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Induction of Phase I, II and III Drug Metabolism/Transport by Xenobiotics

Xu Chang Jiang    (Department of Pharmaceutics, Ernest Mario School of Pharmacy   ); Li Christina YongTao    (Department of Pharmaceutics, Ernest Mario School of Pharmacy   ); Kong AhNg Tony    (Department of Pharmaceutics, Ernest Mario School of Pharmacy  );
  • 초록

    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 ret-inoid 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 fib rate-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 GYP 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 GAR 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 coord


  • 참고문헌 (159)

    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) 
    2. Brinkmann, U. and Eichelbaum, M., Polymorphisms in the ABC drug transporter gene MDR1. Pharmacogenomics J., 1, 59-64 (2001) 
    3. 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) 
    4. Coumoul, X., Diry, M., and Barouki, R., PXR-dependent induc- tion of human CYP3A4 gene expression by organochlorine pesticides. Biochem. Pharmacol., 64, 1513-1519 (2002) 
    5. Dean, M., Hamon, Y., and Chimini, G., The human ATP-binding cassette (ABC) transporter superfamily. J. Lipid Res., 42, 1007-1017 (2001) 
    6. 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) 
    7. 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) 
    8. 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) 
    9. 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) 
    10. 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) 
    11. Guenthner, T. M., Qato, M., Whalen, R., and Glomb, S., Similarities between catalase and cytosolic epoxide hydrolase. Drug Metab. Rev., 20, 733-748 (1989) 
    12. 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) 
    13. Hahn, M. E., Aryl hydrocarbon receptors: diversity and evolution. Chem. Biol. Interact., 141, 131-160 (2002) 
    14. Honkakoski, P. and Negishi, M., Characterization of a pheno- barbital-responsive enhancer module in mouse P450 Cyp2b10 gene. J. Biol. Chem., 272, 14943-14949 (1997) 
    15. 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) 
    16. Huang, X., Powell-Coffman, J. A., and Jin, Y., The AHR-1 aryl hydrocarbon receptor and its co-factor the AHA-1 aryl hydro- carbon receptor nuclear translocator specify GABAergic neuron cell fate in C. elegans. Development, 131, 819-828 (2004) 
    17. 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) 
    18. 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) 
    19. 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) 
    20. 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: character- ization of their DNA binding activity and preparation of a DNA complex. J. Biochem. (Tokyo), 134, 83-90 (2003) 
    21. Kim, R. B., Organic anion-transporting polypeptide (OATP) transporter family and drug disposition. Eur. J. Clin. Invest., 33 Suppl 2, 1-5 (2003) 
    22. 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) 
    23. 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) 
    24. 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) 
    25. 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) 
    26. 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) 
    27. 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) 
    28. 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 carci- noma cell line after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin or 3-methylcholanthrene. Biochem. Pharmacol., 56, 599-612 (1998) 
    29. 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) 
    30. 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) 
    31. Mizuno, N., Niwa, T., Yotsumoto, Y., and Sugiyama, Y., Impact of drug transporter studies on drug discovery and develop- ment. Pharmacol. Rev., 55, 425-461 (2003) 
    32. 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) 
    33. Owuor, E. D. and Kong, A. N., Antioxidants and oxidants regulated signal transduction pathways. Biochem. Pharmacol., 64, 765-770 (2002) 
    34. 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) 
    35. 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) 
    36. 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) 
    37. 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) 
    38. Sueyoshi, T. and Negishi, M., Phenobarbital response elements of cytochrome P450 genes and nuclear receptors. Annu. Rev. Pharmacol. Toxicol., 41, 123-143 (2001) 
    39. Tugwood, J. D., Issemann, I., Anderson, R. G., Bundell, K. R., McPheat, W. L., and Green, S., The mouse peroxisome pro- liferator activated receptor recognizes a response element in the 5' flanking sequence of the rat acyl CoA oxidase gene. EMBO. J., 11, 433-439 (1992) 
    40. 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) 
    41. 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) 
    42. 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, Nurr1, and Nor1. Mol. Endocrinol., 10, 1656-1666 (1996) 
    43. Elferink, C. J., Aryl hydrocarbon receptor-mediated cell cycle control. Prog. Cell Cycle Res., 5, 261-267 (2003) 
    44. 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) 
    45. Johnson, B. M., Charman, W. N., and Porter, C. J., Application of compartmental modeling to an examination of in vitro intestinal permeability data: assessing the impact of tissue uptake, P-glycoprotein, and CYP3A. Drug Metab. Dispos., 31, 1151-1160 (2003) 
    46. 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) 
    47. 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) 
    48. 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) 
    49. 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) 
    50. Kawamoto, T., Sueyoshi, T., Zelko, I., Moore, R., Washburn, K., and Negishi, M., Phenobarbital-responsive nuclear translo- cation of the receptor CAR in induction of the CYP2B gene. Mol. Cell Biol., 19, 6318-6322 (1999) 
    51. 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) 
    52. 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. F., et al., The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature. DNA Cell Biol., 10, 1-14 (1991) 
    53. 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) 
    54. 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) 
    55. Chandra, P. and Brouwer, K. L., The complexities of hepatic drug transport: current knowledge and emerging concepts. Pharm. Res., 21, 719-735 (2004) 
    56. Maheo, K., Antras-Ferry, J., Morel, F., 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) 
    57. Bolton, J. L. and Chang, M., Quinoids as reactive intermediates in estrogen carcinogenesis. Adv. Exp. Med. Biol., 500, 497-507 (2001) 
    58. 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) 
    59. 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) 
    60. Coles, B. F., Chen, G., Kadlubar, F. F., 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) 
    61. 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) 
    62. 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) 
    63. 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 expression via a Nrf2-dependent mechanism. J. Biol. Chem., 275, 39907-39913 (2000a) 
    64. 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) 
    65. 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) 
    66. 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) 
    67. 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) 
    68. 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) 
    69. Simpson, A. E., The cytochrome P450 4 (CYP4) family. Gen. Pharmacol., 28, 351-359 (1997) 
    70. 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 Keap1 sensor modified by inducers. Proc. Natl. Acad. Sci. U.S.A., 101, 2040-2045 (2004) 
    71. Wolters, H., Elzinga, B. M., Baller, J. F., Boverhof, R., Schwarz, M., Stieger, B., Verkade, H. J., and Kuipers, F., Effects of bile salt flux variations on the expression of hepatic bile salt transporters in vivo in mice. J. Hepatol., 37, 556-563 (2002) 
    72. 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) 
    73. Jelinek, D. F., 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) 
    74. 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) 
    75. 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) 
    76. 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 UGT1A1in liver and cultured primary hepatocytes: evidence for both genetic and environmental influences. Hepatology, 30, 476-484 (1999) 
    77. Mackenzie, P. I., Owens, I. S., Burchell, B., Bock, K. W., Bairoch, A., Belanger, A., Fournel-Gigleux, S., Green, M., Hum, D. W., Iyanagi, T., Lancet, D., Louisot, P., Magdalou, J., Chowdhury, J. R., Ritter, J. K., Schachter, H., Tephly, T. R., Tipton, K. F., and Nebert, D. W., The UDP glycosyltransferasegene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics, 7, 255-269 (1997) 
    78. Rowlands, J. C. and Gustafsson, J. A., Aryl hydrocarbon receptor-mediated signal transduction. Crit. Rev. Toxicol., 27, 109-134 (1997) 
    79. 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) 
    80. Meyer, U. A., Overview of enzymes of drug metabolism. J. Pharmacokinet. Biopharm., 24, 449-459 (1996) 
    81. 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) 
    82. 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) 
    83. 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) 
    84. Jaiswal, A. K., Jun and Fos regulation of NAD(P)H: quinone oxidoreductase gene expression. Pharmacogenetics, 4, 1-10 (1994) 
    85. 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) 
    86. Tukey, R. H. and Strassburg, C. P., Human UDP-glucuronosyl- transferases: metabolism, expression, and disease. Annu. Rev. Pharmacol. Toxicol., 40, 581-616 (2000) 
    87. Hinson, J. A. and Forkert, P. G., Phase II enzymes and bioactivation. Can. J. Physiol. Pharmacol., 73, 1407-1413 (1995) 
    88. Jelinek, D. F. and Russell, D. W., Structure of the rat gene encoding cholesterol 7 alpha-hydroxylase. Biochemistry, 29, 7781-7785 (1990) 
    89. 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) 
    90. 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) 
    91. 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) 
    92. Banoglu, E., Current status of the cytosolic sulfotransferases in the metabolic activation of promutagens and procarcinogens. Curr. Drug Metab., 1, 1-30 (2000) 
    93. 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) 
    94. Dinkova-Kostova, A. T., Protection against cancer by plant phenylpropenoids: induction of mammalian anticarcinogenic enzymes. Mini Rev. Med. Chem., 2, 595-610 (2002a) 
    95. 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) 
    96. 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) 
    97. 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) 
    98. 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) 
    99. Zhou, Y. C., Davey, H. W., McLachlan, M. J., Xie, T., and Waxman, D. J., Elevated basal expression of liver peroxisomalbeta-oxidation enzymes and CYP4A microsomal fatty acid omega-hydroxylase in STAT5b(-/-) mice: cross-talk in vivo between peroxisome proliferator-activated receptor and signal transducer and activator of transcription signaling pathways. Toxicol. Appl. Pharmacol., 182, 1-10 (2002) 
    100. 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) 
    101. 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) 
    102. 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) 
    103. 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) 
    104. 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) 
    105. Teng, S., Jekerle, V., and Piquette-Miller, M., Induction of ABCC3 (MRP3) by pregnane X receptor activators. Drug Metab. Dispos., 31, 1296-1299 (2003) 
    106. 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) 
    107. 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) 
    108. 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) 
    109. 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) 
    110. Honkakoski, P., Sueyoshi, T., and Negishi, M., Drug-activated nuclear receptors CAR and PXR. Ann. Med., 35, 172-182 (2003) 
    111. Mangelsdorf, D. J. and Evans, R. M., The RXR heterodimers and orphan receptors. Cell, 83, 841-850 (1995) 
    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) 
    113. 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) 
    114. 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) 
    115. Kumar, R. and Thompson, E. B., The structure of the nuclear hormone receptors. Steroids, 64, 310-319 (1999) 
    116. 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) 
    117. 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) 
    118. Wang, H. and LeCluyse, E. L., Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin. Pharmacokinet., 42, 1331-1357 (2003) 
    119. 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) 
    120. 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) 
    121. 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. Gastroen- terology., 121, 140-147 (2001) 
    122. Issemann, I. and Green, S., Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature, 347, 645-650 (1990) 
    123. 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) 
    124. 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) 
    125. 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) 
    126. 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 Keap1 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) 
    127. Guengerich, F. P., Cytochromes p450, drugs, and diseases. Mol. Intervent., 3, 194-204 (2003) 
    128. King, C. D., Rios, G. R., Green, M. D., and Tephly, T. R., UDP-glucuronosyltransferases. Curr. Drug Metab., 1, 143-161 (2000) 
    129. 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) 
    130. 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) 
    131. 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) 
    132. Tew, K. D. and Ronai, Z., GST function in drug and stress response. Drug Resist. Updat., 2, 143-147 (1999) 
    133. 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. V. et al., Nomenclature for N-acetyltransferases. Pharmacogenetics., 5, 1-17 (1995) 
    134. 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) 
    135. Schoonjans, K., Staels, B., and Auwerx, J., Role of the peroxi- some proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J. Lipid Res., 37, 907-925 (1996) 
    136. 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) 
    137. Gonzalez, F. J. and Fernandez-Salguero, P., The aryl hydro- carbon receptor: studies using the AHR-null mice. Drug Metab. Dispos., 26, 1194-1198 (1998) 
    138. Honkakoski, P., Zelko, I., Sueyoshi, T., and Negishi, M., The nuclear orphan receptor CAR-retinoid X receptor heterodimeractivates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol. Cell Biol., 18, 5652-5658 (1998b) 
    139. 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) 
    140. 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 enzymes in vivo by the cancer chemoprotective agent, 3H-1, 2-dimethiole-3-thione. Mol. Med., 7, 135-145 (2001) 
    141. Moscow, J. A. and Dixon, K. H., Glutathione-related enzymes, glutathione and multidrug resistance. Cytotechnology, 12, 155-170 (1993) 
    142. 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) 
    143. 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) 
    144. 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 (Slc21a5)-mediated transport. Pharm. Res., 19, 147-153 (2002) 
    145. Tirona, R. G. and Kim, R. B., Pharmacogenomics of organic anion-transporting polypeptides (OATP). Adv. Drug Deliv. Rev., 54, 1343-1352 (2002) 
    146. 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) 
    147. 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) 
    148. 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) 
    149. Lewis, D. F., P450 structures and oxidative metabolism of xenobiotics. Pharmacogenomics, 4, 387-395 (2003) 
    150. 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) 
    151. 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) 
    152. 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-associatedprotein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J. Biol. Chem., 277, 2908-2915 (2002) 
    153. Weinshilboum, R. M., Otterness, D. M., Aksoy, I. A., Wood, T. C.,Her, C., and Raftogianis, R. B., Sulfation and sulfotransferases1: Sulfotransferase molecular biology: cDNAs and genes. FASEB J., 11, 3-14 (1997) 
    154. 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) 
    155. 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. BioI. Chem., 272, 3137-3140 (1997) 
    156. 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) 
    157. Willson, T. M. and Kliewer, S. A., PXR, CAR and drug metabolism. Nat. Rev. Drug Discov., 1, 259-266 (2002) 
    158. 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 detoxificationof cholestatic bile acids. Proc. Natl. Acad. Sci. U.S.A., 98, 3375-3380 (2001) 
    159. Xiong, H., Yoshinari, K., Brouwer, K. L., and Negishi, M., Role of constitutive androstane receptor in the in vivo induction of Mrp3 and CYP2B1/2 by phenobarbital. Drug Metab. Dispos., 30, 918-923 (2002) 
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    1. Lee, Dong-Wook ; Lim, Heung-Bin 2006. "The Effect of Korean Red Ginseng Water-extract on Aging-related Changes in the Xenobiotic Metabolizing Enzyme System in the Liver of Rats" 韓國藥用作物學會誌 = Korean journal of medicinal crop science, 14(6): 329~335     
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