Vázquez-Gómez G, Rubio-Lightbourn J, Espinosa-Aguirre JJ

Idioma: Español
Referencias bibliográficas: 143
Paginas: 54-67
Archivo PDF: 952.86 Kb.

RESUMEN

El benzo[a]pireno (b[a]p), es un hidrocarburo aromático policíclico (PAH) producto de combustiones incompletas de materia orgánica. Es considerado como carcinógeno debido a que los metabolitos derivados de su biotransformación, como el benzo [a] pireno diol epóxido (b[a]pDE), tienen propiedades mutagénicas y carcinogénicas . El b[a]p es metabolizado por las enzimas citocromos P450 1A1 (CYP1A1) y el citocromo P450 1B1 (CYP1B1 ) cuya expresión es inducida por la vía de señalización del receptor de hidrocarburos de arilo (AhR). Algunos estudios sugieren que el AhR es capaz de modular otros procesos celulares, además de la desintoxicación de xenobióticos como el desarrollo, diferenciación, proliferación, respuesta inmune, promoción del cáncer y apoptosis. Esto mediante la modulación de vías de señalización mediadas por proteínas cinasas como la del receptor del factor de crecimiento epidermal (EGFR, por sus siglas en inglés). Sin embargo, no es clara la función del AhR en estos procesos ni cómo el AhR es capaz de interactuar con otras vías de señalización. Las alteraciones celulares inducidas por b[a]p son complejas y pueden estar mediadas por más de una vía de señalización y la activación de múltiples genes, por lo que es esencial saber qué vías están involucradas en el metabolismo de los PAH para una mejor comprensión de las bases moleculares de enfermedades como el cáncer.

REFERENCIAS (EN ESTE ARTÍCULO)

1. Hecht, S. Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nature Reviews Cancer. 3: 733-744 (2003).

2. Vogelstein, B., Papadopoulous, N., Velculescu, V., Zhou, S., Díaz, L. & Kinzler, K. Cancer genome landscapes. Science. 339: 1546-1558 (2013).

3. Hoffman, E., et al. Cloning of a factor required for activity of the Ah (dioxin) receptor. Science. 252: 954-958 (1991).

4. Hogenesch, J., et al. Characterization of a subset of the basic-helixloop- helix-PAS superfamily that interacts with components of the dioxin signaling pathway. The Journal of Biological Chemistry. 272: 8581-8593 (1997).

5. Gu, Y., Hogenesch, J. & Bradfield, C. The PAS Superfamily: Sensors of Environmental and Developmental Signals. Annual Review of Pharmacology and Toxicology. 40: 519-561 (2000).

6. Wu, D., Potluri, N., Kim, Y. & Rastinejad, F. Structure and dimerization properties of the aryl hydrocarbon receptor PAS-A domain. Molecular Cell Biology. 33: 4346-4356 (2013).

7. Ema, M., et al. cDNA cloning and structure of mouse putative Ah receptor. Biochemical and Biophysical Research Communications. 184: 246-253 (1992).

8. Burbach, K., Poland, A. & Bradfield, C. Cloning of the Ahreceptor cDNA reveals a distinctive ligand-activated transcription factor. Proceedings of the National Academy of Sciences. 89: 8185-8189 (1992).

9. Schmidt, J., Carver, L. & Bradfield, C. Molecular characterization of the murine Ahr gene. Organization, promoter analysis, and chromosomal assignment. The Journal of Biological Chemistry. 268: 22203-22209 (1993).

10. Dolwick, K., Schmidt, J., Carver, L., Swanson, H. & Bradfield, C. Cloning and expression of a human Ah receptor cDNA. Molecular Pharmacology. 44: 911-917 (1993).

11. Poland, A., Palen, D. & Glover, E. Analysis of the four alleles of the murine aryl hydrocarbon receptor. Molecular Pharmacology. 46: 915-921 (1994).

12. Chang, C., Smith, D., Prasad, V., Sidman, C., Nebert, D. & Puga, A. Ten nucleotide differences, five of which cause amino acid changes, are associated with the Ah receptor locus polymorphism of C57BL/6 and DBA/2 mice. Pharmacogenetics. 3: 312-321 (1993).

13. Carver, L., Hogenesch, J. & Bradfield, C. Tissue specific expression of the rat Ah-receptor and ARNT mRNAs. Nucleic Acids Research. 22: 3038–3044 (1994).

14. Korkalainen, M., Tuomisto, J. & Pohjanvirta, R. Restructured transactivation domain in hamster AH receptor. Biochemical and Biophysical Research Communication. 273: 272-281 (2000).

15. Hahn, M. Aryl hydrocarbon receptors: diversity and evolution. Chemico-Biological Interactions. 141: 131-160 (2002).

16. Kim, E., Hahn, M., Iwata, H., Tanabe, S. & Miyazaki, N. cDNA cloning of an aryl hydrocarbon receptor from Baikal seals (Phoca sibirica). Marine Environmental Research. 54: 285- 289 (2002).

17. Walker, M., Heid, S., Smith, S. & Swanson, H. Molecular characterization and developmental expression of the aryl hydrocarbon receptor from the chick embryo. Comparative Biochemistry and Physiology part C Toxicology Pharmacology. 126: 305-319 (2000).

18. Karchner, S., Kennedy, S., Trudeau, S. & Hahn, M. Towards molecular understanding of species differences in dioxin sensitivity: initial characterization of Ah receptor cDNAs in birds and an amphibian. Marine and Environmental Research. 50: 51-56 (2000).

19. Hahn, M., Karchner, S., Shapiro, M. & Perera, S. Molecular evolution of two vertebrate aryl hydrocarbon (dioxin) receptors (AHR1 and AHR2) and the PAS family. Proceedings of the National Academy of Sciences. 94: 13743-13748 (1997).

20. Hahn, M. The aryl hydrocarbon receptor: a comparative perspective. Comparative Biochemistry and Physiology part C Toxicology Pharmacology. 121: 23-53 (1998).

21. Butler, R., Kelley, M., Powell, W., Hahn, M. & Van Beneden, R. An aryl hydrocarbon receptor (AHR) homologue from the soft-shell clam, Mya arenaria: evidence that invertebrate AHR homologues lack 2,3,7,8- tetrachlorodibenzo-p-dioxin and beta-naphthoflavone binding. Gene. 278: 223-234 (2001).

22. Duncan, D., Burgess, E. & Duncan, I. Control of distal antennal identity and tarsal development in Drosophila by spinelessaristapedia, a homolog of the mammalian dioxin receptor. Genes and Development. 12: 1290-1303 (1998).

23. Micka, J., Milatovich, A., Menon, A., Grabowski. G., Puga, A. & Nebert, D. Human Ah receptor (AHR) gene: localization to 7p15 and suggestive correlation of polymorphism with CYP1A1 inducibility. Pharmacogenetics. 7: 95-101 (1997).

24. Tirona, R. & Kim, R. Nuclear receptors and drug disposition gene regulation. Journal of Pharmaceutical Sciences. 94: 1169- 1186 (2005).

25. Hao, N., Whitelaw, M., Shearwin, K., Dodd, I. & Chapman-Smith, A. Identification of residues in the N‑terminal PAS domains important for dimerization of Arnt and AhR. Nucleic Acids Research. 39: 3695-3709 (2011).

26. Kewley, R., Whitelaw, M. & Chapman-Smith, A. The mammalian basic helixloop-helix/PAS family of transcriptional regulators. The International Journal of Biochemistry and Cell Biology. 36: 189-204 (2004).

27. Adachi, J., et al. Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine. The Journal of Biological Chemistry. 276: 31475-31478 (2001).

28. Schaldach, C., Riby, J. & Bjeldanes, L. Lipoxin A4: a new class of ligand for the Ah receptor. Biochemistry. 38: 7594-7600 (1999).

29. Wei, Y., Hellenberg, H., Rannug, U. & Rannug, A. Rapid and transient induction of CYP1A1 gene expression in human cells by the tryptophan photoproduct 6-formylindolo [3, 2] carbazole. Chemico-Biological Interactions. 110: 39-55 (1998).

30. Denison, M. & Nagy, S. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annual Review of Pharmacology and Toxicology. 43: 309-334 (2003).

31. Hao, N., Lee, K., Furness, S., Bosdotter, C., Poellinger, L. & Whitelaw, M. Xenobiotics and loss of cell adhesion drive distinct transcriptional outcomes by aryl hydrocarbon receptor signaling. Molecular Pharmacology. 82: 1082-1093 (2012).

32. Hankinson, O. Why does ARNT2 behave differently from ARNT? Toxicology Sciences. 103: 1-3 (2008).

33. Bersten, D., Sullivan, A., Peet, D. & Whitelaw, M. bHLH-PAS proteins in cancer. Nature Reviews Cancer. 13: 827-841 (2013).

34. Enan, E. & Matsumura, F. Evidence for a second pathway in the action mechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Significance of Ah-receptor mediated activation of protein kinase under cell-free conditions. Biochemical Pharmacology. 49: 249-261 (1995).

35. Blankenship, A. & Matsumura, F. 2,3,7,8-Tetrachlorodibenzopdioxin- induced activation of a protein tyrosine kinase, pp60src, in murine hepatic cytosol using a cell-free system. Molecular Pharmacology. 52: 667-675 (1997).

36. Kobayashi, A., Sogawa, K. & Fujii-Kuriyama, Y. Cooperative interaction between AhR-ARNT and SP1 for the drug- inducible expression of CYP1A1 gene. The Journal of Biological Chemestry. 271: 12310-12316 (1996).

37. Fujii-Kuriyama, Y. & Mimura, J. Molecular mechanisms of AhR functions in the regulation of cytochrome P450 genes. Biochemical and Biophysical Research Communications. 338: 311-317 (2005).

38. Hankinson, O. The Aril Hydrocarbon Receptor Complex. Annual Review of Pharmacology and Toxicology. 35: 307-340 (1995).

39. Waxman, D. P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Archives of Biochemistry and Biophysics. 369: 11-23 (1999).

40. Emmons, R., et al. The spineless-aristapedia and tango bHLH-PAS proteins interact to control antennal and tarsal development in Drosophila. Development. 126: 3937-3945 (1999).

41. Huang, X., Powell-Coffman, J. & 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).

42. Qin, H. & Powell-Coffman, J. The Caenorhabditis elegans aryl hydrocarbon receptor, AHR-1, regulates neuronal development. Developmental Biology. 270: 64-75 (2004).

43. Kawajiri, K. & Fujii-Kuriyama, Y. Cytochrome P450 gene regulation and physiological functions mediated by the aryl hydrocarbon receptor. Archives of Biochemistry and Biophysics. 464: 207- 212 (2007).

44. Konig, J., Nies, AT., Cui, Y., Leier, I. & Keppler, D. Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochimica et Biophysica Acta. 1461: 377- 394 (1999).

45. Roberts, B. & Whitelaw, M. Degradation of the basic helix-loophelix/ Per-ARNT-Sim homology domain dioxin receptor via the ubiquitin/proteasome pathway. The Journal of Biological Chemistry. 274: 36351-36356 (1999).

46. Pollenz, R. The aryl-hydrocarbon receptor, but not the arylhydrocarbon receptor nuclear translocator protein, is rapidly depleted in hepatic and nonhepatic culture cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Molecular Pharmacology. 49: 391-398 (1996).

47. Davarinos, N. & Pollenz, R. Aryl hydrocarbon receptor imported into the nucleus following ligand binding is rapidly degraded via the cytosplasmic proteasome following nuclear export. The Journal of Biological Chemistry. 274: 28708-28715 (1999).

48. Berg, P. & Pongratz, I. Differential usage of nuclear export sequences regulates intracellular localization of the dioxin (aryl hydrocarbon) receptor. The Journal of Biological Chemistry. 276: 43231-43238 (2001).

49. Mimura, J., Ema, M, Sogawa, K. & Fujii-Kuriyama, Y. Identification of a novel mechanism of regulation of Ah (dioxin) receptor function. Genes and Development 13: 20-25 (1999).

50. Murray, I., Patterson, A. & Perdew, H. Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nature Reviews Cancer. 14: 801-814 (2014).

51. Osborn, M. & Crosby, T. Benzopyrenes. Cambridge Monographs on Cancer Research. Cambridge University Press, Cambridge, pp. 1-323 (1987).

52. Hecht, S. Cigarette smoking and lung cancer: chemical mechanisms and approaches to prevention. The Lancet Oncology. 3: 461- 469 (2002).

53. Verma, N., Rettenmeier, A. & Schmitz-Spanke, S. Exposure of primary porcine urothelial cells to benzo(a)pyrene: in vitro uptake, intracellular concentration and biological response. Archives of Toxicology. 86: 1861-1871 (2012).

54. Sun, J., Wolff, R. & Kanapilly, G. Deposition, retention, and biological fate of inhaled benzo(a)pyrene adsorbed onto ultrafine particles and as a pure aerosol. Toxicology and Applied Pharmacology. 65: 231-244 (1982).

55. Sun, J., Wolff, R., Kanapilly, G. & McClellan, R. Lung retention and metabolic fate of inhaled benzo(a)pyrene associated with diesel exhaust particles. Toxicology and Applied Pharmacology. 73: 48-59 (1984).

56. Yamazaki, H., Terada, M., Tsuboi, A., Matsubara, C., Hata, T. & Kakiuchi, Y. Distribution and binding pattern of benzo(a) pyrene in rat liver, lung and kidney constituents after oral administration. Toxicolological and Environmental Chemistry. 15: 71-81 (1987).

57. Kelman, B. & Springer, D. Movements of benzo[a]pyrene across the hemochorial placenta of the guinea pig. Proceedings of the Society for Experimental Biology and Medicine. 169: 58-62 (1982).

58. Alexandrov, K., Rojas, M. & Satarug, S. The critical DNA damage by benzo(a)pyrene in lung tissues of smokers and approaches to preventing its formation. Toxicology Letters. 198: 63-68 (2010).

59. Rodgman, A., Smith, C. & Perfetti, T. The composition of cigarette smoke: a retrospective, with emphasis on polycyclic components. Human and Experimental Toxicology. 19: 573- 595 (2000).

60. Schmidt, J., Su, G., Reddy, J., Simon, C. & Bradfield, C. Characterization of a murine Ahr null allele: Involvement of the Ah receptor in hepatic growth and development. Proceddings of the National Academy of Sciences. 93: 6731-6736 (1996).

61. Kapitulnik, J., Wislocki, P., Levin, W., Yagi, H., Jerina, D. & Conney, A. Tumorigenicity studies with diol-epoxides of benzo (a) pyrene which indicate that (+/-)-trans-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7, 8, 8, 10- tetrahy drobenzo[a]pyrene is an ultimate carcinogen in newborn mice. Cancer Research. 38: 354-358 (1978).

62. Lavin, W., Wood, A., Yagi, H., Jerina, D. & Conney, A. (+/)- trans-7,8-dihydroxy-7,8 dihydrobenzo[a]pyrene: a potent skin carcinogen when applied topically to mice. Proceedings of the National Academy of Sciences. 73: 3867-3871 (1976).

63. Ling, H., et al. Crystal structure of a benzo[a]pyrene diol epoxide adduct in a ternary complex with a DNA polymerase. Proceedings of the National Academy of Sciences. 101: 2265- 2269 (2003).

64. Shimada, T. Xenobiotic-Metabolizing Enzymes Involved in Activation and Detoxification of Carcinogenic Polycyclic Aromatic Hydrocarbons. Drug metabolism and pharmacokinetics. 21: 257-276 (2006).

65. Rushmore, T. & Kong, A. Pharmacogenomics, regulation and signaling pathways of phase I and II drug metabolizing enzymes. Current Drug Metabolism. 3: 481-490 (2002).

66. Weinshilboum, R., Otterness, D., Aksoy, I., Wood, T., Her, C. & Raftogianis, R. Sulfotransferase molecular biology: cDNAs and genes. The FASEB Journal. 11: 3-14 (1997).

67. Mackenzie, P., et al. The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics. 7: 255-269 (1997).

68. Tukey, R. & Strassburg, C. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annual Review of Pharmacology and Toxicology. 40: 581-616 (2000).

69. Jaiswal, A. Jun and Fos regulation of NAD(P)H: quinone oxidoreductase gene expression. Pharmacogenetics. 4: 1-10 (1994).

70. Guenthner, T. Epoxide Hydrolase. In: G. Mulder (ed.) Conjugation Reactions in Drug Metabolism (London. Taylor & Francis, 1990). pp. 365-404.

71. Rushmore, T., Pickett, C. & Lu, A. Xenobiotic and antioxidant induction of the Ya subunit Gene. Berlin Heidelberg: Springer- Verlag. p. 79-107 (1994).

72. Vatsis, K.P., et al. Nomenclarure for N-acetyltransferases. Pharmacogenetics. 5: 1-17 (1995).

73. Weng, M., et al. Alleviation of benzo[a]pyrene-diolepoxide-DNA damage in human lung carcinoma by glutathione S-transferase M2. DNA Repair. 4: 493-502 (2005).

74. Sherratt, P.J., Pulford, D.J., Harrison, D.J., Green, T. & Hayes, J.D. Evidence that human class Theta glutathione S-transferase T1-1 can catalyse the activation of dichloromethane, a liver and lung carcinogen in the mouse. Comparison of the tissue distribution of GST T1-1 with that of classes Alpha, Mu and Pi GST in human. Biochemical Journal. 326: 837-846 (1997).

75. Sundberg, K., Widersten, M., Seidel, A., Mannervik, B. & Jernstrom, B. Glutathione conjugation of bay- and fjord-region diol epoxides of polycyclic aromatic hydrocarbons by glutathione transferases M1-1 and P1-1. Chemical Research Toxicology. 10: 1221-1227 (1997).

76. Robertson, I., Guthenberg, C., Mannervik, B. & Jernstrom, B. Differences in stereoselectivity and catalytic efficiency of three human glutathione transferases in the conjugation of glutathione with 7 beta, 8 alpha-dihydroxy-9 alpha,10 alphaoxy- 7,8,9,10- tetrahydrobenzo[a]pyrene. Cancer Research. 46: 2220-2224 (1986a).

77. Hu, X., et al. Mechanism of differential catalytic efficiency of two polymorphic forms of human glutathione S-transferase P1-1 in the glutathione conjugation of carcinogenic diol epoxide of chrysene. Archives of Biochemistry and Biophysics. 345: 32-38 (1997).

78. Hayes, J. & Pulford, D. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Critical Reviews in Biochemistry and Molecular Biology. 30: 445-600 (1995).

79. Robertson, I., Jensson, H., Mannervik, B. & Jernstrom, B. Glutathione transferases in rat lung: the presence of transferase 7-7, highly efficient in the conjugation of glutathione with the carcinogenic (+)-7 beta,8 alpha-dihydroxy-9 alpha,10 alphaoxy- 7,8,9,10- tetrahydrobenzo[a]pyrene. Carcinogenesis. 7: 295-299 (1986b).

80. Mannervik, B. & Danielson, U. Glutathione transferases – structure and catalytic activity. CRC Critical Reviews in Biochemistry. 23: 283-337 (1988).

81. Sundberg, K., et al. Differences in the catalytic efficiencies of allelic variants of glutathione transferase P1-1 towards carcinogenic diol epoxides of polycyclic aromatic hydrocarbons. Carcinogenesis. 19: 433-436 (1998).

82. Slaga, T., et al. Marked differences in the skin tumor-initiating activities of the optical nantiomers of the diastereomeric benzo(a)pyrene 7,8-diol-9,10-epoxides. Cancer Research. 39: 67-71 (1979).

83. Thakker, D., et al. Metabolism of benzo[a]pyrene VI. Stereoselective metabolism of benzo[a]pyrene and benzo[a]pyrene 7, 8- dihydrodiol to diol epoxides. Chemico-Biological Interactions. 16: 281-300 (1977).

84. Dennissenko, M., Pao, A., Tang, M. & Pfeifer, G. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hot spots in P53. Science. 274: 430-432 (1996).

85. Phillips, D. Smoking-related DNA and protein adducts in human tissues. Carcinogenesis. 23: 1979-2004 (2002).

86. Mollerup, S., et al. Sex differences in risk of lung cancer: expression of genes in the PAH bioactivation pathway in relation to smoking and bulky DNA adducts. International Journal of Cancer. 119: 741-744 (2006).

87. Phillips, D., et al. Relationship between mutagenicity and DNA adduct formation in mammalian cells for fjord- and bay-region diolepoxides of polycyclic aromatic hydrocarbons. Chemico- Biological Interactions. 80: 177-186 (1991).

88. Gelboin, H. Benzo[alpha]pyrene metabolism, activation and carcinogenesis: role and regulation of mixedfunction oxidases and related enzymes. Physiologycal Reviews. 60: 1107-1166 (1980).

89. Cavalieri, E. & Rogan, E. The approach to understanding aromatic hydrocarbon carcinogenesis. The central role of radical cations in metabolic activation. Pharmacology and Therapeutics. 55: 183-199 (1992).

90. Sullivan, P. Free radicals of benzo(a)pyrene and derivatives. Environmental Health Perspectives. 64: 283-295 (1985).

91. Wislocki, P., et al. Mutagenicity and cytotoxicity of benzo(a)pyrene arene oxides, phenols, uinones, and dihydrodiols in bacterial and mammalian cells. Cancer Research. 36: 3350-3357 (1976).

92. Zhu, H., Li, Y. & Trush, M. Characterization of benzo[a]pyrene quinone-induced toxicity to primary cultured bone marrow stromal cells from DBA/2 mice: potential role of mitochondrial dysfunction. Toxicology and Applied Pharmacology. 130: 108-20 (1995).

93. Abbott, B., Birnbaum, L. & Perdew, G. Developmental Expression of Two Members of a New Class of Transcription Factors: I. Expression of Aryl Hydrocarbon Receptor in the C57BL/6N Mouse Embryo. Developmental Dynamics. 204: 133-143 (1995).

94. Fernández-Salguero, P., et al. Inmune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science. 268: 722-726 (1995).

95. Schmidt, J. & Bradfield, C. Ah receptor signaling pathways. Annual Review of Cell and Developmental Biology. 12: 55-89 (1996).

96. Mimura, J., et al. Loss of teratogenic response to 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor. Genes Cells. 2: 645-654 (1997).

97. Olayioye, M., Neve, R., Lane, H. & Hynes, N. The ErbB signaling network: receptor heterodimerization in development and cancer. The EMBO Journal. 19: 3159-3167 (2000).

98. Prenzel, N., Fischer, O., Streit, S., Hart, S. & Ullrich, A. The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocrine- Related Cancer. 8: 11-31 (2001).

99. Riese, D. & Stern, D. Specificity within the EGF family/ErbB receptor family signaling network. Bioessays. 20: 41-48 (1998).

100. Hackel, P., Zwick, E., Prenzel, N. & Ullrich, A. Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Current Opinion in Cell Biology. 11: 184-189 (1999).

101. Wiley, H., Herbst, J., Walsh, B., Lauffenburger, D., Rosenfeld, M. & Gill, G. The role of tyrosine kinase activity in endocytosis, compartmentation, and down-regulation of the epidermal growth factor receptor. The Journal of Biological Chemistry. 266: 11083-11094 (1991).

102. De Luca, A., et al. The role of the EGFR signaling in tumor microenvironment. Jounal of Cellular Physiology. 214: 559- 567 (2008).

103. Heimberg, M., Weinstein, I., LeQuire, V. & Cohen, S. The induction of fatty liver in neonatal animals by a purified protein (EGF) from mouse submaxillary gland. Life Sciences. 4: 1625-1633 (1965).

104. Yamamoto, T., Cui, X. & Shuler, C. Role of ERK1/2 signaling during EGF-induced inhibition of palatal fusion. Developmental Biology. 260: 512-521 (2003).

105. Rose, S., Stahn, R., Passovoy, D. & Herschman, H. Epidermal growth factor enhancement of skin tumor induction in mice. Experientia. 32: 913-915 (1976).

106. Gupta, B., Vos, J., Moore, J., Zinkl, J. & Bullock, B. Pathologic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in laboratory animals. Environmental Health Perspectives. 5: 125-140 (1973).

107. Poland, A., Palen, D. & Glover, E. Tumour promotion by TCDD in skin of HRS/J hairless mice. Nature. 300: 271-273 (1982).

108. Abbott, B. & Birnbaum, L. TCDD exposure of human embryonic palatal shelves in organ culture alters the differentiation of medial epithelial cells. Teratology. 43: 119-132 (1991).

109. Abbott, B., Harris, M. & Birnbaum, L. Comparisons of the effects of TCDD and hydrocortisone on growth factor expression provide insight into their interaction in the embryonic mouse palate. Teratology. 45: 35-53 (1992).

110. Madhukar, B., Brewster, D. & Matsumura, F. Effects of in vivoadministered 2,3,7,8-tetrachlorodibenzo-p-dioxin on receptor binding of epidermal growth factor in the hepatic plasma membrane of rat, guinea pig, mouse, and hamster. Proceedings of the National Academy of Sciences. 81: 7407-7411 (1984).

111. Bombick, D., Madhukar, B., Brewster, D. & Matsumura, F. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) causes increases in protein kinases particularly protein kinase C in the hepatic plasma membrane of the rat and the guinea pig. Biochemical and Biophysical Research Communications. 127: 296-302 (1985).

112. Bombick, D. & Matsumura, F. TCDD (2,3,7,8- tetrachlorodibenzop- dioxin) causes an increase in protein tyrosine kinase activities at an early stage of poisoning in vivo in rat hepatocyte membranes. Life Sciences. 41: 429-436 (1987a).

113. Bombick, D. & Matsumura, F. 2,3,7,8-Tetrachlorodibenzo-pdioxin causes elevation of the levels of the protein tyrosine kinase pp60c-src. Journal of Biochemical Toxicology. 2: 141-154 (1987b).

114. Ebner, K., Matsumura, F., Enan, E. & Olsen, H. 2,3,7,8- Tetrachlorodibenzo-p-dioxin (TCDD) alters pancreatic membrane tyrosine phosphorylation following acute treatment. Journal of Biochemical Toxicology. 8: 71-81 (1993).

115. Enan, E. & Matsumura, F. Significance of TCDD-induced changes in protein phosphorylation in the adipocyte of male guinea pigs. Journal Biochemical Toxicology. 9: 159-170 (1994).

116. Hunter, T. & Cooper, J. Protein-tyrosine kinases. Annual Review of Biochemistry. 54: 897-930 (1985).

117. Madhukar, B., Ebner, K., Matsumura, F., Bombick, D., Brewster, D. & Kawamoto, T. 2,3,7,8-Tetrachlorodibenzo-p-dioxin causes an increase in protein kinases associatedwith epidermal growth factor receptor in the hepatic plasma membrane. Journal of Biochemical Toxicology. 3: 261-277 (1988).

118. Choi, E., Toscano, D., Ryan, J., Riedel, N. & Toscano Jr, W. Dioxin induces transforming growth factor-alpha in human keratinocytes. The Journal of Biological Chemistry. 266: 9591-9597 (1991).

119. Gaido, K., Maness, S., Leonard, L. & Greenlee, W. 2,3,7,8- Tetrachlorodibenzo-p-dioxin-dependent regulation of transforming growth factors-alpha and -beta 2 expression in a human keratinocyte cell line involves both transcriptional and post-transcriptional control. The Journal of Biological Chemistry. 267: 24591-24595 (1992).

120. Abbott, B. & Birnbaum, L. TCDD-induced altered expression of growth factors may have a role in producing cleft palate and enhancing the incidence of clefts after coadministration of retinoic acid and TCDD. Toxicology and applied pharmacology. 106: 418-432 (1990).

121. Enan, E. & Matsumura, F. Identification of c-Src as the integral component of the cytosolic Ah receptor complex, transducing the signal of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the protein phosphorylation pathway. Biochemical Pharmacology. 52: 1599-1612 (1996).

122. Sato, K., Sato, A., Aoto, M. & Fukami, Y. c-Src phosphorylates epidermal growth factor receptor on tyrosine 845. Biochemical and Biophysical Research Communication. 215: 1078-1087 (1995).

123. Biscardi, J., Maa, M., Tice, D., Cox, M., Leu, T. & Parsons, S. c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function. The Journal of Biological Chemistry. 274: 8335-8343 (1999).

124. Kohle, C., Gschaidmeier, H., Lauth, D., Topell, S., Zitzer, H. & Bock, K. 2,3,7,8- etrachlorodibenzo-p-dioxin (TCDD)- mediated membrane translocation of c-Src protein kinase in liver WB-F344 cells. Archives of Toxicology. 73: 152-158 (1999).

125. Belsches, A., Haskell, M. & Parsons, S. Role of c-Src tyrosine kinase in EGF-induced mitogenesis. Frontier in Biosciences. 2: d501-d518 (1997).

126. Dunlap, D., Moreno-Aliaga, M., Wu, Z. & Matsumura, F. Differential toxicities of TCDD in vivo among normal, c-src knockout, geldanamycin- and quercetin-treated mice. Toxicology. 135: 95-107 (1999).

127. Dunlap, D. & Matsumura, F. Analysis of difference in vivo effects of TCDD between c-src +/+ mice, c-src deficient, -/+ and -/-B6, 129-Src(tm 1 sor) mice and their wild-type littermates. Chemosphere. 40:1241-1246 (2000).

128. Dunlap, D., Ikeda, I., Nagashima, H., Vogel, C. & Matsumura, F. Effects of src-deficiency on the expression of in vivo toxicity of TCDD in a strain of c-src knockout mice procured through six generations of backcrossings to C57BL/6 mice. Toxicology. 172: 125-141 (2002).

129. Park, S., et al. TCDD causes suppression of growth and differentiation of MCF10A, human mammary epithelial cells by interfering with their insulin receptor signaling through c-Src kinase and ERK activation. Journal of Biochemical and Molecular Toxicology. 18: 322-331 (2004).

130. Tannheimer, S., Ethier, S., Caldwell, K. & Burchiel, S. Benzo[a]pyrene and TCDD-induced alterations in tyrosine phosphorylation and insulin-like growth factor signaling pathways in the MCF-10A human mammary epithelial cell line. Carcinogenesis. 19: 1291-1297 (1998).

131. Kwon, M., Jeong, K., Choi, E. & Lee, B. 2,3,7,8-Tetrachlorodibenzop- dioxin (TCDD)-induced activation of mitogen-activated protein kinase signaling pathway in Jurkat T cells. Pharmacology and Toxicology. 93: 186-190 (2003).

132. Park, S., et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin activates ERK and p38 mitogen-activated protein kinases in RAW 264.7 cells. Anticancer Research. 25: 2831-2836 (2005).

133. Randi, A., Sánchez, M., Álvarez, L., Cardozo, J., Pontillo, C. & de Pisarev, D. Hexachlorobenzene triggers AhR translocation to the nucleus, c-Src activation and EGFR transactivation in rat liver. Toxicology Letters. 177: 116-122 (2008).

134. Fritsche, E., et al. Lightening up the UV response by identification of the aryl hydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. Proceedings of the National Academy of Sciences. 104: 8851-8856 (2007).

135. Pentland, A., Schoggins, J., Scott, G., Khan, K. & Han, R. Reduction of UV-induced skin tumors in hairless mice by selective COX-2 inhibition. Carcinogenesis. 20: 1939-1944 (1999).

136. Shimizu, Y., et al. Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proceeding of the National Academy of Sciences. 97: 779-782 (2000).

137. Cheon, H., et al. Signaling pathway for 2,3,7,8-tetrachlorodibenzopdioxin- induced TNF-alpha production in differentiated THP-1 human macrophages. Experimental and Molecular Medicine. 39: 524-534 (2007).

138. Johansson, C., Yndestad, A., Enserink, J., Ree, A., Aukrust, P. & Tasken, K. The epidermal growth factor-like growth factor amphiregulin is strongly induced by the adenosine 3’, 5’-monophosphate pathway in various cell types. Endocrinology. 145: 5177-5184 (2004).

139. Hao, N. & Whitelaw, M. The emerging roles of AhR in Physiology and immunity. Biochemical Pharmacology. 86: 561-570 (2013).

140. Du, B., Altorki, N., Kopelovich, L., Subbaramaiah, K. & Dannenberg, A. Tobacco smoke stimulates the transcription of amphiregulin in human oral epithelial cells: evidence of a cyclic AMP-responsive element binding protein-dependent mechanism. Cancer Research. 65: 5982–5988 (2005).

141. Piiper, A., et al. Protein kinase A mediates cAMP-induced tyrosine phosphorylation of the epidermal growth factor receptor. Biochemical and Biophysical Research Communications. 301: 848-854 (2003).

142. Choi, S., Miller, M. & Harper, P. In utero exposure to 2,3,7,8- tetrachlorodibenzo-p-dioxin induces amphiregulin gene expression in the developing mouse ureter. Toxicology Sciences. 94: 163-174 (2006).

143. Patel, R., Kim, D., Peters, J. & Perdew, G. The aryl hydrocarbon receptor directly regulates expression of the potent mitogen epiregulin. Toxicology Sciences. 89: 75-82 (2006).