On the impact of the molecule structure in chemical carcinogenesis

  • Andreas Luch
Part of the Experientia Supplementum book series (EXS, volume 99)


Cancer is as a highly complex and multifactorial disease responsible for the death of hundreds of thousands of people in the western countries every year. Since cancer is clonal and due to changes at the level of the genetic material, viruses, chemical mutagens and other exogenous factors such as short-waved electromagnetic radiation that alter the structure of DNA are among the principal causes. The focus of this present review lies on the influence of the molecular structure of two well-investigated chemical carcinogens from the group of polycyclic aromatic hydrocarbons (PAHs), benzo[a]pyrene (BP) and dibenzo[a,l]pyrene (DBP). Although there is only one additional benzo ring present in the latter compound, DBP exerts much stronger genotoxic and carcinogenic effects in certain tumor models as compared to BP. Actually, DBP has been identified as the most potent tumorigen among all carcinogenic PAHs tested to date. The genotoxic effects of both compounds investigated in mammalian cells in culture or in animal models are described. Comparison of enzymatic activation, DNA binding levels of reactive diol-epoxide metabolites, efficiency of DNA adduct repair and mutagenicity provides some clues on why this compound is about 100-fold more potent in inducing tumors than BP. The data published during the past 20 years support and strengthen the idea that compound-inherent physicochemical parameters, along with inefficient repair of certain kinds of DNA lesions formed upon metabolic activation, can be considered as strong determinants for high carcinogenic potency of a chemical.


Nucleotide Excision Repair Mouse Skin Chemical Carcinogenesis Carcinogenic PAHs Polycyclic Aromatic Hydro 
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.


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  1. 1.
    Doll R, Peto R (1981) The causes of cancer: Quantitative estimates of avoidable risks of cancer in the United States today. J Nat Cancer Inst 66: 1191–1308PubMedGoogle Scholar
  2. 2.
    Lichtenstein P, Holm, NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K (2000) Environmental and heritable factors in the causation of cancer. N Engl J Med 343: 78–85PubMedCrossRefGoogle Scholar
  3. 3.
    Czene K, Lichtenstein P, Hemminki K (2002) Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish family-cancer database. Int J Cancer 99: 260–266PubMedCrossRefGoogle Scholar
  4. 4.
    Kolonel LN, Altshuler D, Henderson BE (2004) The multiethic cohort study: Exploring genes, lifestyle and cancer risk. Nat Rev Cancer 4: 519–527PubMedCrossRefGoogle Scholar
  5. 5.
    Colditz GA, Sellers TA, Trapido E (2006) Epidemiology-Identifying the causes and preventability of cancer? Nat Rev Cancer 6: 75–83PubMedCrossRefGoogle Scholar
  6. 6.
    Peto F (2001) Cancer epidemiology in the last century and the next decade. Nature 411: 390–395PubMedCrossRefGoogle Scholar
  7. 7.
    Luch A (2002) Cell cycle control and cell division: Implications for chemically induced carcinogenesis. ChemBioChem 3: 506–516PubMedCrossRefGoogle Scholar
  8. 8.
    Chen F, Shi X (2002) Intracellular signal transduction of cells in response to carcinogenic metals. Crit Rev Oncol Hematol 42: 105–121PubMedCrossRefGoogle Scholar
  9. 9.
    Wilson S, Jones L, Coussens C, Hanna K (2002) Cancer and the Environment: Gene-Environment Interaction. National Academy Press, Washington D.C.Google Scholar
  10. 10.
    Cogliano VJ, Baan RA, Straif K, Grosse Y, Secretan B, El Ghissassi F (2008) Use of mechanistic data in IARC evaluations. Environ Mol Mutag 49: 100–109CrossRefGoogle Scholar
  11. 11.
    Luch A (2006) The mode of action of organic carcinogens on cellular structures. EXS 96: 65–95PubMedGoogle Scholar
  12. 12.
    van Delft JHM, van Agen E, van Breda SGJ, Herwijnen MH, Staal YCM, Kleinjans JCS (2004) Discrimination of genotoxic from non-genotoxic carcinogens by gene expression profiling. Carcinogenesis 25: 1265–1276PubMedCrossRefGoogle Scholar
  13. 13.
    Cook JW, Hewett CL, Hieger I (1933) The isolation of a cancer-producing hydrocarbon from coal tar. J Chem Soc 395–405Google Scholar
  14. 14.
    Cook JW, Haslewood GAD, Hewett CL, Hieger I, Kennaway EL, Mayneord WV (1937) Chemical compounds as carcinogenic agents. Am J Cancer 29: 219–259Google Scholar
  15. 15.
    Phillips DH (1983) Fifty years of benzo[a]pyrene. Nature 303: 468–472PubMedCrossRefGoogle Scholar
  16. 16.
    Bachmann WE, Cook JW, Dansi A, De Worms CGM, Haslewood GAD, Hewett CL, Robinson AM (1937) Production of cancer by pure hydrocarbons. IV. Proc R Soc (Lond) B 123: 343–368CrossRefGoogle Scholar
  17. 17.
    Wynder EL, Wright G (1957) A study of tobacco carcinogenesis. Cancer 10: 255–271PubMedCrossRefGoogle Scholar
  18. 18.
    Orris L, van Duuren BL, Kosak AI, Nelson N, Schmitt FL (1958) The carcinogenicity for mouse skin and the aromatic hydrocarbon content of cigarette-smoke condensates. J Natl Cancer Inst 21: 557–561PubMedGoogle Scholar
  19. 19.
    Wynder EL, Hoffmann D (1961) Carcinogenicity of dibenzo[a,l]pyrene. Nature 192: 1092–1093PubMedCrossRefGoogle Scholar
  20. 20.
    Lacassagne A, Buu-Hoï NP, Zajadela F, Lavit-Lamy D (1963) Activité cancérogéne élevée du 1.2: 3.4-dibenzopyréne et 1.2:4.5-dibenzopyrène. Compt Rend Acad Sci Paris 256: 2728–2730Google Scholar
  21. 21.
    Hoffmann D, Wynder EL (1966) Beitrag zur carcinogenen Wirkung von Dibenzpyrenen. Z Krebsforsch 68: 137–149PubMedCrossRefGoogle Scholar
  22. 22.
    Vingiello FA, Yanez F, Greenwood EJ (1966) The synthesis of dibenzo[a,l]pyrene. J Chem Soc Chem Commun 863–864Google Scholar
  23. 23.
    Vingiello FA, Youssef AK (1967) The isomerization of 12-phenylbenz[a]anthracene. J Chem Soc Chem Commun 863–864Google Scholar
  24. 24.
    Carruthers W (1966) Synthesis of dibenzo[a,l]pyrene. J Chem Soc Chem Commun 548–549Google Scholar
  25. 25.
    Lacassagne A, Buu-Hoï NP, Zajdela F, Vingiello FA (1968) The true dibenzo[a,l]pyrene, a new, potent carcinogen. Naturwissenschaften 55: 43PubMedCrossRefGoogle Scholar
  26. 26.
    Masuda Y, Kagawa R (1972) A novel synthesis and carcinogenicity of dibenzo[a,l]pyrene. Chem Pharm Bull 20: 2736–2737PubMedGoogle Scholar
  27. 27.
    Cavalieri EL, Rogan EG, Higginbotham S, Cremonesi P, Salmasi S (1989) Tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland of dibenzo[a]pyrenes: The very potent environmental carcinogen dibenzo[a,l]pyrene. J Cancer Res Clin Oncol 115: 67–72PubMedCrossRefGoogle Scholar
  28. 28.
    Cavalieri EL, Higginbotham S, RamaKrishna NVS, Devanesan PD, Todorovic R, Rogan EG, Salmasi S (1991) Comparative dose-response tumorigenicity studies of dibenzo[a,l]pyrene versus 7,12-dimethylbenz[a]anthracene, benzo[a]pyrene and two dibenzo[a,l]pyrene dihydrodiols in mouse skin and rat mammary gland. Carcinogenesis 12: 1939–1944PubMedCrossRefGoogle Scholar
  29. 29.
    LaVoie EJ, He ZM, Meegalla RL, Weyand EH (1993) Exceptional tumor-initiating activity of 4-fluorobenzo[j]fluoranthene on mouse skin: Comparison with benzo[j]fluoranthene, 10-fluorobenzo[ j]fluoranthene, benzo[a]pyrene, dibenzo[a,l]pyrene and 7,12-dimethylbenz[a]anthracene. Cancer Lett 70: 7–14PubMedCrossRefGoogle Scholar
  30. 30.
    Higginbotham S, RamaKrishna NVS, Johansson SL, Rogan RG, Cavalieri EL (1993) Tumor-initiating activity and carcinogenicity of dibenzo[a,l]pyrene versus 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene at low doses in mouse skin. Carcinogenesis 14: 875–878PubMedCrossRefGoogle Scholar
  31. 31.
    Swauger JE, Steichen TJ, Murphy PA, Kinsler S (2002) An analysis of the mainstream smoke chemistry of samples of the U.S. cigarette market acquired between 1995 and 2000. Regul Toxicol Pharmacol 35: 142–156PubMedCrossRefGoogle Scholar
  32. 32.
    Rodgman A (2003) The composition of cigarette smoke: Problems with lists of tumorigens. Beitr Tabakforsch Int 20: 402–437Google Scholar
  33. 33.
    Seidel A, Frank H, Behnke A, Schneider D, Jacob J (2004) Determination of dibenzo[a,l]pyrene and other fjord-region PAH isomers with MW 302 in environmental matrices. Polycyclic Aromat Compd 24: 759–771CrossRefGoogle Scholar
  34. 34.
    Mumford JL, Harris DB,Williams K, Chuang JC, Cooke M (1987) Indoor air sampling and mutagenicity studies of emissions from unvented coal combustion. Environ Sci Technol 21: 308–311CrossRefGoogle Scholar
  35. 35.
    Mumford JL, Xueming L, Fuding H, Xu BL, Chuang JC (1995) Human exposure and dosimetry of polycyclic aromatic hydrocarbons in urine from Xuan Wei, China with high lung cancer mortality associated with exposure to unvented coal smoke. Carcinogenesis 16: 3031–3036PubMedCrossRefGoogle Scholar
  36. 36.
    Kozin IS, Gooijer C, Velthorst NH (1995) Direct determination of dibenzo[a,l]pyrene in crude extracts of environmental samples by laser excited Shpol’skii spectroscopy. Anal Chem 67: 1623–1626CrossRefGoogle Scholar
  37. 37.
    Luch A, Baird WM (2005) Metabolic activation of polycylic aromatic hydrocarbons. In: A Luch (ed.): The Carcinogenic Effects of Polycyclic Aromatic Hydrocarbons. Imperial College Press, London, 19–96Google Scholar
  38. 38.
    Brown CM, Reisfeld B, Mayeno AN (2008) Cytochromes P450: A structure-based summary of biotransformation using representative substrates. Drug Metab Rev 40: 1–100PubMedCrossRefGoogle Scholar
  39. 39.
    Shimada T, Fujii-Kuriyama Y (2004) Metabolic activation of polycyclic aromatic hydrocarbons to carcinogens by cytochromes P450 1A1 and 1B1. Cancer Sci 95: 1–6PubMedCrossRefGoogle Scholar
  40. 40.
    Shimada T (2006) Xenobiotic-metabolizing enzymes involved in activation and detoxification of carcinogenic polycyclic aromatic hydrocarbons. Drug Metab Pharmacokinet 21: 257–276PubMedCrossRefGoogle Scholar
  41. 41.
    Nebert DW, Dalton TP, Okey AB, Gonzalez FJ (2004) Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J Biol Chem 279: 23847–23850PubMedCrossRefGoogle Scholar
  42. 42.
    Nebert DW, Roe AL, Dieter MZ, Solis WA,Yang Y, Dalton TP (2000) Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control and apoptosis. Biochem Pharmacol 59: 65–85PubMedCrossRefGoogle Scholar
  43. 43.
    Marston CP, Pereira C, Ferguson J, Fischer K, Hedstrom O, Dashwood WM, Baird WM (2001) Effect of a complex environmental mixture from coal tar containing polycyclic aromatic hydrocarbons (PAH) on the tumor initiation, PAH-DNA binding and metabolic activation of carcinogenic PAH in mouse epidermis. Carcinogenesis 22: 1077–1086PubMedCrossRefGoogle Scholar
  44. 44.
    Mahadevan B, Marston CP, Dashwood WM, Li Y, Pereira C, Baird WM (2005) Effect of a standardized complex mixture derived from coal tar on the metabolic activation of carcinogenic polycyclic aromatic hydrocarbons in human cells in culture. Chem Res Toxicol 18: 224–231PubMedCrossRefGoogle Scholar
  45. 45.
    Katz AK, Carrell HL, Glusker JP (1998) Dibenzo[a,l]pyrene (dibenzo[def,p]chrysene): Fjordregion distortions. Carcinogenesis 19: 1641–1648PubMedCrossRefGoogle Scholar
  46. 46.
    Sims P, Grover PL, Swaisland A, Pal K, Hewer A (1974) Metabolic activation of benzo[a]pyrene proceeds by a diol-epoxide. Nature 252: 326–328PubMedCrossRefGoogle Scholar
  47. 47.
    Yagi H, Thakker DR, Hernandez O, Koreeda M, Jerina DM (1977) Synthesis and reactions of the highly mutagenic 7,8-diol 9,10-epoxides of the carcinogen benzo[a]pyrene. J Am Chem Soc 99: 1604–1611PubMedCrossRefGoogle Scholar
  48. 48.
    Morisseau C, Hammock BD (2005) Epoxide hydrolases: Mechanisms, inhibitor designs, and biological roles. Annu Rev Pharmacol Toxicol 45: 311–333PubMedCrossRefGoogle Scholar
  49. 49.
    Shimada T, Oda Y, Gillam EMJ, Guengerich FP, Inoue K (2001) Metabolic activation of polycyclic aromatic hydrocarbons and their dihydrodiol derivatives and other procarcinogens by cytochrome P450 1A1 and 1B1 allelic variants and other human cytochrome P450 enzymes in Salmonella typhimurium NM2009. Drug Metab Dispos 29: 1176–1182PubMedGoogle Scholar
  50. 50.
    Yang SK, McCourt DW, Roller PP, Gelboin HV (1976) Enzymatic conversion of benzo[a]pyrene leading predominantly to the diol-epoxide r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[ a]pyrene through a single enantiomer of r-7,t-8-dihydroxy-7,8-dihydrobenzo[a]pyrene. Proc Natl Acad Sci USA 73: 2594–2598PubMedCrossRefGoogle Scholar
  51. 51.
    Yang SK, McCourt DW, Leutz JC, Gelboin HV (1977) Benzo[a]pyrene diol epoxides: Mechanisms of enzymatic formation and optically active intermediates. Science 196: 1199–1201PubMedCrossRefGoogle Scholar
  52. 52.
    Wood AW, Chang RL, Levin W,Yagi H, Thakker DR, Jerina DM, Conney AH (1977) Differences in mutagenicity of the optical enantiomers of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides. Biochem Biophys Res Commun 77: 1389–1396PubMedCrossRefGoogle Scholar
  53. 53.
    Buening MK, Wislocki PG, Levin W, Yagi H, Thakker DR, Akagi H, Kooreda M, Jerina DM, Conney AH (1978) Tumorigenicity of the optical enantiomers of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides in newborn mice: Exceptional activity of (+)-7b,8a-dihydroxy-9a,10a-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. Proc Natl Acad Sci USA 75: 5358–5361PubMedCrossRefGoogle Scholar
  54. 54.
    Thakker DR, Levin W, Yagi H, Wood AW, Conney AH, Jerina DM (1988) Stereoselective biotransformation of polycyclic aromatic hydrocarbons to ultimate carcinogens. In: AW Wainer, D Dryer (eds): Stereochemical Aspects of Pharmacologically Active Compounds. Marcel Dekker, New York, 217–296Google Scholar
  55. 55.
    Yang SK (1988) Stereoselectivity of cytochrome P-450 isozymes and epoxide hydrolase in the metabolism of polycyclic aromatic hydrocarbons. Biochem Pharmacol 37: 61–70PubMedCrossRefGoogle Scholar
  56. 56.
    Ralston SL, Lau HHS, Seidel A, Luch A, Platt KL, Baird WM (1994) The potent carcinogen dibenzo[a,l]pyrene is metabolically activated to fjord-region 11,12-diol 13,14-epoxides in human mammary carcinoma MCF-7 cell cultures. Cancer Res 54: 887–890PubMedGoogle Scholar
  57. 57.
    Ralston SL, Seidel A, Luch A, Platt KL, Baird WM (1995) Stereoselective activation of dibenzo[ a,l]pyrene to (-)-anti-(11R,12S,13S,14R)-and (+)-syn-(11S,12R,13S,14R)-11,12-diol-13,14-epoxides which bind extensively to deoxyadenosine residues of DNA in the human mammary carcinoma cell line MCF-7. Carcinogenesis 16: 2899–2907PubMedCrossRefGoogle Scholar
  58. 58.
    Devanesan PD, Cremonesi P, Nunnally JE, Rogan EG, Cavalieri EL (1990) Metabolism and mutagenicity of dibenzo[a,e]pyrene and the very potent environmental carcinogen dibenzo[a,l]pyrene. Chem Res Toxicol 3: 580–586PubMedCrossRefGoogle Scholar
  59. 59.
    Li KM, Todorovic R, Rogan EG, Cavalieri EL, Ariese F, Suh M, Jankowiak R, Small GJ (1995) Identification and quantitation of dibenzo[a,l]pyrene-DNA adducts formed by rat liver microsomes in vitro: Preponderance of depurinating adducts. Biochemistry 34: 8043–8049PubMedCrossRefGoogle Scholar
  60. 60.
    Arif JM, Gupta RC (1997) Microsome-mediated bioactivation of dibenzo[a,l]pyrene and identification of DNA adducts by 32P-postlabeling. Carcinogenesis 18: 1999–2007PubMedCrossRefGoogle Scholar
  61. 61.
    Shou M, Korzekwa KR, Crespi CL, Gonzalez FJ, Gelboin HV (1994) The role of 12 cDNAexpressed human, rodent, and rabbit cytochromes P450 in the metabolism of benzo[a]pyrene and benzo[a]pyrene trans-7,8-dihydrodiol. Mol Carcinog 10: 159–168PubMedCrossRefGoogle Scholar
  62. 62.
    Bauer E, Guo Z, Ueng YF, Bell LC, Zeldin D, Guengerich FP (1995) Oxidation of benzo[a]pyrene by recombinant human cytochrome P450 enzymes. Chem Res Toxicol 8: 136–142PubMedCrossRefGoogle Scholar
  63. 63.
    Shou M, Krausz KW, Gonzalez FJ, Gelboin HV (1996) Metabolic activation of the potent carcinogen dibenzo[a,l]pyrene by human recombinant cytochromes P450, lung and liver microsomes. Carcinogenesis 17: 2429–2433PubMedCrossRefGoogle Scholar
  64. 64.
    Luch A, Schober W, Soballa VJ, Raab G, Greim H, Jacob J, Doehmer J, Seidel A (1999) Metabolic activation of dibenzo[a,l]pyrene by human cytochrome P450 1A1 and 1B1 expressed in V79 Chinese hamster cells. Chem Res Toxicol 12: 353–364PubMedCrossRefGoogle Scholar
  65. 65.
    King LC, Adams L, Allison F, Kohan MJ, Nelson G, Desai D, Amin S, Ross JA (1999) A quantitative comparison of dibenzo[a,l]pyrene DNA adduct formation by recombinant human cytochrome P450 microsomes. Mol Carcinog 26: 74–82PubMedCrossRefGoogle Scholar
  66. 66.
    Schober W, Luch A, Soballa VJ, Raab G, Stegeman JJ, Doehmer F, Jacob F, Seidel A (2006) On the species-specific biotransformation of dibenzo[a,l]pyrene. Chem Biol Interact 161: 37–48PubMedCrossRefGoogle Scholar
  67. 67.
    Phillips DH, Glatt HR, Seidel A, Bochnitschek W, Oesch F, Grover PL (1986) Mutagenic potential and DNA adducts formed by diol-epoxides, triol-epoxides and K-region epoxide of chrysene in mammalian cells. Carcinogenesis 7: 1739–1743PubMedCrossRefGoogle Scholar
  68. 68.
    Phillips DH, Hewer A, Seidel A, Steinbrecher T, Schrode R, Oesch F, Glatt HR (1991) Relationship between mutagenicity and DNA adduct formation in mammalian cells for fjordregion and bay-region diol-epoxides of polycyclic aromatic hydrocarbons. Chem Biol Interact 80: 177–186PubMedCrossRefGoogle Scholar
  69. 69.
    Glatt H, Piée A, Pauly K, Steinbrecher T, Schrode R, Oesch F, Seidel A (1991) Fjord-and bayregion diol-epoxides investigated for stability, SOS induction in Escherichia coli and mutagenicity in Salmonella typhimurium and mammalian cells. Cancer Res 51: 1659–1667PubMedGoogle Scholar
  70. 70.
    Hughes NC, Phillips DH (1990) Covalent binding of dibenzpyrenes and benzo[a]pyrene to DNA: Evidence for synergistic and inhibitory interactions when applied in combination to mouse skin. Carcinogenesis 11: 1611–1619PubMedCrossRefGoogle Scholar
  71. 71.
    Ross JA, Nelson GB, Wilson KH, Rabinowitz JR, Galati A, Stoner GD, Nesnow S, Mass MJ (1995) Adenomas induced by polycyclic aromatic hydrocarbons in strain A/J mouse lung correlate with time-integrated DNA adduct levels. Cancer Res 55: 1039–1044PubMedGoogle Scholar
  72. 72.
    Prahalad AK, Ross JA, Nelson GB, Roop BC, King LC, Nesnow S, Mass MJ (1997) Dibenzo[a,l]pyrene-induced DNA adduction, tumorigenicity, and Ki-ras oncogene mutations in strain A/J mouse lung. Carcinogenesis 18: 1955–1963PubMedCrossRefGoogle Scholar
  73. 73.
    Arif JM, Smith WA, Gupta RC (1997) Tissue distribution of DNA adducts in rats treated by intramammillary injection with dibenzo[a,l]pyrene, 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene. Mutat Res 378: 31–39PubMedGoogle Scholar
  74. 74.
    Gill HS, Kole PL, Wiley JC, Li KM, Higginbotham S, Rogan EG, Cavalieri EL (1994) Synthesis and tumor-initiating activity in mouse skin of dibenzo[a,l]pyrene syn-and anti-fjord-region diolepoxides. Carcinogenesis 15: 2455–2460PubMedCrossRefGoogle Scholar
  75. 75.
    Amin S, Krzeminski J, Rivenson A, Kurtzke C, Hecht SS, El-Bayoumy K (1995) Mammary carcinogenicity in female CD rats of fjord region diol epoxides of benzo[c]phenanthrene, benzo[g]chrysene and dibenzo[a,l]pyrene. Carcinogenesis 16: 1971–1974PubMedCrossRefGoogle Scholar
  76. 76.
    Amin S, Desai D, Dai W, Harvey RG, Hecht SS (1995) Tumorigenicity in newborn mice of fjord region and other sterically hindered diol epoxides of benzo[g]chrysene, dibenzo[a,l]pyrene (dibenzo[def,p]chrysene), 4H-cyclopenta[def]chrysene and fluoranthene. Carcinogenesis 16: 2813–2817PubMedCrossRefGoogle Scholar
  77. 77.
    Poirier MC (2004) Chemical-induced DNA damage and human cancer risk. Nat Rev Cancer 4: 630–637PubMedCrossRefGoogle Scholar
  78. 78.
    Xue W, Warshawsky D (2005) Metabolic activation of polycyclic and heterocyclic aromatic hydrocarbons and DNA damage: A review. Toxicol Appl Pharmacol 206: 73–93PubMedCrossRefGoogle Scholar
  79. 79.
    Koreeda M, Moore PD, Wislocki PG, Levin W, Conney AH, Yagi H, Jerina DM (1978) Binding of benzo[a]pyrene 7,8-diol 9,10-epoxides to DNA, RNA, and protein of mouse skin occurs with high stereoselectivity. Science 199: 778–781PubMedCrossRefGoogle Scholar
  80. 80.
    Melendez-Colon VJ, Luch A, Seidel A, Baird WM (1999) Cancer initiation by polycyclic aromatic hydrocarbons results from formation of stable DNA adducts rather than apurinic sites. Carcinogenesis 20: 1885–1891PubMedCrossRefGoogle Scholar
  81. 81.
    Melendez-Colon VJ, Luch A, Seidel A, Baird WM (2000) Formation of stable DNA adducts and apurinic sites upon metabolic activation of bay and fjord region polycyclic aromatic hydrocarbons in human cell cultures. Chem Res Toxicol 13: 10–17PubMedCrossRefGoogle Scholar
  82. 82.
    Mahadevan B, Luch A, Bravo CF, Atkin J, Steppan LB, Pereira C, Kerkvliet NI, Baird WM (2005) Dibenzo[a,l]pyrene induced DNA adduct formation in lung tissue in vivo. Cancer Lett 227: 25–32PubMedCrossRefGoogle Scholar
  83. 83.
    Szeliga J, Dipple A (1998) DNA adduct formation by polycyclic aromatic hydrocarbon dihydrodiol epoxides. Chem Res Toxicol 11: 1–11PubMedCrossRefGoogle Scholar
  84. 84.
    Roberts KP, Lin CH, Jankowiak R, Small GJ (1999) On-line identification of diastereomeric dibenzo[a,l]pyrene diol epoxide-derived deoxyadenosine adducts by capillary electrophoresis-fluorescence line-narrowing and non-line narrowing spectroscopy. J Chromatogr A 853: 159–170PubMedCrossRefGoogle Scholar
  85. 85.
    Jankowiak R, Lin CH, Zamzow D, Roberts KP, Li KM, Small GJ (1999) Spectral and conformational analysis of deoxyadenosine adducts derived from syn-and anti-dibenzo[a,l]pyrene diol epoxides: Fluorescence studies. Chem Res Toxicol 12: 768–777PubMedCrossRefGoogle Scholar
  86. 86.
    Luch A, Glatt HR, Platt KL, Oesch F, Seidel A (1994) Synthesis and mutagenicity of the diastereomeric fjord-region 11,12-dihydrodiol 13,14-epoxides of dibenzo[a,l]pyrene. Carcinogenesis 15: 2507–2516PubMedCrossRefGoogle Scholar
  87. 87.
    Seidel A, Friedberg T, Löllmann B, Schwierzok A, Funk M, Frank H, Holler R, Oesch F, Glatt HR (1998) Detoxification of optically active bay-and fjord-region polycyclic aromatic hydrocarbon dihydrodiol epoxides by human glutathione transferase P1-1 expressed in Chinese hamster V79 cells. Carcinogenesis 19: 1975–1981PubMedCrossRefGoogle Scholar
  88. 88.
    Glatt HR (2005) Indicator assays for polycyclic aromatic hydrocarbon-induced genotoxicity. In: A Luch (ed.): The Carcinogenic Effects of Polycyclic Aromatic Hydrocarbons. Imperial College Press, London, 283–314Google Scholar
  89. 89.
    Jerina DM, Sayer JM, Agarwal SK,Yagi H, Levin W,Wood AW, Conney AH, Preuss-Schwarz D, Baird WM, Pigott MA, Dipple A (1986) Reactivity and tumorigenicity of bay-region diol epoxides derived from polycyclic aromatic hydrocarbons. In: JJ Kocsis, DJ Jollow, CM Witmer, JO Nelson, R Snyder (eds): Biological Reactive Intermediates III, Mechanisms of Action in Animal Models and Human Diseases. Plenum Press, New York, 11–30Google Scholar
  90. 90.
    Jankowiak R, Ariese F, Hewer A, Luch A, Zamzow D, Hughes NC, Phillips DH, Seidel A, Platt KL, Oesch F, Small G (1998) Structure, conformations, and repair of DNA adducts from dibenzo[ a,l]pyrene: 32P-postlabeling and fluorescence studies. Chem Res Toxicol 11: 674–685PubMedCrossRefGoogle Scholar
  91. 91.
    Devanesan P, Ariese F, Jankowiak R, Small GJ, Rogan EG, Cavalieri EL (1999) A novel method for the isolation and identification of stable DNA adducts formed by dibenzo[a,l]pyrene and dibenzo[a,l]pyrene 11,12-dihydrodiol 13,14-epoxides in vitro. Chem Res Toxicol 12: 796–801PubMedCrossRefGoogle Scholar
  92. 92.
    Wei SJ, Chang RL, Wong CQ, Bhachech N, Cui XX, Hennig E, Yagi Y, Sayer JM, Jerina DM, Preston BD, Conney AH (1991) Dose-dependent differences in the profile of mutations induced by an ultimate carcinogen from benzo[a]pyrene. Proc Natl Acad Sci USA 88: 11227–11230PubMedCrossRefGoogle Scholar
  93. 93.
    Wei SJ, Chang RJ, Hennig E, Cui XX, Merkler KA, Wong CQ, Yagi H, Jerina DM, Conney AH (1994) Mutagenic selectivity at the HPRT locus in V79 cells: Comparison of mutations caused by bay-region benzo[a]pyrene 7,8-diol-9,10-epoxide enantiomers with high and low carcinogenic activity. Carcinogenesis 15: 1729–1735PubMedCrossRefGoogle Scholar
  94. 94.
    Chakravarti D, Pelling JC, Cavalieri EL, Rogan EG (1995) Relating aromatic hydrocarboninduced DNA adducts and c-Ha-ras mutations in mouse skin papillomas: The role of apurinic sites. Proc Natl Acad Sci USA 92: 10422–10426PubMedCrossRefGoogle Scholar
  95. 95.
    Chakravarti D, Venugopal D, Mailander PC, Meza JL, Higginbotham S, Cavalieri EL, Rogan EG (2008) The role of polycyclic aromatic hydrocarbon-DNA adducts in inducing mutations in mouse skin. Mutat Res 649: 161–178PubMedGoogle Scholar
  96. 96.
    Mahadevan B, Dashwood WM, Luch A, Pecaj A, Doehmer J, Seidel A, Pereira C, Baird WM (2003) Mutations induced by (-)-anti-11R,12S-dihydrodiol 13S,14R-epoxide of dibenzo-[a,l]pyrene in the coding region of the hypoxanthine phosphoribosyltransferase (hprt) gene in Chinese hamster V79 cells. Environ Mol Mutagen 41: 131–139PubMedCrossRefGoogle Scholar
  97. 97.
    Yoon JH, Besaratinia A, Feng Z, Tang MS, Amin S, Luch A, Pfeifer GP (2004) DNA damage, repair, and mutation induction by (+)-syn-and (-)-anti-dibenzo[a,l]pyrene-11,12-diol-13,14-epoxides in mouse cells. Cancer Res 64: 7321–7328PubMedCrossRefGoogle Scholar
  98. 98.
    Conney AH, Chang RL, Cui XX, Schiltz M, Yagi H, Jerina DM, Wei SJ (2001) Dose-dependent differences in the profile of mutations induced by carcinogenic (R,S,S,R) bay-and fjord-region diol epoxides of polycyclic aromatic hydrocarbons. Adv Exp Med Biol 500: 697–707PubMedGoogle Scholar
  99. 99.
    Friedberg EC (2001) How nucleotide excision repair protects against cancer. Nat Rev Cancer 1: 22–33PubMedCrossRefGoogle Scholar
  100. 100.
    Naegeli H, Geacintov NE (2005) Mechanisms of repair of polycylic aromatic hydrocarboninduced DNA damage. In: A Luch (ed.): The Carcinogenic Effects of Polycyclic Aromatic Hydrocarbons. Imperial College Press, London, 211–258Google Scholar
  101. 101.
    Geacintov NE, Broyde S, Buterin T, Naegeli H, Wu M, Yan S, Patel DJ (2002) Thermodynamic and structural factors in the removal of bulky DNA adducts by the nucleotide excision repair machinery. Biopolymers 65: 202–210PubMedCrossRefGoogle Scholar
  102. 102.
    Hess MT, Gunz D, Luneva N, Geacintov NE, Naegeli H (1997) Base pair conformation-dependent excision of benzo[a]pyrene diol epoxide-guanine adducts by human nucleotide excision repair enzymes. Mol Cell Biol 17: 7069–7076PubMedGoogle Scholar
  103. 103.
    Geacintov NE, Cosman M, Hingerty BE, Amin S, Broyde S, Patel DJ (1997) NMR solution structures of stereoisomeric covalent polycyclic aromatic carcinogen-DNA adducts: Principles, patterns, and diversity. Chem Res Toxicol 10: 111–146PubMedCrossRefGoogle Scholar
  104. 104.
    Ross JA, Nesnow S (1999) Polycyclic aromatic hydrocarbons: Correlation between DNA adducts and ras oncogene mutations. Mutat Res 424: 155–166PubMedGoogle Scholar
  105. 105.
    Marshall CJ, Vousden KH, Phillips DH (1984) Activation of c-Ha-ras-1 proto-oncogene by in vitro modification with a chemical carcinogen, benzo[a]pyrene diol-epoxide. Nature 310: 586–589PubMedCrossRefGoogle Scholar
  106. 106.
    Vousden KH, Bos JL, Marshall CJ, Phillips DH (1986) Mutations activating human c-Ha-ras1 protooncogene (HRAS1) induced by chemical carcinogens and depurination. Proc Natl Acad Sci USA 83: 1222–1226PubMedCrossRefGoogle Scholar
  107. 107.
    Balmain A, Pragnell IB (1983) Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene. Nature 303: 72–74PubMedCrossRefGoogle Scholar
  108. 108.
    Buterin T, Hess MT, Luneva N, Geacintov NE, Amin S, Kroth H, Seidel A, Naegeli H (2000) Unrepaired fjord region polycyclic aromatic hydrocarbon-DNA adducts in ras codon 61 mutational hot spots. Cancer Res 60: 1849–1856PubMedGoogle Scholar
  109. 109.
    Lin CH, Huang X, Kolbanovskii A, Hingerty BE, Amin S, Broyde S, Geacintov NE, Patel DJ (2001) Molecular topology of polycyclic aromatic carcinogens determines DNA adduct conformation: A link to tumorigenic activity. J Mol Biol 306: 1059–1080PubMedCrossRefGoogle Scholar
  110. 110.
    Ruan Q, Kolbanovskiy A, Zhuang, P, Chen J, Krzeminski J, Amin S, Geacintov NE (2002) Synthesis and characterization of site-specific and stereoisomeric fjord dibenzo[a,l]pyrene diol epoxide-N6-adenine adducts: Unusual thermal stabilization of modified DNA duplexes. Chem Res Toxicol 15: 249–261PubMedCrossRefGoogle Scholar
  111. 111.
    Geacintov NE, Naegeli H, Dinshaw JP, Broyde S (2005) Structural aspects of polycyclic aromatic carcinogen-damaged DNA and its recognition by NER proteins. In: W Siede, YW Kow, PW Doetsch (eds): DNA Damage Recognition. Taylor and Francis, New YorkGoogle Scholar
  112. 112.
    Bos JL (1989) Ras oncogenes in human cancer: A review. Cancer Res 49: 4682–4689PubMedGoogle Scholar
  113. 113.
    Wei SJ, Chang RL, Merkler KA, Gwynne M, Cui XX, Murthy B, Huang MT, Xie JG, Lu YP, Lou YR, Jerina DM, Conney AH (1999) Dose-dependent mutation profile in the c-Ha-ras proto-oncogene of skin tumors in mice initiated with benzo[a]pyrene. Carcinogenesis 20: 1689–1696PubMedCrossRefGoogle Scholar
  114. 114.
    Chakravarti D, Mailander P, Franzen J, Higginbotham S, Cavalieri EL, Rogan EG (1998) Detection of dibenzo[a,l]pyrene-induced H-ras codon 61 mutant gene in preneoplastic Sencar mouse skin using a new PCR-RFLP method. Oncogene 16: 3203–3210PubMedCrossRefGoogle Scholar
  115. 115.
    Nesnow S, Ross JA, Mass MJ, Stoner GD (1998) Mechanistic relationships between DNA adducts, oncogene mutations, and lung tumorigenesis in strain A mice. Exp Lung Res 24: 395–405PubMedCrossRefGoogle Scholar
  116. 116.
    Kleiner HE, Suryanarayana V, Vulimiri V, Hatten WB, Reed MJ, Nebert DW, Jefcoate CR, DiGiovanni J (2004) Role of cytochrome P4501 family members in the metabolic activation of polycyclic aromatic hydrocarbons in mouse epidermis. Chem Res Toxicol 17: 1667–1674PubMedCrossRefGoogle Scholar
  117. 117.
    Buters JTM, Mahadevan B, Ouintanilla-Martinez L, Gonzalez FJ, Greim H, Baird WM, Luch A (2002) Cytochrome P450 1B1 determines the susceptibility to dibenzo[a,l]pyrene-induced tumor formation. Chem Res Toxicol 15: 1127–1135PubMedCrossRefGoogle Scholar
  118. 118.
    Lau HHS, Baird WM (1991) Separation and characterization of postlabeled DNA adducts of stereoisomers of benzo[a]pyrene-7,8-diol-9,10-epoxide by immobilized boronate chromatography and HPLC analysis. Carcinogenesis 15: 907–915CrossRefGoogle Scholar
  119. 119.
    Mahadevan B, Marston CP, Luch A, Dashwood WM, Brooks E, Pereira C, Doehmer J, Baird WM (2007) Competitive inhibition of carcinogen-activating CYP1A1 and CYP1B1 enzymes by a standardized complex mixture of PAH extracted from coal tar. Int J Cancer 120: 1161–1168PubMedCrossRefGoogle Scholar
  120. 120.
    Nesnow S, Davis C, Nelson G, Ross JA, Allison F, Adams L, King LC (1997) Comparison of the morphological transforming activities of dibenzo[a,l]pyrene and benzo[a]pyrene in C3H10T1/2CL8 cells and characterization of the dibenzo[a,l]pyrene-DNA adducts. Carcinogenesis 18: 1973–1978PubMedCrossRefGoogle Scholar
  121. 121.
    Luch A, Coffing SL, Tang YM, Schneider A, Soballa V, Greim H, Jefcoate CR, Seidel A, Greenlee WF, Baird WM, Doehmer J (1998) Stable expression of human cytochrome P450 1B1 in V79 Chinese hamster cells and metabolically catalyzed DNA adduct formation of dibenzo[a,l]pyrene. Chem Res Toxicol 11: 686–695PubMedCrossRefGoogle Scholar
  122. 122.
    Mahadevan B, Luch A, Seidel A, Pelling JC, Baird WM (2001) Effects of the (-)-anti-11R,12Sdihydrodiol 13S,14R-epoxide of dibenzo[a,l]pyrene on DNA adduct formation and cell cycle arrest in human diploid fibroblasts. Carcinogenesis 22: 161–169PubMedCrossRefGoogle Scholar
  123. 123.
    Sundberg K, Dreij K, Seidel A, Jernström B (2002) Glutathione conjugation and DNA adduct formation of dibenzo[a,l]pyrene and benzo[a]pyrene diol epoxides in V79 cells stably expressing different human glutathione transferases. Chem Res Toxicol 15: 170–179PubMedCrossRefGoogle Scholar
  124. 124.
    Dreij K, Seidel A, Jerström B (2005) Differential removal of DNA adducts derived from anti-diol epoxides of dibenzo[a,l]pyrene and benzo[a]pyrene in human cells. Chem Res Toxicol 18: 655–664PubMedCrossRefGoogle Scholar
  125. 125.
    Luch A, Kudla K, Seidel A, Doehmer J, Greim H, Baird WM (1999) The level of DNA modification by (+)-syn-(11S,12R,13S,14R)-and (-)-anti-(11R,12S,13S,14R)-dihydrodiol epoxides of dibenzo[a,l]pyrene determined the effect on the proteins p53 and p21WAF1 in the human mammary carcinoma cell line MCF-7. Carcinogenesis 20: 859–865PubMedCrossRefGoogle Scholar
  126. 126.
    Sundberg K, Widersten M, Seidel A, Mannervik B, Jernström (1997) Glutathione conjugation of bay-and fjord-region diol epoxides of polycyclic aromatic hydrocarbons by glutathione transOn the impact of the molecule structure in chemical carcinogenesis 179 ferases M1-1 and P1-1. Chem Res Toxicol 10: 1221–1227PubMedCrossRefGoogle Scholar
  127. 127.
    Hu X, Herzog C, Zimniak P, Singh SV (1999) Differential protection against benzo[a] pyrene-7,8-dihydrodiol-9,10-epoxide-induced DNA damage in HepG2 cells stably transfected with allelic variants of pi class human glutathione S-transferase. Cancer Res 59: 2358–2362PubMedGoogle Scholar
  128. 128.
    Kushman ME, Kabler SL, Fleming MH, Ravoori S, Gupta RC, Doehmer J, Morrow CS, Townsend AJ (2007) Expression of human glutathione S-transferase P1 confers resistance to benzo[a]pyrene or benzo[a]pyrene-7,8-dihydrodiol mutagenesis, macromolecular alkylation and formation of stable N2-Gua-BPDE adducts in stably transfected V79MZ cells co-expressing hCYP1A1. Carcinogenesis 28: 207–214PubMedCrossRefGoogle Scholar
  129. 129.
    Kushman ME, Kabler SL, Ahmad S, Doehmer J, Morrow CS, Townsend AJ (2007) Cytotoxicity and mutagenicity of dibenzo[a,l]pyrene and (+)-dibenzo[a,l]pyrene-11,12-dihydrodiol in V79MZ cells co-expressing either hCYP1A1 or hCYP1B1 together with human glutathione S-transferase A1. Mutat Res 624: 80–87PubMedGoogle Scholar
  130. 130.
    Lagerqvist A, Hakansson D, Prochazka G, Lundin C, Dreij K, Segerbäck D, Jernström B, Törnqvist F, Seidel A, Erixon K, Jenssen D (2008) Both replication bypass fidelity and repair efficiency influence the yield of mutations per target dose in intact mammalian cells induced by benzo[a]pyrene-diol-epoxide and dibenzo[a,l]pyrene-diol-epoxide. DNA Rep 7: 1202–1212CrossRefGoogle Scholar
  131. 131.
    Pääjärvi G, Jernström B, Seidel A, Stenius U (2008) Anti-diol epoxide of benzo[a]pyrene induces transient Mdm2 and p53 Ser15 phosphorylation, while anti-diol epoxide of dibenzo[a,l]pyrene induces a nontransient p53 Ser15 phosphorylation. Mol Carinog. 47: 301–309CrossRefGoogle Scholar
  132. 132.
    Bigger CA, Sawicki JT, Blake DM, Raymond LG, Dipple A (1983) Products of binding of 7,12-dimethylbenz[a]anthracene to DNA in mouse skin. Cancer Res 43: 5647–5651PubMedGoogle Scholar
  133. 133.
    Wei D, Maher VM, McCormick JJ (1995) Site-specific rates of excision repair of benzo[a]pyrene diol epoxide adducts in the hypoxanthine phosphoribosyltransferase gene of human fibroblasts: Correlation with mutation spectra. Proc Natl Acad Sci USA 92: 2204–2208PubMedCrossRefGoogle Scholar
  134. 134.
    Luch A, Mahadevan B, Baird WM, Doehmer J, Seidel A, Glatt HR, Greim H, Buters (2002) The role of cytochrome P450 1B1 in dibenzo[a,l]pyrene-induced carcinogenesis. Polycyclic Aromat Compd 22: 781–789CrossRefGoogle Scholar
  135. 135.
    Glatt HR, Pabel U, Muckel E, Meinl W (2002) Activation of polycyclic aromatic compounds by cDNA-expressed phase I and phase II enzymes. Polycyclic Aromat Compd 22: 955–967CrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2009

Authors and Affiliations

  • Andreas Luch
    • 1
  1. 1.German Federal Institute for Risk AssessmentBerlinGermany

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