kakizuka, A., and Evans, R. M., Characterization of three RXR genes that mediate the action of 9-cis retinoic acid.Genes Dev., 6, 329–344 (1992).PubMedCrossRefGoogle Scholar
  95. Mangelsdorf, D. J. and Evans, R. M., The RXR heterodimers and orphan receptors.Cell, 83,841–850 (1995).PubMedCrossRefGoogle Scholar
  96. Menke, J. G., Macnaul, K. L., Hayes, N. S., Baffic, J., Chao, Y. S., Elbrecht, A., Kelly, L. J., Lam, M. H., Schmidt, A., Sahoo, S., Wang, J., Wright, S. D., Xin, P., Zhou, G, Moller, D. E., and Sparrow, C. P., A novel liver X receptor agonist establishes species differences in the regulation of cholesterol 7alpha-hydroxylase (CYP7a).Endocrinology, 143,2548–2558(2002).PubMedCrossRefGoogle Scholar
  97. Meyer, U. A., Overview of enzymes of drug metabolism.J. Pharmacokinet. Biopharm., 24,449–459 (1996).PubMedCrossRefGoogle Scholar
  98. Mizuno, N., Niwa, T., Yotsumoto, Y., and Sugiyama, Y., Impact of drug transporter studies on drug discovery and development.Pharmacol. Rev., 55,425–461 (2003).PubMedCrossRefGoogle Scholar
  99. Moore, L. B., Parks, D. J., Jones, S. A., Bledsoe, R. K., Consler, T. G., Stimmel, J. B., Goodwin, B., Liddle, C, Blanchard, S. G, Willson, T. M., Collins, J. L., and Kliewer, S. A., Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands.J. Biol. Chem., 275,15122–15127 (2000).PubMedCrossRefGoogle Scholar
  100. Moscow, J. A. and Dixon, K. H., Glutathione-related enzymes, glutathione and multidrug resistance.Cytotechnology, 12, 155–170(1993).PubMedCrossRefGoogle Scholar
  101. Nakajima, M., Iwanari, M., and Yokoi, T., Effects of histone deacetylation and DNA methylation on the constitutive and TCDD-inducible expressions of the human CYP1 family in MCF-7 and HeLa cells.Toxicol. Lett., 144, 247–256 (2003).PubMedCrossRefGoogle Scholar
  102. Nebert, D. W., Nelson, D. R., Coon, M. J., Estabrook, R. W., Feyereisen, R., Fujii-Kuriyama, Y., Gonzalez, F. J., Guengerich, F. P., Gunsalus, I. C., Johnson, E. R.,et al., The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature.DNA Cell Biol., 10,1–14(1991).PubMedGoogle Scholar
  103. Nelson, D. R., Koymans, L., Kamataki, T., Stegeman, J. J., Feyereisen, R., Waxman, D. J., Waterman, M. R., Gotoh, O., Coon, M. J., Estabrook, R. W., Gunsalus, I. C., and Nebert, D. W., P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature.Pharmacogenetics, 6,1–42 (1996).PubMedCrossRefGoogle Scholar
  104. Nguyen, T., Sherratt, P. J., Huang, H. C, Yang, C. S., and Pickett, C. B., Increased protein stability as a mechanism that enhances Nrf2-mediated transcriptional activation of the antioxidant response element. Degradation of Nrf2 by the 26 S proteasome.J. Biol. Chem., 278,4536–4541 (2003).PubMedCrossRefGoogle Scholar
  105. Owuor, E. D. and Kong, A. N., Antioxidants and oxidants regulated signal transduction pathways.Biochem. Pharmacol., 64, 765–770 (2002).PubMedCrossRefGoogle Scholar
  106. Paquet, Y., Trottier, E., Beaudet, M. J., and Anderson, A., Mutational analysis of the CYP2B2 phenobarbital response unit and inhibitory effect of the constitutive androstane receptor on phenobarbital responsiveness.J. Biol. Chem., 275, 38427–38436 (2000).PubMedCrossRefGoogle Scholar
  107. Pascussi, J. M., Dvorak, Z., Gerbal-Chaloin, S., Assenat, E., Maurel, P., and Vilarem, M. J., Pathophysiological factors affecting CAR gene expression.Drug Metab. Rev., 35, 255–268 (2003a).PubMedCrossRefGoogle Scholar
  108. Pascussi, J. M., Gerbal-Chaloin, S., Drocourt, L., Maurel, P., and Vilarem, M. J., The expression of CYP2B6, CYP2C9 and CYP3A4 genes: a tangle of networks of nuclear and steroid receptors.Biochim. Biophys. Acta, 1619,243–253 (2003b).PubMedGoogle Scholar
  109. Peet, D. J., Turley, S. D., Ma, W., Janowski, B. A., Lobaccaro, J. M., Hammer, R. E., and Mangelsdorf, D. J., Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha.Cell, 93, 693–704 (1998).PubMedCrossRefGoogle Scholar
  110. Perloff, M. D., von Moltke, L. L, and Greenblatt, D. J., Ritonavir and dexamethasone induce expression of CYP3A and P-glycoprotein in rats.Xenobiotica, 34,133–150 (2004).PubMedCrossRefGoogle Scholar
  111. Ramsden, R., Beck, N. B., Sommer, K. M., and Omiecinski, C. J., Phenobarbital responsiveness conferred by the 5’-flanking region of the rat CYP2B2 gene in transgenic mice.Gene, 228,169–179(1999).PubMedCrossRefGoogle Scholar
  112. Reichel, C., Gao, B., Van Montfoort, J., Cattori, V., Rahner, C., Hagenbuch, B., Stieger, B., Kamisako, T., and Meier, P. J., Localization and function of the organic anion-transporting polypeptide Oatp2 in rat liver.Gastroenterology, 117, 688–695(1999).PubMedCrossRefGoogle Scholar
  113. Ritter, J. K., Kessler, F. K., Thompson, M. T, Grove, A. D., Auyeung, D. J., and Fisher, R. A., Expression and inducibility of the human bilirubin UDP-glucuronosyltransferase UGT1A1 in liver and cultured primary hepatocytes: evidence for both genetic and environmental influences.Hepatology 30, 476–484(1999).PubMedCrossRefGoogle Scholar
  114. Rowlands, J. C. and Gustafsson, J. A., Aryl hydrocarbon receptor-mediated signal transduction.Crit. Rev. Toxicol., 27, 109–134(1997).PubMedCrossRefGoogle Scholar
  115. Rushmore, T. H., King, R. G, Paulson, K. E., and Pickett, C. B., Regulation of glutathione S-transferase Ya subunit gene expression: identification of a unique xenobiotic-responsive element controlling inducible expression by planar aromatic compounds.Proc. Natl. Acad. Sci. U.S.A., 87, 3826–3830 (1990).PubMedCrossRefGoogle Scholar
  116. Rushmore, T. H. and Kong, A. N., Pharmacogenomics, regulation and signaling pathways of phase I and II drug metabolizing enzymes.Curr. Drug Metab., 3, 481–490 (2002).PubMedCrossRefGoogle Scholar
  117. Schilter, B., Turesky, R. J., Juillerat, M., Honegger, P., and Guigoz, Y., Phase I and phase II xenobiotic reactions and metabolism of the food-borne carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in aggregating liver cell cultures.Biochem. Pharmacol., 45,1087–1096 (1993).PubMedCrossRefGoogle Scholar
  118. Schoonjans, K., Staels, B., and Auwerx, J., Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression.J. Lipid Res., 37, 907–925 (1996).PubMedGoogle Scholar
  119. Shen, G., Hebbar, V., Nair, S. S., Xu, C., Li, W., Lin, W., Keum, Y. S., Han, J., Gallo, M. A., and Kong, A. N., Regulation of Nrf2 transactivation domain activity: The differential effects of mitogen-activated protein kinase cascades and synergistic stimulation effect of Raf and CREB binding protein.J. Biol. Chem., 279,23052–23060 (2004).PubMedCrossRefGoogle Scholar
  120. Shimizu, Y., Nakatsuru, Y., Ichinose, M., Takahashi, Y., Kume, H., Mimura, J., Fujii-Kuriyama, Y, and Ishikawa, T, Benzo[a] pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor.Proc. Natl. Acad. Sci. U.S.A., 97, 779–782 (2000).PubMedCrossRefGoogle Scholar
  121. Shitara, Y., Sugiyama, D., Kusuhara, H., Kato, Y., Abe, T., Meier, P. J., Itoh, T., and Sugiyama, Y., Comparative inhibitory effects of different compounds on rat oatpl (slc21a1)- and Oatp2 (Slc21 a5)-mediated transport.Pharm. Res., 19, 147–153 (2002).PubMedCrossRefGoogle Scholar
  122. Simpson, A. E., The cytochrome P450 4 (CYP4) family.Gen. Pharmacol., 28,351–359 (1997).PubMedGoogle Scholar
  123. Song, X., Xie, M., Zhang, H., Li, Y, Sachdeva, K., and Yan, B., The pregnane X receptor binds to response elements in a genomic context-dependent manner, and PXR activator rifampicin selectively alters the binding among target genes.Drug Metab. Dispos., 32, 35–42 (2004).PubMedCrossRefGoogle Scholar
  124. Staudinger, J., Liu, Y, Madan, A., Habeebu, S., and Klaassen, C. D., Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor.Drug Metab. Dispos., 29,1467–1472 (2001a).PubMedGoogle Scholar
  125. Staudinger, J. L., Goodwin, B., Jones, S. A., Hawkins-Brown, D., MacKenzie, K. I., LaTour, A., Liu, Y, Klaassen, C. D., Brown, K. K., Reinhard, J., Willson, T. M., Koller, B.H., and Kliewer, S. A., The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.Proc. Natl. Acad. Sci. U.S.A., 98, 3369–3374 (2001b).PubMedCrossRefGoogle Scholar
  126. Staudinger, J. L., Madan, A., Carol, K. M., and Parkinson, A., Regulation of drug transporter gene expression by nuclear receptors.Drug Metab. Dispos., 31, 523–527 (2003).PubMedCrossRefGoogle Scholar
  127. Stewart, D., Killeen, E., Naquin, R., Alam, S., and Alam, J., Degradation of transcription factor Nrf2 via the ubiquitin-proteasome pathway and stabilization by cadmium.J. Biol. Chem., 278,2396–2402 (2003).PubMedCrossRefGoogle Scholar
  128. Sueyoshi, T., Kawamoto, T., Zelko, I., Honkakoski, P., and Negishi, M., The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene.J. Biol. Chem., 274, 6043–6046 (1999).PubMedCrossRefGoogle Scholar
  129. Sueyoshi, T. and Negishi, M., Phenobarbital response elements of cytochrome P450 genes and nuclear receptors.Annu. Rev. Pharmacol. Toxicol., 41,123–143 (2001).PubMedCrossRefGoogle Scholar
  130. Sugatani, J., Kojima, H., Ueda, A., Kakizaki, S., Yoshinari, K., Gong, Q. H., Owens, I. S., Negishi, M., and Sueyoshi, T., The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR.Hepatology, 33, 1232–1238(2001).PubMedCrossRefGoogle Scholar
  131. Teng, S., Jekerle, V., and Piquette-Miller, M., Induction of ABCC3 (MRP3) by pregnane X receptor activators.Drug Metab. Dispos., 31,1296–1299 (2003).PubMedCrossRefGoogle Scholar
  132. Tew, K. D. and Ronai, Z., GST function in drug and stress response.Drug Resist. Updat., 2,143–147 (1999).PubMedCrossRefGoogle Scholar
  133. Tirana, R. G. and Kim, R. B., Pharmacogenomics of organic anion-transporting polypeptides (OATP).Adv. Drug Deliv. Rev., 54,1343–1352(2002).CrossRefGoogle Scholar
  134. Tugwood, J. D., Aldridge, T. C., Lambe, K. G., Macdonald, N., and Woodyatt, N. J., Peroxisome proliferator-activated receptors: structures and function.Ann. N. Y. Acad. Sci., 804, 252–265(1996).PubMedCrossRefGoogle Scholar
  135. Tugwood, J. D., Issemann, I., Anderson, R. G, Bundell, K. R., McPheat, W. L, and Green, S., The mouse peroxisome proliferator activated receptor recognizes a response element in the 5’ flanking sequence of the rat acyl CoA oxidase gene.EMBO. J., 11, 433–439 (1992).PubMedGoogle Scholar
  136. Tukey, R. H. and Strassburg, C. P., Human UDP-glucuronosyl-transferases: metabolism, expression, and disease.Annu. Rev. Pharmacol. Toxicol., 40, 581–616 (2000).PubMedCrossRefGoogle Scholar
  137. Turgeon, D., Carrier, J. S., Levesque, E., Hum, D. W., and Belanger, A., Relative enzymatic activity, protein stability, and tissue distribution of human steroid-metabolizing UGT2B subfamily members.Endocrinology., 142, 778–787 (2001).PubMedCrossRefGoogle Scholar
  138. Tzeng, S. J. and Huang, J. D., Transcriptional regulation of the rat Mrp3 promoter in intestine cells.Biochem. Biophys. Res. Commun., 291,270–277 (2002).PubMedCrossRefGoogle Scholar
  139. Vatsis, K. P., Weber, W. W., Bell, D. A., Dupret, J. M., Evans, D. A., Grant, D. M., Hein, D. W., Lin, H. J., Meyer, U. A., Relling, M. al., Nomenclature for N-acetyltransferases.Pharmacogenetics., 5,1–17 (1995).PubMedCrossRefGoogle Scholar
  140. Venkateswaran, A., Laffitte, B. A., Joseph, S. B., Mak, P. A., Wilpitz, D. C, Edwards, P. A., and Tontonoz, P., Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha.Proc. Natl. Acad. Sci. U.S.A., 97, 12097–12102 (2000).PubMedCrossRefGoogle Scholar
  141. Wakabayashi, N., Dinkova-Kostova, A. T, Holtzclaw, W. D., Kang, M. I., Kobayashi, A., Yamamoto, M., Kensler, T. W., and Talalay, P., Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keapl sensor modified by inducers.Proc. Natl. Acad. Sci. U.S.A., 101, 2040–2045 (2004).PubMedCrossRefGoogle Scholar
  142. Wang, H., Chen, J., Hollister, K., Sowers, L. C., and Forman, B. M., Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.Mol. Cell, 3, 543–553 (1999).PubMedCrossRefGoogle Scholar
  143. Wang, H., Faucette, S., Sueyoshi, T, Moore, R., Ferguson, S., Negishi, M., and LeCluyse, E. L, 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 (2003).PubMedCrossRefGoogle Scholar
  144. Wang, H. and LeCluyse, E. L., Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes.Clin. Pharmacokinet., 42,1331–1357 (2003).PubMedCrossRefGoogle Scholar
  145. Waxman, D. J., P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR.Arch. Biochem. Biophys., 369,11–23 (1999).PubMedCrossRefGoogle Scholar
  146. Wei, P., Zhang, J., Dowhan, D. H., Han, Y, and Moore, D. D., Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response.Pharmacogenomics J., 2,117–126 (2002).PubMedCrossRefGoogle Scholar
  147. Weinshilboum, R. M., Otterness, D. M., Aksoy, I. A., Wood, T C, Her, C, and Raftogianis, R. B., Sulfation and sulfotransferases 1: Sulfotransferase molecular biology: cDNAs and genes.FASEB J., 11,3–14(1997).PubMedGoogle Scholar
  148. Willson, T. M. and Kliewer, S. A., PXR, CAR and drug metabolism.Nat. Rev. Drug Discov., 1,259–266 (2002).PubMedCrossRefGoogle Scholar
  149. Wolters, H., Elzinga, B. M., Bailer, J. F, Boverhof, R., Schwarz, M., Stieger, B., Verkade, H. J., and Kuipers, R, Effects of bile salt flux variations on the expression of hepatic bile salt transportersin vivo in mice.J. Hepatol., 37, 556–563 (2002).PubMedCrossRefGoogle Scholar
  150. Xie, W., Barwick, J. L, Downes, M., Blumberg, B., Simon, C. M., Nelson, M. C, Neuschwander-Tetri, B. A., Brunt, E. M., Guzelian, P. S., and Evans, R. M., Humanized xenobiotic response in mice expressing nuclear receptor SXR.Nature, 406, 435–439 (2000a).PubMedCrossRefGoogle Scholar
  151. Xie, W., Barwick, J. L, Simon, C. M., Pierce, A. M., Safe, S., Blumberg, B., Guzelian, P. S., and Evans, R. M., Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR.Genes Dev., 14,3014–3023 (2000b).PubMedCrossRefGoogle Scholar
  152. Xie, W., Radominska-Pandya, A., Shi, Y., Simon, C. M., Nelson, M. C, Ong, E. S., Waxman, D. J., and Evans, R. M., An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids.Proc. Natl. Acad. Sci. U.S.A., 98, 3375–3380(2001).PubMedCrossRefGoogle Scholar
  153. Xiong, H., Yoshinari, K., Brouwer, K. L, and Negishi, M., Role of constitutive androstane receptor in thein vivo induction of Mrp3 and CYP2B1/2 by phenobarbital.Drug Metab. Dispos., 30,918–923(2002).PubMedCrossRefGoogle Scholar
  154. Yu, R., Chen, C, Mo, Y. Y, Hebbar, V., Owuor, E. D., Tan, T. H., and Kong, A. N. T., Activation of mitogen-activated protein kinase pathways induces antioxidant response element-mediated gene expressionvia a Nrf2-dependent mechanism.J. Biol. Chem., 275, 39907–39913 (2000a).PubMedCrossRefGoogle Scholar
  155. Yu, R., Lei, W., Mandlekar, S., Weber, M. J., Der, C. J., Wu, J., and Kong, A. N. T., Role of a mitogen-activated protein kinase pathway in the induction of phase II detoxifying enzymes by chemicals.J. Biol. Chem., 274, 27545–27552 (1999).PubMedCrossRefGoogle Scholar
  156. Yu, R., Mandlekar, S., Lei, W., Fahl, W. E., Tan, T. H., and Kong, A. N. T, p38 mitogen-activated protein kinase negatively regulates the induction of phase II drug-metabolizing enzymes that detoxify carcinogens.J. Biol. Chem., 275, 2322–2327 (2000b).PubMedCrossRefGoogle Scholar
  157. Yu, S., Rao, S., and Reddy, J. K., Peroxisome proliferator-activated receptors, fatty acid oxidation, steatohepatitis and hepatocarcinogenesis.Curr. Mol. Med., 3, 561–572 (2003).PubMedCrossRefGoogle Scholar
  158. Zetterstrom, R. H., Solomin, L., Mitsiadis, T., Olson, L., and Perlmann, T., Retinoid X receptor heterodimerization and developmental expression distinguish the orphan nuclear receptors NGFI-B, Nurrl, and Nor1.Mol. Endocrinol., 10, 1656–1666 (1996).PubMedCrossRefGoogle Scholar
  159. Zhou, Y. C, Davey, H. W., McLachlan, M. J., Xie, T, and Waxman, D. J., Elevated basal expression of liver peroxisomal beta-oxidation enzymes and CYP4A microsomal fatty acid omega-hydroxylase in STAT5b(-/-) mice: cross-talkin vivo between peroxisome proliferator-activated receptor and signal transducer and activator of transcription signaling pathways.Toxicol. Appl. Pharmacol., 182, 1–10 (2002).PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2005

Authors and Affiliations

  • Changjiang Xu
    • 1
  • Christina Yong-Tao Li
    • 1
  • Ah-Ng Tony Kong
    • 1
  1. 1.Department of Pharmaceutics, Ernest Mario School of Pharmacy, RutgersThe State University of New JerseyPiscatawayUSA

Personalised recommendations