Induction of Cytochrome P450 Enzymes That Metabolize Xenobiotics

  • James P. WhitlockJr.
  • Michael S. Denison


One of the many interesting aspects of the cytochrome P450 enzymes is that some are inducible; that is, following exposure of the cell to an inducing chemical, enzyme activity increases, in some cases by orders of magnitude. The induction phenomena were first recognized because they produced alterations in pharmacological responses to drugs or other xenobiotics. For example, animals chronically exposed to barbiturates become “tolerant” to the hypnotic effects of these drugs, because they induce the cytochrome P450 enzymes responsible for their own metabolism.1 Similarly, the induction of cytochrome P450 enzymes reduced the incidence of neoplasia in animals exposed to chemical carcinogens2 Such examples illustrate two interesting points. First, inducers are often substrates for the induced enzymes; thus, enzyme activity increases only as needed. Second, enzyme induction usually enhances detoxification, particularly when low to moderate concentrations of substrate are present; thus, under most conditions, induction is a protective mechanism, whereby the cell can detoxify lipophilic compounds that might otherwise accumulate. Both characteristics are likely to facilitate the survival of the cell in a potentially toxic chemical environment.


Cytochrome P450 Enzyme Induction Mechanism Cytochrome P450 Gene Aryl Hydrocarbon Hydroxylase Aryl Hydrocarbon Hydroxylase Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Remmer, H., and Merker, H. J., 1963, Drug-induced changes in the liver endoplasmic reticulum: Association with drug-metabolizing enzymes, Science 142: 1657–1658.PubMedCrossRefGoogle Scholar
  2. 2.
    Conney, A. H., Miller, E. C., and Miller, J. A., 1956, The metabolism of methylated aminoazo dyes. 5. Evidence for induction of enzyme synthesis in the rat by 3-methylcholanthrene, Cancer Res. 16: 450–459.PubMedGoogle Scholar
  3. 3.
    Park, B. K., and Breckenridge, A. M., 1981, Clinical implications of enzyme induction and enzyme inhibition, Clin. Pharmacokinet. 6: 1–24.PubMedCrossRefGoogle Scholar
  4. 4.
    Thomas, S. H. L., 1993, Paracetamol (acetaminophen) poisoning, Pharmacol. Ther. 60: 91–120.PubMedCrossRefGoogle Scholar
  5. 5.
    Conney, A. H., 1967, Pharmacological implications of microsomal enzyme induction, Pharmacol. Rev. 19: 317–366.PubMedGoogle Scholar
  6. 6.
    Whitlock, J. P., Jr., 1986, The regulation of cytochrome P450 gene expression, Annu. Rev. Pharmacol. Toxicol. 26: 333–369.PubMedCrossRefGoogle Scholar
  7. 7.
    Nebert, D. W., and Gonzalez, F. J., 1987, P450 genes: Structure, evolution, and regulation, Annu. Rev. Biochem. 56: 945–993.PubMedCrossRefGoogle Scholar
  8. 8.
    Okey, A. B., 1990, Enzyme induction in the cytochrome P450 system, Pharmacol. Ther. 45: 241–298.PubMedCrossRefGoogle Scholar
  9. 9.
    Conney, A. H., 1982, Induction of microsomal enzymes by foreign compounds and carcinogenesis by polycycic aromatic hydrocarbons, Cancer Res. 42: 4875–4917.PubMedGoogle Scholar
  10. 10.
    Gelboin, H. V., 1980, Benzo(a)pyrene metabolism, activation, and carcinogenesis: Role and regulation of mixed-function oxidases and related enzymes, Physiol. Rev. 60: 1107–1166.PubMedGoogle Scholar
  11. 11.
    Negishi, M., Swan, D. C., Enquist, L. W., and Nebert, D. W., 1981, Isolation and characterization of a cloned DNA sequence associated with the murine Ah locus and 3-methylcholanthrene-induced form of cytochrome P450, Proc. Natl. Acad. Sci. USA 78: 800–804.PubMedCrossRefGoogle Scholar
  12. 12.
    Gonzalez, E J., Tukey, R. H., and Nebert, D. W., 1984, Structural gene products of the Ah locus. Transcriptional regulation of cytochrome Pi-450 and P3–450 mRNA levels by 3-methylcholanthrene, Mol. Pharmacol. 26: 117–121.PubMedGoogle Scholar
  13. 13.
    Israel, D. I., and Whitlock, J. P., Jr., 1984, Regulation of cytochrome P1–450 gene transcription by 2,3,7,8-tetrachlorodibenzo-p-dioxin in wild type and variant mouse hepatoma cells, J. Biol. Chem. 259: 5400–5402.PubMedGoogle Scholar
  14. 14.
    Poland, A. P., Glover, E., and Kende, A. S., 1976, Stereospecific, high affinity binding of 2,3,7,8tetrachlorodibenzo-p-dioxin by hepatic cytosol: Evidence that the binding species is the receptor for the induction of aryl hydrocarbon hydroxylase, J. Biol. Chem. 251: 4936–4946.PubMedGoogle Scholar
  15. 15.
    Poland, A., and Knutson, J. C., 1982, 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related aromatic hydrocarbons: Examination of the mechanism of toxicity, Annu. Rev. Pharmacol. Toxicol. 22: 517–554.Google Scholar
  16. 16.
    Hankinson, 0., 1983, Dominant and recessive aryl hydrocarbon hydroxylase-deficient mutants of the mouse hepatoma line, Hepa 1, and assignment of the recessive mutants to three complementation groups, Somatic Cell Genet. 9: 497–514.CrossRefGoogle Scholar
  17. 17.
    Miller, A. G., Israel, D. I., and Whitlock, J. P., Jr., 1983, Biochemical and genetic analysis of variant mouse hepatoma cells defective in the induction of benzo(a)pyrene-metabolizing enzyme activity, J. Biol. Chem. 258: 3523–3527.PubMedGoogle Scholar
  18. 18.
    Whitlock, J. P., Jr., 1993, Mechanistic aspects of dioxin action, Chem. Res. Toxicol. 6: 754–763.PubMedCrossRefGoogle Scholar
  19. 19.
    Poland, A., Glover, E., Ebetino, E H., and Kende, A. S., 1986, Photoaffinity labeling of the Ah receptor, J. Biol. Chem. 261: 6352–6365.PubMedGoogle Scholar
  20. 20.
    Bradfield, C. A., Glover, E., and Poland, A., 1991, Purification and N-terminal amino acid sequence of the Ah receptor from the C57BL/6J mouse, Mol. Pharmacol. 39: 13–19.PubMedGoogle Scholar
  21. 21.
    Poland, A., Glover, E., and Bradfield, C. A., 1991, Characterization of polyclonal antibodies to the Ah receptor prepared by immunization with a synthetic peptide hapten, Mol. Pharmacol. 39: 20–26.PubMedGoogle Scholar
  22. 22.
    Burbach, K. M., Poland, A., and Bradfield, C. A., 1992, Cloning of the Ah-receptor cDNA reveals a novel ligand-activated transcription factor, Proc. Natl. Acad. Sci. USA 89: 8185–8189.PubMedCrossRefGoogle Scholar
  23. 23.
    Erna, M., Sugawa, K., Wanatabe, N., Chujoh, Y., Matsushita, N., Gotoh, O., Funae, Y., and FujiiKuriyama, Y., 1992, cDNA cloning and structure of mouse putative Ah receptor, Biochem. Biophys. Res. Commun. 184: 246–253.Google Scholar
  24. 24.
    Pollenz, R. C., Sattler, C. A., and Poland, A., 1994, The arylhydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator protein show distinct subcellular localizations in Hepa lcic7 cells by immunofluorescence microscopy, Mol. Pharmacol. 45: 428–438.PubMedGoogle Scholar
  25. 25.
    Hoffman, E. C., Reyes, H., Chu, F-F., Sander, E, Conley, L. H., Brooks, B. A., and Hankinson, O., 1991, Cloning of a factor required for activity of the Ah dioxin receptor, Science 252: 954–958.PubMedCrossRefGoogle Scholar
  26. 26.
    Reyes, H., Reiz-Porszasz, S., and Hankinson, O., 1992, Identification of the Ah receptor nuclear translocator protein (Amt) as a component of the DNA binding form of the Ah receptor, Science 256: 1193–1195.PubMedCrossRefGoogle Scholar
  27. 27.
    Whitelaw, M., Pongratz, I., Wilhelmsson, A., Gustafsson, J. A., and Poellinger, L., 1993, Ligand-dependent recruitment of the Amt coregulator determines DNA recognition by the dioxin receptor, Mol. Cell. Biol. 13: 2504–2514.PubMedGoogle Scholar
  28. 28.
    Matsushita, N., Sogawa, K., Erna, M., Yoshido, A., and Fujii-Kuriyama, Y., 1993, A factor binding to the xenobiotic responsive element (XRE) of P-4501A 1 gene consists of at least two helix—loop—helix proteins, Ah receptor and Amt, J. Biol. Chem. 268: 21002–21006.PubMedGoogle Scholar
  29. 29.
    Probst, M. R., Reisz-Porsasz, S., Agbunag, R. V., Ong, M. S., and Hankinson, 0., 1993, Role of the aryl hydrocarbon (Ah) receptor nuclear translocator protein (ARNT) in aryl hydrocarbon (dioxin) receptor action, Mol. Pharmacol. 44: 511–518.PubMedGoogle Scholar
  30. 30.
    Perdew, G. H., 1988, Association of the Ah receptor with the 90 kDa heat shock protein, J. Biol. Chem. 263: 13802–13805.PubMedGoogle Scholar
  31. 31.
    Pongratz, I., Mason, G. G. F., and Poellinger, L., 1992, Dual roles of the 90 kDa heat shock protein hsp90 in modulating functional activities of the dioxin receptor, J. Biol. Chem. 267: 13728–13734.PubMedGoogle Scholar
  32. 32.
    Okino, S. T., Pendurthi, U. R., and Tukey, R. H., 1992, Phorbol esters inhibit the dioxin receptor-mediated transcriptional activation of the mouse Cyplal and Cypla2 genes by 2,3,7,8 tetrachlorodibenzo-p-dioxin, J. Biol. Chem. 267: 6991–6998.PubMedGoogle Scholar
  33. 33.
    Carrier, F., Owens, R. A., Nebert, D. W., and Puga, A., 1992, Dioxin-dependent activation of murine CyplA1 gene transcription requires protein kinase C-dependent phosphorylation, Mol. Cell. Biol. 12: 1856–1863.PubMedGoogle Scholar
  34. 34.
    Berghard, A., Gradin, K., Pongratz, I., Whitelaw, M., and Poellinger, L., 1993, Cross-coupling of signal transduction pathways: The dioxin receptor mediates induction of cytochrome P450A 1 expression via a protein kinase C mechanism, Mol. Cell. Biol. 13: 677–689.PubMedGoogle Scholar
  35. 35.
    Schafer, M. W., Madhukar, B. V., Swanson, H. I., Tullis, K., and Denison, M. S., 1993, Protein kinase C is not involved in Ah receptor transformation and DNA binding, Arch. Biochem. Biophys. 307: 267–271.PubMedCrossRefGoogle Scholar
  36. 36.
    Hunter, T., and Karin, M., 1992, The regulation of transcription by phosphorylation, Cell 70: 375–387.PubMedCrossRefGoogle Scholar
  37. 37.
    Lusska, A., Wu, L., and Whitlock, J. P., Jr., 1992, Superinduction of CYPIA1 transcription by cycloheximide, J. Biol. Chem. 267: 15146–15151.PubMedGoogle Scholar
  38. 38.
    Watson, A. J., Weir-Brown, K. I., Bannister, R. M., Chu, F. F., Reisz-Porszasz, S., Fujii-Kuriyama, Y., Sogawa, K., and Hankinson, 0., 1992, Mechanism of action of a repressor of dioxin-dependent induction of Cyp1A1 gene transcription, Mol. Cell. Biol. 12: 2115–2123.PubMedGoogle Scholar
  39. 39.
    Gasiewicz, T. A., Elferink, C. J., and Henry, E. C., 1991, Characterization of multiple forms of the Ah receptor: Recognition of a dioxin-responsive enhancer involves heteromer formation, Biochemistry 30: 2909–2916.PubMedCrossRefGoogle Scholar
  40. 40.
    Perdew, G. H., 1992, Chemical cross-linking of the cytosolic and nuclear forms of the Ah receptor in hepatoma cell line lcic7, Biochem. Biophys. Res. Commun. 182: 55–62.PubMedCrossRefGoogle Scholar
  41. 41.
    Elferink, C. J., Gasiewicz, T. A., and Whitlock, J. P., Jr., 1990, Protein—DNA interactions at a dioxin-responsive enhancer: Evidence that the transformed Ah receptor is heteromeric, J. Biol. Chem. 265: 20708–20712.PubMedGoogle Scholar
  42. 42.
    Swanson, H. I., Tullis, K., and Denison, M. S., 1993, Binding of transformed Ah receptor complex to a dioxin responsive transcriptional enhancer: Evidence for two distinct heteromeric DNA-binding forms, Biochemistry 32: 12841–12849.PubMedCrossRefGoogle Scholar
  43. 43.
    Jones, P. B. C., Durrin, L. K., Galeazzi, D. R., and Whitlock, J. P., Jr., 1986, Control of cytochrome PI-450 gene expression: Analysis of a dioxin-responsive enhancer system, Proc. Natl. Acad. Sci. USA 83: 2802–2806.PubMedCrossRefGoogle Scholar
  44. 44.
    Jones, K. W., and Whitlock, J. P., Jr., 1990, Functional analysis of the transcriptional promoter for the CYP1A1 gene, Mol. Cell. Biol. 10: 5098–5105.PubMedGoogle Scholar
  45. 45.
    Denison, M. S., Fisher, J. M., and Whitlock, J. P., Jr., 1989, Protein—DNA interactions at recognition sites for the dioxin—Ah receptor complex, J. Biol. Chem. 264: 16478–16482.PubMedGoogle Scholar
  46. 46.
    Hapgood, J., Cuthill, S., Denis, M., Poellinger, L., and Gustafsson, J.-A.,1989, Specific protein—DNA interactions at a xenobiotic-responsive element: Copurification of dioxin receptor and DNA-binding activity, Proc. Natl. Acad. Sci. USA 86: 60–64.Google Scholar
  47. 47.
    Lusska, A., Shen, E., and Whitlock, J. P., Jr., 1993, Protein—DNA interactions at a dioxin-responsive enhancer: Analysis of six bona fide DNA-binding sites for the liganded Ah receptor, J. Biol. Chem. 268: 6575–6580.PubMedGoogle Scholar
  48. 48.
    Yao, E. F., and Denison, M. S., 1992, DNA sequence determinants for binding of transformed Ah receptor to a dioxin-responsive enhancer, Biochemistry 31: 5060–5067.PubMedCrossRefGoogle Scholar
  49. 49.
    Shen, E. S., and Whitlock, J. P., Jr., 1992, Protein—DNA interactions at a dioxin-responsive enhancer: Mutational analysis of the DNA binding site for the liganded Ah receptor, J. Biol. Chem. 267: 6815–6819.PubMedGoogle Scholar
  50. 50.
    Shen, E. S., and Whitlock, J. P., Jr., 1989, The potential role of DNA methylation in the response to 2,3,7,8-tetrachlorodibenzo-p-dioxin, J. Biol. Chem. 264: 17754–17758.PubMedGoogle Scholar
  51. 51.
    Elferink, C. J., and Whitlock, J. P., Jr., 1990, 2,3,7,8-Tetrachlorodibenzo-p-dioxin inducible, Ah receptor-mediated bending of enhancer DNA, J. Biol. Chem. 265: 5718–5721.Google Scholar
  52. 52.
    Wu, L., and Whitlock, J. P., Jr., 1993, Mechanism of dioxin action: Receptor—enhancer interactions in intact cells, Nucleic Acids Res. 21: 119–125.PubMedCrossRefGoogle Scholar
  53. 53.
    Durrin, L. K., and Whitlock, J. P., Jr., 1989, 2,3,7,8-Tetrachlorodibenzo-p-dioxin: Ah receptor-mediated change in cytochrome P1–450 chromatin structure occurs independent of transcription, Mol. Cell. Biol. 9: 5733–5737.Google Scholar
  54. 54.
    Wu, L., and Whitlock, J. P., Jr., 1992, Mechanism of dioxin action: Ah receptor-mediated increase in promoter accessibility in vivo, Proc. Natl. Acad. Sci. USA 89: 4811–4815.PubMedCrossRefGoogle Scholar
  55. 55.
    Morgan, J. E., and Whitlock, J. P., Jr., 1992, Transcription-dependent and transcription-independent nucleosome disruption induced by dioxin, Proc. Natl. Acad. Sci. USA 89: 11622–11626.PubMedCrossRefGoogle Scholar
  56. 56.
    Kornberg, R. D., and Lorch, Y., 1992, Chromatin structure and transcription, Annu. Rev. Cell Biol. 8: 563–587.PubMedCrossRefGoogle Scholar
  57. 57.
    Hardwick, J., Gonzalez, F. J., and Kasper, C. B., 1983, Transcriptional regulation of rat liver epoxide hydrolase, NADPH-cytochrome P-450 oxidoreductase and cytochrome P-450b genes by phenobarbital, J. Biol. Chem. 258: 8081–8085.PubMedGoogle Scholar
  58. 58.
    MacKenzie, P. I., 1986, Rat liver UDP-glucuronosyl transferase: Sequence and expression of a cDNA encoding a phenobarbital-inducible form, J. Biol. Chem. 261: 6119–6125.PubMedGoogle Scholar
  59. 59.
    Waxman, D. J., and Azaroff, L., 1992, Phenobarbital induction of cytochrome P-450 gene expression, Biochem. J. 281: 577–592.PubMedGoogle Scholar
  60. 60.
    Gonzalez, E J., 1989, The molecular biology of cytochrome P-450s, Pharmacol. Rev. 40: 243–288.Google Scholar
  61. 61.
    Wilson, N. M., Christou, M., Turner, C. R., Wrighton, S. A., and Jefcoate, C. R., 1984, Binding and metabolism of benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene by seven purified forms of P-450, Carcinogenesis 5: 1475–1483.PubMedCrossRefGoogle Scholar
  62. 62.
    Christou, M., Wilson, N. M., and Jefcoate, C. R., 1987, Expression and function of three P-450 isozymes in rat hepatic tissues, Arch. Biochem. Biophys. 258: 519–534.PubMedCrossRefGoogle Scholar
  63. 63.
    Wolf, C. R., Miles, J. S., Seiman, S., Burke, M. D., Rosendowski, B. N., Kelly, K., and Smith, W. E., 1988, Evidence that catalytic differences of two structurally homologous forms of cytochrome P450 are related to their heure environment, Biochemistry 27: 1597–1603.PubMedCrossRefGoogle Scholar
  64. 64.
    Suwa, Y., Mizukami, Y., Sogawa, K., and Fuji-Kuriyama, Y., 1985, Gene structure of a major form of phenobarbital-inducible P-450 in rat liver, J. Biol. Chem. 260: 7980–7981.PubMedGoogle Scholar
  65. 65.
    Yamazoe, Y., Shimada, M., Murayama, N., and Kato, R., 1987, Suppression of levels of phenobarbital-inducible rat liver cytochrome P-450 by pituitary hormone, J. Biol. Chem. 262: 7423–7428.PubMedGoogle Scholar
  66. 66.
    Atchinson, M., and Adesnick, M., 1983, A cytochrome P450 multigene family: Characterization of a gene activated by phenobarbital administration, J. Biol. Chem. 258: 11285–11295.Google Scholar
  67. 67.
    Omiecinski, C. J., Walz, F. J., Jr., and Vlasuk, G. P., 1985, Phenobarbital induction of rat liver cytochromes P-450b and P-450c: Quantitation of specific RNAs by hybridization to synthetic oligodeoxyribonucleotide probes, J. Biol. Chem. 260: 3247–3250.PubMedGoogle Scholar
  68. 68.
    Kocarek, T. A., Schuetz, E. G., and Guzefian, P. S., 1990, Differentiated induction of cytochrome P450b/e and P450p mRNAs by dose of phenobarbital in primary cultures of adult rat hepatocytes, Mol. Pharmacol. 38: 440–444.PubMedGoogle Scholar
  69. 69.
    Mattschloss, L. A., Holbs, A. A., Steggles, A. W., May, B. K., and Elliott, W. H., 1986, Isolation and characterization of genomic clones for two chicken phenobarbital-inducible cytochrome P-450 genes, J. Biol. Chem. 261: 9438–9443.Google Scholar
  70. 70.
    Hansen, A. J., and May, B. K., 1989, Sequence of a chicken phenobarbital-inducible cytochrome P-450 cDNA: Regulation of two P-450 tnRNAs transcribed from different genes, DNA 8: 179–191.PubMedCrossRefGoogle Scholar
  71. 71.
    Hamilton, J. W., Bement, W. J., Sinclair, P. R., Sinclair, J. F, and Wetterhahn, K. E., 1988, Expression of 5-aminolevulinate synthase and cytochrome P-450 mRNAs in chicken embryo hepatocytes in vivo and in culture, Biochem. J. 255: 267–275.PubMedGoogle Scholar
  72. 72.
    Hamilton, J. W., and Wetterhahn, K. E., 1989, Differential effects of chromium (VI) on constitutive and inducible gene expression in chick embryo liver in vivo and correlation with chromium (VI)-induced DNA damage, Mol. Carcinogen. 2: 274–286.CrossRefGoogle Scholar
  73. 73.
    Fulco, A. J., 1991, P450BM-3 and other inducible bacterial P-450 cytochromes: Biochemistry and regulation, Annu. Rev. Pharmacol. Toxicol. 31: 177–203.PubMedCrossRefGoogle Scholar
  74. 74.
    Bhat, G. J., Rangarajan, P. N., and Padmanaban, G., 1987, Differential effects of cycloheximide on rat liver cytochrome P-450 gene transcription in the whole animal and hepatoma cell culture, Biochem. Biophys. Res. Commun. 148: 1118–1123.PubMedCrossRefGoogle Scholar
  75. 75.
    Burger, H., Schuetz, E. G., Schuetz, J. D., and Guzefian, P. S., 1990, Divergent effects of cycloheximide on the induction of class II and class III cytochrome P450 mRNAs in cultures of adult rat hepatocytes, Arch. Biochem. Biophys. 281: 204–211.PubMedCrossRefGoogle Scholar
  76. 76.
    Hamilton, J. W., Bernent, W. J., Sinclair, P. R., Sinclair, J. F., Alcedo, J. A., and Wetterhahn, K. E., 1992, Inhibition of protein synthesis increases the transcription of the phenobarbital-inducible CYP2H1 and CYP2H2 genes in chick embryo hepatocytes, Arch. Biochem. Biophys. 298: 96–104.PubMedCrossRefGoogle Scholar
  77. 77.
    Dogra, S. C., Hahn, C. N., and May, B. K., 1993, Superinduction by cycloheximide of cytochrome P4502H 1 and 5-aminolevulinate synthase gene transcription in chick embryo liver, Arch. Biochem. Biophys. 300: 531–534.PubMedCrossRefGoogle Scholar
  78. 78.
    Schuetz, E. G., Schuetz, J. D., May, B., and Guzefian, P. S., 1990, Regulation of cytochrome P-450b/e and P-450p gene expression by growth hormone in adult rat hepatocytes cultured on a reconstituted basement membrane, J. Biol. Chem. 265: 1188–1192.PubMedGoogle Scholar
  79. 79.
    Waxman, D. J., Morrissey, J. J., Naik, S., and Jauregui, H. 0., 1990, Phenobarbital induction of cytochrome P-450. High level, long term responsiveness of primary rat hepatocyte cultures to drug induction and glucocorticoid dependence of phenobarbital response, Biochem. J. 271: 113–119.PubMedGoogle Scholar
  80. 80.
    Williams, J. F., Bernent, W. J., Sinclair, J. F., and Sinclair, R R., 1991, Effect of interleukin 6 on phenobarbital induction of cytochrome P-450IIB in cultured rat hepatocytes, Biochem. Biophys. Res. Commun. 178: 1049–1055.PubMedCrossRefGoogle Scholar
  81. 81.
    Tieney, B., and Bresnick, E., 1981, Differences in the binding of 3-methylcholanthrene and phenobarbitone to rat liver cytosolic and nuclear protein fractions, Arch. Biochem. Biophys. 210: 729–739.CrossRefGoogle Scholar
  82. 82.
    Poland, A., Mak, I., Glover, E., Boatman, R. J., Ebetino, F. H., and Kende, A. S., 1980, 1,4-Bis[2-(3,5dichloropyridyloxy)]benzene, a potent phenobarbital-like inducer of microsomal monooxygenase activity, Mol. Pharmacol. 18: 571–580.Google Scholar
  83. 83.
    Poland, A., Mak, I., and Glover, E., 1981, Species differences in responsiveness to 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene, a potent phenobarbital-like inducer of microsomal monooxygenase activity, Mol. Pharmacol. 20: 442–450.PubMedGoogle Scholar
  84. 84.
    Smith, G., Henderson, C. J., Parker, M. G., White, R., Bars, R. G., and Wolf, C. 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.Google Scholar
  85. 85.
    He, J., and Fulco, A. J., 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.PubMedGoogle Scholar
  86. 86.
    Shaw, G., and Fulco, A. J., 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.PubMedGoogle Scholar
  87. 87.
    Shaw, G., and Fulco, A. J., 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.PubMedGoogle Scholar
  88. 88.
    Rangarajan, P. N., and Padmanaban, G., 1989, Regulation of cytochrome P-450b/e gene expression by a heme-and phenobarbitone-modulated transcription factor, Proc. Natl. Acad. Sci. USA 86: 3963–3967.PubMedCrossRefGoogle Scholar
  89. 89.
    Shaw, P. M., Adesnik, M., Weiss, M. C., and 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.PubMedGoogle Scholar
  90. 90.
    Hahn, C. N., Hansen, A. J., and May, B. K., 1991, Transcriptional regulation of the chicken CYP2H 1 gene: Localization of a phenobarbital-responsive enhancer domain, J. Biol. Chem. 266: 17031–17039.PubMedGoogle Scholar
  91. 91.
    Ramsden, R., Sommer, K. M., and Omiecinski, C. J., 1993, Phenobarbital induction and tissue-specific expression of the rat CYP2B2 gene in transgenic mice, J. Biol. Chem. 268: 21722–21726.PubMedGoogle Scholar
  92. 92.
    Doostdar, H., Grant, M. H., Melvin, W. T., Wolf, C. R., and Burke, M.D., 1993, The effects of inducing agents on cytochrome P450 and UDP-glucuronyl-transferase activities in human HEPG2 hepatoma cells, Biochem. Pharmacol. 46: 629–635.PubMedCrossRefGoogle Scholar
  93. 93.
    Pinkus, R., Bergelson, S., and 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.PubMedGoogle Scholar
  94. 94.
    Lock, E. A., Mitchell, A. M., and Elcombe, C. R., 1989, Biochemical mechanisms of induction of hepatic peroxisome proliferation, Annu. Rev. Pharmacol. Toxicol. 29: 145–163.PubMedCrossRefGoogle Scholar
  95. 95.
    Orton, T. C., and Parker, G. L., 1982, The effect of hypolipidemic drugs on the hepatic microsomal drug metabolizing enzyme system of the rat: Induction of cytochrome(s) P-450 with specificity toward terminal hydroxylation of lauric acid, Drug Metab. Dispos. 10: 110–115.PubMedGoogle Scholar
  96. 96.
    Tamburini, P. P., Masson, H., Bains, S. K., Makowski, R. J., Morris, B., and Gibson, G. G., 1984, Multiple forms of hepatic cytochrome P450: Purification, characterization, and comparison of a novel clofibrate-induced isozyme with other forms of cytochrome P-450, Eur. J. Biochem. 139: 235–246.PubMedCrossRefGoogle Scholar
  97. 97.
    Hardwick, J. P., Song, B.-J., Huberman, E., and Gonzalez, F. J., 1987, Isolation, complementary DNA sequence, and regulation of rat hepatic lauric acid w-hydroxylase (cytochrome P-450L40)), J. Biol. Chem. 262: 801–810.PubMedGoogle Scholar
  98. 98.
    Reddy, J. K., Goel, S. K., Nemali, M. R., Carrino, J. J., Laffler, T. G., Reddy, M. K., Sperbeck, S. J., Osumi, T., Hashimoto, T., Lalwani, N. D., and Rao, M. S., 1986, Transcriptional regulation of peroxisomal fatty acyl-CoA oxidase and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase in rat liver by peroxisome proliferators, Proc. Natl. Acad. Sci. USA 83: 1747–1751.PubMedCrossRefGoogle Scholar
  99. 99.
    Issemann, I., and Green, S., 1990, Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators, Nature 347: 645–650.PubMedCrossRefGoogle Scholar
  100. 100.
    Göttlicher, M., Widmark, E., Li, Q., and Gustafsson, J.-A., 1992, Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor, Proc. Natl. Acad. Sci. USA 89: 4653–4657.PubMedCrossRefGoogle Scholar
  101. 101.
    Zhu, Y., Alvares, K., Huang, Q., Rao, M. S., and Reddy, J. K., 1993, Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver, J. Biol. Chem. 268: 26817–26820.PubMedGoogle Scholar
  102. 102.
    Sher, T., Yi, H.-E, McBride, O. W., and Gonzalez, F. J., 1993, cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor, Biochemistry 32: 5598–5604.Google Scholar
  103. 103.
    Dreyer, C., Krey, G., Keller, H., Givel, F., Helftenbein, G., and Wahli, W., 1992, Control of the peroxisomal (3-oxidation pathway by a novel family of nuclear hormone receptors, Cell 68: 879–887.PubMedCrossRefGoogle Scholar
  104. 104.
    Evans, R. M., 1988, The steroid and thyroid hormone receptor superfamily, Science 240: 889–895.PubMedCrossRefGoogle Scholar
  105. 105.
    Tugwood, J. D., Issemann, I., Anderson, R. G., Bundell, K. R., McPheat, W. L., and Green, S., 1992, 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.PubMedGoogle Scholar
  106. 106.
    Muerhoff, A. S., Griffin, K. J., and Johnson, E. F., 1992, The peroxisome proliferator-activated receptor mediates the induction of CYP4A6, a cytochrome P450 fatty acid tu-hydroxylase, by clofibric acid, J. Biol. Chem. 267: 19051–19053.PubMedGoogle Scholar
  107. 107.
    Bell, D. R., and Elcombe, C. R., 1991, Induction of acyl-CoA oxidase and cytochrome P450IVA1 RNA in rat primary hepatocyte cultures by peroxisome proliferators, Biochem. J. 280: 249–253.PubMedGoogle Scholar
  108. 108.
    Kaikaus, R. M., Chan, W. K., Lysenko, N., Ray, R., Ortiz de Montellano, P. R., and Bass, N. M., 1993, Induction of peroxisomal fatty acid (3-oxidation and liver fatty acid-binding protein by peroxisome proliferators, J. Biol. Chem. 268: 9593–9603.PubMedGoogle Scholar
  109. 109.
    Kliewar, S. A., Umesono, K., Noonan, D. J., Heyman, R. A., and Evans, R. A., 1992, Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors, Nature 358: 771–774.CrossRefGoogle Scholar
  110. 110.
    Bogazzi, R, Hudson, L. D., and Nikodem, V. M., 1994, A novel heterodimerization partner for thyroid hormone receptor, J. Biol. Chem. 269: 11683–11686.PubMedGoogle Scholar
  111. 111.
    Selye, H., 1971, Hormones and resistance, J. Pharmacol. Sci. 60: 1–28.CrossRefGoogle Scholar
  112. 112.
    Elshourbagy, N. A., and Guzelian, P. S., 1980, Separation, purification, and characterization of a novel form of hepatic cytochrome P-450 from rats treated with pregnenolone-16a-carbonitrile, J. Biol. Chem. 255: 1279–1285.PubMedGoogle Scholar
  113. 113.
    Wang, R. W., Kari, P. H., Lu, A. Y. N., Thomas, P. E., Guengerich, F. P., and Vyas, K. P., 1991, Biotransformation of lovastatin. IV. Identification of cytochrome P4503A proteins as the major enzymes responsible for the oxidative metabolism of lovastatin in rat and human liver microsomes, Arch. Biochem. Biophys. 290: 355–361.PubMedCrossRefGoogle Scholar
  114. 114.
    Kronbach, T., Fischer, V., and Meyer, U. A., 1988, Cyclosporine metabolism in human liver: Identification of a cytochrome P-450 III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs, Clin. Pharmacol. Ther. 43: 630–635.PubMedCrossRefGoogle Scholar
  115. 115.
    Guengerich, F. P., Martin, M. V., Beaune, P. H., Kremers, P., Wolff, T., and Waxman, D. J., 1986, Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphisms in oxidative drug metabolism, J. Biol. Chem. 261: 5051–5060.PubMedGoogle Scholar
  116. 116.
    Watkins, P. B., Wrighton, S. A., Maurel, P., Schuetz, E. G., Mendez-Picon, G., Parker, G. A., and Guzelian, P. S., 1985, Identification of an inducible form of cytochrome P-450 in human liver, Proc. Natl. Acad. Sci. USA 82: 6310–6314.PubMedCrossRefGoogle Scholar
  117. 117.
    Kronbach, T., Mathys, D., Umeno, M., Gonzalez, F. J., and Meyer, U. A., 1989, Oxidation of midazolam and triazolam by human liver cytochrome P4501I1A4, Mol. Pharmacol. 36: 89–96.PubMedGoogle Scholar
  118. 118.
    Aoyama, T., Yamano, S., Waxman, D. J., Lapenson, D. P., Meyer, U. A., Fischer, V., Tyndale, R., Inaba, T., Kalow, W., Gelbirn, H. V., and Gonzales, F. J., 1989, Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver, J. Biol. Chem. 264: 10388–10395.PubMedGoogle Scholar
  119. 119.
    Hardwick, J. P., Gonzalez, F. J., and Kasper, C. B., 1983, Cloning of DNA complementary to cytochrome P450 induced by pregnenolone-16a-carbonitrile, J. Biol. Chem. 258: 10182–10186.PubMedGoogle Scholar
  120. 120.
    Wrighton, S. A., Schuetz, E. G., Watkins, P. B., Maurel, P., Barwick, J., Bailey, B. S., Hartle, H. T., Young, B., and Guzelian, P. S., 1985, Demonstration in multiple species of inducible hepatic cytochromes P-450 and their mRNAs related to the glucocorticoid-inducible cytochrome P-450 of the rat, Mol. Pharmacol. 28: 312–321.PubMedGoogle Scholar
  121. 121.
    Gonzalez, F. J., Song, B.-J., and Hardwick, J.P., 1986, Pregnenolone-16a-carbonitrile-inducible P-450 gene family: Gene conversion and differential regulation, Mol. Cell. Biol. 6: 2969–2976.PubMedGoogle Scholar
  122. 122.
    Simmons, D. L., McQuiddy, P., and Kasper, C. B., 1987, Induction of the hepatic mixed-function oxidase system by synthetic glucocorticoids, J. Bio!. Chem. 262: 326–332.Google Scholar
  123. 123.
    Schuetz, E. G., and Guzelian, P. S., 1984, Induction of cytochrome P-450 by glucocorticoids in rat liver. II. Evidence that glucocorticoids regulate induction of cytochrome P-450 by a non-classical receptor mechanism, J. Bio!. Chem. 259: 2007–2012.Google Scholar
  124. 124.
    Watkins, P. B., Wrighton, S. A., Schuetz, E. G., Maurel, R, and Guzelian, R. S., 1986, Macrolide antibiotics inhibit the degradation of the glucocorticoid-responsive cytochrome P-450p in rat hepatocytes in vivo and in primary monolayer culture, J. Biol. Chem. 261: 6264–6271.PubMedGoogle Scholar
  125. 125.
    Schuetz, E. G., Wrighton, S. A., Safe, S. H., and Guzelian, R. S., 1986, Regulation of cytochrome P-450p by phenobarbital and phenobarbital-like inducers in adult rat hepatocytes in primary mono-layer culture and in vivo, Biochemistry 25: 1124–1133.PubMedCrossRefGoogle Scholar
  126. 126.
    Schuetz, E. G., Omiecinski, C. J., Li, D., Muller-Eberhard, U., Kleinman, H. K., Elswick, B., and Guzelian, R. S., 1988, Regulation of gene expression in adult rat hepatocytes cultured on a basement membrane matrix, J. Cell. Physiol. 134: 309–323.PubMedCrossRefGoogle Scholar
  127. 127.
    Schuetz, E. G., Schuetz, J. D., Strom, S. C., Thompson, M. T., Fisher, R. A., Molowa, D. T., Li, D., and Guzelian, R. S., 1993, Regulation of human liver cytochromes P-450 in family 3A in primary and continuous culture of human hepatocytes, Hepatology 18: 1254–1262.PubMedCrossRefGoogle Scholar
  128. 128.
    Lieber, C. S., and DeCarli, L. M., 1968, Ethanol oxidation by hepatic microsomes: Adaptive increase after ethanol feeding, Science 162: 917–918.PubMedCrossRefGoogle Scholar
  129. 129.
    Koop, D. R., and Coon, M. J., 1986, Ethanol oxidation and toxicity: Role of alcohol P-450 oxygenase, Alcohol. Clin. Exp. Res. 10: 445–49s.CrossRefGoogle Scholar
  130. 130.
    Koop, D. R., Morgan, E. T., Tarr, G. E., and Coon, M. J., 1982, Purification and characterization of a unique isozyme of cytochrome P-450 from liver microsomes of ethanol-treated rabbits, J. Biol. Chem. 257: 8472–8480.PubMedGoogle Scholar
  131. 131.
    Koop, D. R., and Tierney, D. J., 1990, Multiple mechanisms in the regulation of ethanol-inducible cytochrome P450IIE1, BioEssays 12: 429–435.Google Scholar
  132. 132.
    Casazza, J. P., Felver, M. E., and Veech, R. L., 1984, The metabolism of acetone in rat, J. Biol. Chem. 259: 231–236.PubMedGoogle Scholar
  133. 133.
    Umeno, M., Song, B.-J., Kozak, C., Gelboin, H. V., and Gonzalez, F. J., 1988, The rat P450IIE1 gene: Complete intron and exon sequence, chromosome mapping, and correlation of developmental expression with specific 5’ cytosine demethylation, J. Biol. Chem. 263: 4956–4962.PubMedGoogle Scholar
  134. 134.
    Song, B.-J., Matsunaga, T., Hardwick, J. P., Park, S. S., Veech, R. L., Yang, C. S., Gelboin, H. V., and Gonzalez, F. J., 1987, Stabilization of cytochrome P450j messenger ribonucleic acid in the diabetic rat, Mol. Endocrinol. 1: 542–547.PubMedCrossRefGoogle Scholar
  135. 135.
    Dong, Z., Hong, J., Ma, Q., Li, D., Bullock, J., Gonzalez, F. J., Park, S. S., Gelboin, H. V., and Yang, C. S., 1988, Mechanism of induction of cytochrome P-450 ac (P-450j) in chemically induced and spontaneously diabetic rats, Arch. Biochem. Biophys. 263: 29–35.PubMedCrossRefGoogle Scholar
  136. 136.
    Koop, D. R., Crump, B. C., Nordblom, G. D., and Coon, M. J., 1985, Immunochemical evidence for induction of the alcohol-oxidizing cytochrome P-450 of rabbit liver microsomes by diverse agents: Ethanol, imidazole, trichloroethylene, acetone, pyrazole, and isoniazid, Proc. Natl. Acad. Sci. USA 82: 4065–4069.PubMedCrossRefGoogle Scholar
  137. 137.
    Song, B.-J., Veech, R. L., Park, S. S., Gelboin, H. V., and Gonzalez, F. J., 1989, Induction of rat hepatic N-nitrosodimethylamine demethylase by acetone is due to protein stabilization, J. Biol. Chem. 264: 3568–3572.PubMedGoogle Scholar
  138. 138.
    Eliasson, E., Johansson, I., and Ingelman-Sundberg, M., 1988, Ligand-dependent maintenance of ethanol-inducible cytochrome P-450 in primary hepatocyte cell cultures, Biochem. Biophys. Res. Commun. 150: 436–443.PubMedCrossRefGoogle Scholar
  139. 139.
    Eliasson, E., Johansson, I., and Ingelman-Sundberg, M., 1990, Substrate, hormone, and cAMP-regulated cytochrome P450 degradation, Proc. Natl. Acad. Sci. USA 87: 3225–3229.PubMedCrossRefGoogle Scholar
  140. 140.
    Gonzalez, F. J., and Nebert, D. W., 1990, Evolution of the P450 gene superfamily, Trends Genet. 6: 182–186.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • James P. WhitlockJr.
    • 1
  • Michael S. Denison
    • 2
  1. 1.Department of Molecular PharmacologyStanford University School of MedicineStanfordUSA
  2. 2.Department of Environmental ToxicologyUniversity of California, DavisDavisUSA

Personalised recommendations