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2000 | 47 | 4 | 1093-1105
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Phenobarbital-induced expression of cytochrome P450 genes.

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In contrast to the well-known Ah receptor-mediated regulation of the CYP1A1 gene by polycyclic aromatic hydrocarbons, the molecular mechanism by which phenobarbital (PB) and PB-like inducers affect transcription of CYP genes remains unknown; no receptor for these chemicals has been found to date. However, in the last 5 years PB-responsive sequences have been identified in the 5' flanking regions of several P450 genes. The phenobarbital-responsive enhancer unit (PBRU) of CYP2B gene family members contain two potential nuclear receptor binding sites (NR1 and NR2) that flank a nuclear factor 1 (NF-1) binding motif. The nuclear factors that regulate PBRU activity have not yet been characterized. It seems that PB may activate multiple nuclear orphan receptors to induce various CYP genes. CYP2B and CYP3A genes appear to be targets for the orphan receptors CAR and PXR, respectively. It is also possible that the pleiotropic effects of PB can, in part, be explained by the ability of the CAR-RXR heterodimer to bind to a variety of nuclear receptor binding motifs. The induction of cytochromes P450 may result in interactions between xenobiotics and in the interference of xenobiotic metabolism and endogenous signalling pathways.
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  • II Department of Histology and Embryology, Silesian Medical Academy, Katowice, Poland
  • 1. Nelson, D., Koymans, L., Kamataki, T., Stegeman, J., Feyereisen, R., Waxman, D., Waterman, M., Gotoh, O., Coon, M., Estabrook, R., Gunsalus, I. & Nebert, D. (1996) P450 superfamily: Update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6, 1-42.
  • 2. Denison, M. & Whitlock, J. (1995) Xenobiotic- inducible transcription of cytochrome P450 genes. J. Biol. Chem. 270, 18175-18178.
  • 3. Guengerich, F. (1995) Human cytochrome P450 enzymes; in Cytochrome P450: Structure, Mechanisms and Biochemistry (Ortiz de Montellano, P., ed.) pp. 473-575, Plenum Press, New York.
  • 4. Bartsch, H., Castegnaro, M., Rojas, M., Camus, A.-M., Alexandrov, K. & Lang, M. (1992) Expression of pulmonary cytochrome P4501A1 and carcinogen DNA adduct formation in high risk subjects for tobacco-related lung cancer. Toxicol. Lett. 64/65, 477-483.
  • 5. Kato, S., Bowman, E., Harrington, A., Blomeke, B. & Shields, P. (1995) Human lung carcinogen-DNA adduct levels mediated by genetic polymorphisms in vivo. J. Natl. Cancer Inst. 87, 902-907.
  • 6. Aust, S., Chignell, C., Bray, T., Kalyanaraman, B. & Mason, R. (1993) Contemporary issues in toxicology. Free radicals in toxicology. Toxicol. Appl. Pharmacol. 120, 168-178.
  • 7. Dizdaroglu, M. (1998) Mechanisms of free radical damage to DNA; in DNA and Free Radicals: Techniques, Mechanisms and Applications (Aruoma, O. & Halliwell, B., eds.) pp. 3-26, OICA Int. Saint Lucia, London.
  • 8. Villard, P.-H., Seree, E., Re, J.-L., De Meo, M., Barra, Y., Attolini, L., Dumenil, G., Catalin, J., Durand, A. & Lacarelle, B. (1998) Effects of tobacco smoke on the gene expression of the Cyp1a, Cyp2b, Cyp2e, and Cyp3a subfamilies in mouse liver and lung: Relation to single strand breaks of DNA. Toxicol. Appl. Pharmacol. 148, 195-204.
  • 9. Czekaj, P. & Nowaczyk-Dura, G. (1996) Effects of different synthetic steroid combinations on the activity of mixed function oxidase system and on the morphology of rat liver. Exp. Toxic. Pathol. 48 (Suppl. II) 82-87.
  • 10. Czekaj, P. & Nowaczyk-Dura, G. (1999) Inhibiting effect of ethinylestradiol/levonorgestrel combination on microsomal enzymatic activities in rat liver and kidney. Eur. J. Drug Metab. Pharmacokinet. 24, 243-248.
  • 11. Czekaj, P., Wiaderkiewicz, A. & Wiaderkiewicz, R. (2000) Immunodetection of cytochrome P450 isoforms in fetus and adult female Wistar rats. Acta Pol. Toxicol. 1, 17-31.
  • 12. Chien, J., Thummel, K. & Slattery, J. (1997) Pharmacokinetic consequences of induction of CYP2E1 by ligand stabilization. Drug Metab. Dispos. 25, 1165-1175.
  • 13. Whitlock, J. & Denison, M. (1995) Human cytochrome P450 enzymes; in Cytochrome P450: Structure, Mechanisms and Biochemistry (Ortiz de Montellano, P., ed.) pp. 367-390, Plenum Press, New York.
  • 14. Brockmöller, J., Cascorbi, I., Kerb, R., Sachse, C. & Roots, I. (1998) Polymorphisms in xenobiotic conjugation and disease predisposition. Toxicol. Lett. 102-103, 173-183.
  • 15. Waxman, D. & Azaroff, L. (1992) Phenobarbital induction of cytochrome P-450 gene expression. Biochem. J. 281, 577-592.
  • 16. Frueh, F., Zanger, U. & Meyer, U. (1997) Extent and character of phenobarbital-mediated changes in gene expression in the liver. Mol. Pharmacol. 51, 363-369.
  • 17. Smith, G., Henderson, C., Parker, M., White, R., Bars, R. & Wolf, R. (1993) 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene, an extremely potent modulator of mouse hepatic cytochrome P-450 gene expression. Biochem. J. 289, 807- 813.
  • 18. Honkakoski, P., Moore, R., Washburn, K. & Negishi, M. (1998) Activation by diverse xenochemicals of the 51-base pair phenobarbital-responsive enhancer module in the Cyp2b10 gene. Mol. Pharmacol. 53, 597-601.
  • 19. Chang, T., Yu, L., Maurel, P. & Waxman, D. (1997) Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: Response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. Cancer Res. 57, 1946-1954.
  • 20. Anderson, G. (1998) A mechanistic approach to antiepileptic drug interactions. Ann. Pharmacother. 32, 554-563.
  • 21. Dogra, S., Whitelaw, M. & May, B. (1997) Transcriptional activation of cytochrome P450 genes by different classes of chemical inducers. Clin. Exp. Pharmacol. Physiol. 25, 1-9.
  • 22. Shaw, P., Adesnik, M., Weiss, M. & Corcos, L. (1993) The phenobarbital-induced transcriptional activation of cytochrome P-450 genes is blocked by the glucocorticoid-progesterone antagonist RU486. Mol. Pharmacol. 44, 775- 783.
  • 23. Pinkus, R., Bergelson, S. & Daniel, V. (1993) Phenobarbital induction of AP-1 binding activity mediates activation of glutathione S-transferase and quinone reductase gene expression. Biochem. J. 290, 637-640.
  • 24. Fulco, A. (1991) P450BM-3 and other inducible bacterial P450 cytochromes: Biochemistry and regulation. Annu. Rev. Pharmacol. Toxicol. 31, 177-203.
  • 25. Shaw, G. & Fulco, A. (1992) Barbiturate-mediated regulation of expression of the cytochrome P-450BM-3 gene of Bacillus megaterium by Bm3R1 protein. J. Biol. Chem. 267, 5515-5526.
  • 26. Shaw, G. & Fulco, A. (1993) Inhibition by barbiturates of the binding of Bm3R1 repressor to its operator site on the barbiturate-inducible cytochrome P450BM-3 gene of Bacillus megaterium. J. Biol. Chem. 268, 2997-3004.
  • 27. Kemper, B. (1998) Regulation of cytochrome P450 gene transcription by phenobarbital. Prog. Nucleic Acid Res. Mol Biol 61, 23-64.
  • 28. He, J. & Fulco, A. (1991) A barbiturate-regulated protein binding to a common sequence in the cytochrome P450 genes of rodents and bacteria. J. Biol. Chem. 266, 7864-7869.
  • 29. Rangarajan, P. & Padmanaban, G. (1989) Regulation of cytochrome P-450b/e gene expression by a heme- and phenobarbitone-modulated transcription factor. Proc. Natl. Acad. Sci. U.S.A. 86, 3963-3967.
  • 30. Ramsden, R., Sommer, K.M. & Omiecinski, C.J. (1993) Phenobarbital induction and tissue-specific expression of the rat CYP2B2 gene in transgenic mice. J. Biol. Chem. 268, 21722-21726.
  • 31. Park, Y., Li, H. & Kemper, B. (1996) Phenobarbital induction mediated by a distal CYP2B2 sequence in rat liver transiently transfected in situ. J. Biol. Chem. 271, 23725-23728.
  • 32. Shaw, G., Sung, C., Liu, C. & Lin, C. (1998) Evidence against the Bm1P1 protein as a positive transcription factor for barbiturate-mediated induction of cytochrome P450BM1 in Bacillus megaterium. J. Biol. Chem. 273, 7996-8002.
  • 33. Dogra, S. & May, B. (1997) Liver enriched transcription factors, HNF-1, HNF-3 and C/EBP are major contributors to the strong activity of the chicken CYP2H1 promoter in chick embryo hepatocytes. DNA Cell Biol. 16, 1407-1418.
  • 34. Prabhu, L., Upadhya, P., Ram, N., Nirodi, C., Sultana, S., Vatsala, P., Mani, S., Rangarajan, P., Surolia, A. & Padmanaban, G. (1995) A model for the transcriptional regulation of the CYP2B1/B2 gene in rat liver. Proc. Natl. Acad. Sci. U.S.A. 92, 9628-9632.
  • 35. Meyer, U. & Hoffmann, K. (1999) Phenobarbital-mediated changes in gene expression in the liver. Drug Metab. Rev. 31, 365-373.
  • 36. Park, Y. & Kemper, B. (1996) The CYP2B1 proximal promoter contains a functional C/EBP regulatory element. DNA Cell Biol. 15, 693-701.
  • 37. Trottier, E., Belzil, A., Stoltz, C. & Anderson, A. (1995) Localization of a phenobarbital-responsive element (PBRE) in the 5'-flanking region of the rat CYP2B2 gene. Gene 158, 263-268.
  • 38. Stoltz, C., Vachon, M.-H., Trottier, E., Dubois, S., Paquet, Y. & Anderson, A. (1998) The CYP2B2 phenobarbital response unit contains an accessory factor element and a putative glucocorticoid response element essential for conferring maximal phenobarbital responsiveness. J. Biol. Chem. 273, 8528-8536.
  • 39. Honkakoski, P., Zelko, I., Sueyoshi, T. & 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.
  • 40. Sueyoshi, T., Kawamoto, T., Zelko, I., Honkakoski, P. & Negishi, M. (1999) The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene. J. Biol. Chem. 274, 6043-6046.
  • 41. Stoltz, C. & Anderson, A. (1999) Positive regulation of the rat CYP2B2 phenobarbital response unit by the nuclear receptor hexamer half-site nuclear factor 1 complex. Biochem. Pharmacol. 57, 1073-1076.
  • 42. Honkakoski, P. & Negishi, M. (1997) Characterization of a phenobarbital-responsive enhancer module in mouse P450 Cyp2b10 gene. J. Biol. Chem. 272, 14943-14949.
  • 43. Czekaj, P. (1996) Interakcje receptorow hormonu tarczycy i pochodnych witamin A i D z DNA. Post. Biol. Kom. 23, 261-278 (in Polish).
  • 44. Hahn, C., Hansen, A. & May, B. (1991) Transcriptional regulation of the chicken CYP2H1 gene. J. Biol. Chem. 266, 17031- 17039.
  • 45. Dogra, S., Davidson, B. & May, B. (1999) Analysis of a phenobarbital-responsive enhancer sequence located in the 5' flanking region of the chicken CYP2H1 gene: Identification and characterization of functional protein-binding sites. Mol. Pharmacol. 55, 14-22.
  • 46. Enmrak, E. & Gustafsson, J. (1996) Orphan nuclear receptors the first eight years. Mol. Endocrinol. 10, 1293-1307.
  • 47. Baes, M., Gulick, T., Choi, H., Martinoli, M., Simha, D. & Moore, D. (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, 1544-1552.
  • 48. Forman, B., Tzameli, I., Choi, H.-S., Chen, J., Simha, D., Seol, W., Evans, R. & Moore, D. (1998) Androstane metabolites bind to and deactivate the nuclear receptor CAR-β. Nature 395, 612-615.
  • 49. Zhou, Z., Wong, C., Sar, M. & Wilson, E. (1994) The androgen receptor: An overview. Rec. Prog. Horm. Res. 49, 249-274.
  • 50. Kliewer, S., Lehmann, J. & Willson, T. (1999) Orphan nuclear receptors: Shifting endocrinology into reverse. Science 284, 757-760.
  • 51. Lehmann, J., McKee, D., Watson, M., Willson, T., Moore, J. & Kliewer, S. (1998) The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J. Clin. Invest. 102, 1016-102.
  • 52. Hashimoto, H., Toide, K., Kitamura, R., Fujita, M., Tagawa, S., Itoh, S. & Kamataki, T. (1993) Gene structure of CYP3A4, an adult- specific form of cytochrome P450 in human livers, and its transcriptional control. Eur. J. Biochem. 218, 585-595.
  • 53. Kliewer, S., Moore, J., Wade, L., Staudinger, J., Watson, M., Jones, S., McKee, D., Oliver, B., Wilson, T., Zetterström, R., Perlmann, T. & Lehmann, J. (1998) An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92, 73-82.
  • 54. Beato, M. (1989) Gene regulation by steroid hormones. Cell 56, 335-344.
  • 55. Nebert, D. (1994) Drug-metabolizing enzymes in ligand-modulated transcription. Biochem. Pharmacol. I 47, 25-27.
  • 56. Kornberg, R. & Lorch, Y. (1992) Chromatin structure and transcription. Annu. Rev. Cell Biol. 8, 563-587.
  • 57. Sidhu, J. & Omiecinski, C. (1995) cAMP-associated inhibition of phenobarbital-inducible cytochrome P450 gene expression in primary hepatocyte cultures. J. Biol. Chem. 270, 12762-12773.
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