Skip to main content
SpringerLink
Log in

The mode of action of organic carcinogens on cellular structures

  • Chapter
Cancer: Cell Structures, Carcinogens and Genomic Instability

Part of the book series: Experientia Supplementum ((EXS,volume 96))

Abstract

Most genotoxic organic carcinogens require metabolic activation to exert their detrimental effects. The present review summarizes the mechanisms of how organic carcinogens are bioactivated into DNA-reactive descendants. Beginning with the history of discovery of some important human organic carcinogens, the text guides through the development of the knowledge on their molecular mode of action that has grown over the past decades. Some of the most important molecular mechanisms in chemical carcinogenesis, the role of the enzymes involved in bioactivation, the target gene structures of some ultimate carcinogenic metabolites, and implications for human cancer risk assessment are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Doll R, Peto R (1981) The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst 66: 1191–1308

    CAS  PubMed  Google Scholar 

  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: 78–85

    Article  CAS  PubMed  Google Scholar 

  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: 260–266

    Article  CAS  PubMed  Google Scholar 

  4. National Toxicology Program (2004) 10th Report on Carcinogens. U.S. Department of Health and Human Services, Public Health Service (website: http://ehp.niehs.nih.gov/docs/allpubs.html, accessed October 2004) Research Triangle Park, NC, USA

    Google Scholar 

  5. Hill J (1761) Cautions Against the immoderate Use of Snuff. Founded on the known Qualities of the Tobacco Plant; And the Effects it must produce when this Way taken into the Body: And Enforced by Instances of Persons who have perished miserably of Diseases, occasioned, or rendered incurable by its Use. R. Baldwin and J. Jackso, London

    Google Scholar 

  6. Pott P (1775) Cancer Scroti. In: P Pott (ed.): The Chirurgical Works, Vol. 5, Chirurgical Observations Relative to the Cataract, The Polypus of the Nose, The Cancer of the Scrotum, The Different Kinds of Ruptures, and The Mortification of the Toes and Feet, Hawes, W. Clarke, and R. Collins, London pp 60–68

    Google Scholar 

  7. Volkmann R (1874) Ueber Theer-und Russkrebs. Berl Klin Wochenschr 11: 218

    Google Scholar 

  8. Bell J (1876) Paraffin epithelioma of the scrotum. Edinb Med J 22: 135–137

    Google Scholar 

  9. Rehn L (1895) Blasengeschwülste bei Fuchsin-Arbeitern. Arch Klin Chir 50: 588–600

    Google Scholar 

  10. Leichtenstern O (1898) Ueber Harnblasenentzündung und Harnblasengeschwülste bei Arbeitern in Farbfabriken. Dtsch Med Wochenschr 24: 709–713

    Google Scholar 

  11. Henry SA (1947) Occupational cutaneous cancer attributable to certain chemicals in industry. Br Med Bull 4: 389–401

    CAS  Google Scholar 

  12. Yamagiwa K, Ichikawa K (1915) Experimentelle Studie über die Pathogenese der Epithelialgeschwülste. Mitt Med Fak Kaiserl Univ Tokio 15: 295–344 [English version: J Cancer Res vn3: pp1–29 (1918)]

    Google Scholar 

  13. Fischer B (1906) Die experimentelle Erzeugung atypischer Epithelwucherungen und die Entstehung bösartiger Geschwülste. Münch Med Wochenschr 53: 2041–2047

    Google Scholar 

  14. Bayon H (1912) Epithelial proliferation induced by the injection of gasworks tar. Lancet II: 1579

    Google Scholar 

  15. Bloch B, Dreifuss W (1921) Ueber die experimentelle Erzeugung von Carcinomen mit Lymphdrüsen-und Lungenmetastasen durch Teerbestandteile. Schweiz Med Wochenschr 51: 1033–1037

    Google Scholar 

  16. a) Scott A (1922) On the occupation cancer of the paraffin and oil workers of the Scottish shale oil industry. Br Med J II: 1108–1109; b) Legge TM (1922) Epitheliomatous ulceration in industry. Br Med J II: 1110–1111

    Google Scholar 

  17. Passey RD (1922) Experimental soot cancer. Br Med J II: 1112–1113

    Google Scholar 

  18. Kennaway E, Hieger I (1930) Carcinogenic substances and their fluorescence spectra. Br Med J 1: 1044–1046

    Google Scholar 

  19. Cook JW, Haslewood GAD, Hewett CL, Hieger I, Kennaway EL, Mayneord WV (1937) Chemical compounds as carcinogenic agents. Am J Cancer 29: 219–259

    CAS  Google Scholar 

  20. Tsutsui H (1918) Über das künstlich erzeugte Cancroid bei der Maus. Gann 12: 17–21

    Google Scholar 

  21. Cook JW, Hewett CL, Hieger I (1933) The isolation of a cancer-producing hydrocarbon from coal tar. J Chem Soc 395–405

    Google Scholar 

  22. Berenblum I, Bonser GM (1937) Experimental investigation of’ aniline cancer‚. J Ind Hyg Toxicol 19: 86–92

    CAS  Google Scholar 

  23. Hueper WC, Wiley FH, Wolfe HD, Ranta KE, Leming MF, Blood FR (1938) Experimental production of bladder tumors in dogs by administration of beta-naphthylamine. J Ind Hyg Toxicol 20: 46–84

    CAS  Google Scholar 

  24. Yoshida T (1933) Über die serienweise Verfolgung der Veränderungen der Leber der experimentellen Hepatomerzeugung durch o-Aminoazotoluol. Trans Jap Path Soc 23: 636–638

    Google Scholar 

  25. a) Kinosita R (1936) Researches on the carcinogenesis of the various chemical substances. (In Japanese) Gann 30: 423–426; b) Kinosita R (1940) Studies on the cancerogenic azo and related compounds. Yale J Biol Med 12: 287–300

    Google Scholar 

  26. Wilson RH, DeEds F, Cox AJ Jr, (1941) The toxicity and carcinogenic activity of 2-acetamino-fluorene. Cancer Res 1: 595–608

    CAS  Google Scholar 

  27. Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194: 23–28

    CAS  PubMed  Google Scholar 

  28. Miller EC, Miller JA (1947) The presence and significance of bound amino azodyes in the livers of rats fed p-dimethylaminoazobenzene. Cancer Res 7: 468–480

    CAS  Google Scholar 

  29. Miller EC (1951) Studies on the formation of protein-bound derivatives of 3,4-benzpyrene in the epidermal fraction of mouse skin. Cancer Res 11: 100–108

    CAS  PubMed  Google Scholar 

  30. Miller EC, Miller JA (1952) In vivo combinations between carcinogens and tissue constituents and their possible role in carcinogenesis. Cancer Res 12: 547–556

    CAS  PubMed  Google Scholar 

  31. Wheeler GP, Skipper HE (1957) Studies with mustards. III. In vivo fixation of C14 from nitrogen mustard-C14H3 in nucleic acid fractions of animal tissues. Arch Biochem Biophys 72: 465–475

    CAS  PubMed  Google Scholar 

  32. Brookes P, Lawley PD (1960) The reaction of mustard gas with nucleic acids in vitro and in vivo. Biochem J 77: 478–484

    CAS  Google Scholar 

  33. Magee PN, Farber E (1962) Toxic liver injury and carcinogenesis. Methylation of rat-liver nucleic acids by dimethylnitrosamine in vivo. Biochem J 83: 114–124

    CAS  PubMed  Google Scholar 

  34. Brookes P, Lawley PD (1964) Evidence for the binding of polynuclear aromatic hydrocarbons to the nucleic acid of mouse skin: relation between carcinogenic power of hydrocarbons and their binding to deoxyribonucleic acid. Nature 202: 781–784

    CAS  PubMed  Google Scholar 

  35. Sporn MB, Dingman CW (1966) 2-Acetamidofluorene and 3-methylcholanthrene: differences in binding to rat liver deoxyribonucleic acid in vivo. Nature 210: 531–532

    CAS  PubMed  Google Scholar 

  36. Dingman CW, Sporn MB (1967) The binding of metabolites of aminoazo dyes to rat liver DNA in vivo. Cancer Res 27: 938–944

    CAS  PubMed  Google Scholar 

  37. Ames BN, Durston WE, Yamasaki E, Lee FD (1973) Carcinogens are mutagens: a simple test system combining liver homogenates for activation and bacteria for detection. Proc Natl Acad Sci USA 70: 2281–2285

    CAS  PubMed  Google Scholar 

  38. Wiley FH (1938) The metabolism of ß-naphthylamine J Biol Chem 124: 627–630

    CAS  Google Scholar 

  39. Boyland E, Levi AA, Mawson EH, Roe E (1941) Metabolism of polycyclic compounds. 4. Production of a dihydroxy-1:2:5:6-dibenzanthracene from 1:2:5:6-dibenzanthracene. Biochem J 35: 184–191

    CAS  Google Scholar 

  40. Stevenson ES, Dobriner K, Rhoads CP (1942) The metabolism of dimethylaminoazobenzene (Butter Yellow) in rats. Cancer Res 2: 160–167

    CAS  Google Scholar 

  41. Mueller GC, Miller JA (1948) The metabolism of 4-dimethylaminoazobenzene by rat liver homogenates. J Biol Chem 176: 535–544

    CAS  Google Scholar 

  42. Brodie BB, Axelrod J, Cooper JR, Gaudette L, La Du BN, Mitoma C, Udenfried S (1955) Detoxication of drugs and other foreign compounds by liver microsomes. Science 121: 603–604

    CAS  PubMed  Google Scholar 

  43. Omura T, Sato R (1962) A new cytochrome in liver microsomes. J Biol Chem 237: 1375–1376

    CAS  PubMed  Google Scholar 

  44. Lu AYH, Coon MJ (1968) Role of hemoprotein P-450 in fatty acid ω-hydroxylation in a soluble enzyme system from liver microsomes. J Biol Chem 243: 1331–1332

    CAS  PubMed  Google Scholar 

  45. Nelson DR (2004) Cytochrome P450 gene superfamily: http://drnelson.utmem.edu/cytochrome P450.html (accessed October 2004)

    Google Scholar 

  46. Guengerich FP, Shimada T (1991) Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes. Chem Res Toxicol 4: 391–407

    CAS  PubMed  Google Scholar 

  47. Shimada T, Oda Y, Gillam EMJ, Guengerich FP, Inoue K (2001) Metabolic activation of polycyclic aromatic hydrocarbons and other precarcinogens by cytochromes P450 1A1 and P450 1B1 allelic variants and other human cytochromes P450 in Salmonella typhimurium NM2009. Drug Metab Disp 29: 1176–1182

    CAS  Google Scholar 

  48. Nishimura M, Yaguti H, Yoshitsugu H, Naito S, Satoh T (2003) Tissue distribution of mRNA expression of human cytochrome P450 isoforms assessed by high-sensitivity real-time reverse transcription PCR. Yakugaku Zasshi 123: 369–375

    CAS  PubMed  Google Scholar 

  49. Cramer JW, Miller JA, Miller JC (1960) N-Hydroxylation: a new metabolic reaction observed in the rat with the carcinogen 2-acetylaminofluorene. J Biol Chem 235: 885–888

    CAS  PubMed  Google Scholar 

  50. Miller EC, Miller JA, Hartmann HA (1961) N-Hydroxy-2-acetylaminofluorene: a metabolite of 2-acetylaminofluorene with increased carcinogenic activity in the rat. Cancer Res 21: 815–824

    CAS  PubMed  Google Scholar 

  51. DeBraun JR, Smith JYR, Miller EC, Miller JA (1970) Reactivity in vivo of the carcinogen N-hydroxy-2-acetylaminofluorene: increased by sulfate ion. Science 167: 184–186

    Google Scholar 

  52. Weisburger JH, Yamamoto RS, Williams GM, Grantham PH, Matsushima T, Weisburger EK (1972) On the sulfate ester of N-hydroxy-N-2-fluorenylacetamide as a key ultimate hepatocarcinogen. Cancer Res 32: 491–500

    CAS  PubMed  Google Scholar 

  53. Dipple A (1995) DNA adducts of chemical carcinogens. Carcinogenesis 16: 437–441

    CAS  PubMed  Google Scholar 

  54. Guengerich FP (2002) N-Hydroxyarylamines. Drug Metab Rev 34: 607–623

    CAS  PubMed  Google Scholar 

  55. Booth J, Boyland E, Sims P (1961) An enzyme from rat liver catalysing conjugations with glutathione. Biochem J 79: 516–524

    Google Scholar 

  56. a) Barnes MM, James SP, Wood PB (1959) The formation of mercapturic acids. 1. Formation of mercapturic acid and the levels of glutathione in tissues. Biochem J 71: 680–690; b) Bray HG, Franklin TJ, James SP (1959) The formation of mercapturic acids. 2. The possible role of glutathionase. Biochem J 71: 690–696; c) Bray HG, Franklin TJ, James SP (1959) The formation of mercapturic acids. 3. N-Acetylation of S-substituted cysteines in the rabbit, rat and guinea pig. Biochem J 73: 465–473

    CAS  PubMed  Google Scholar 

  57. Guengerich FP (2003) Activations of dihaloalkanes by thiol-dependent mechanisms. J Biochem Mol Biol 36: 20–27

    CAS  PubMed  Google Scholar 

  58. Anders MW, Dekant W (1998) Glutathione-dependent bioactivation of haloalkenes. Annu Rev Pharmacol Toxicol 38: 501–537

    Article  CAS  PubMed  Google Scholar 

  59. McGregor DB, Partensky C, Wilbourn J, Rice JM (1998) An IARC evaluation of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans as risk factors in human carcinogenesis. Environ Health Perspect 106,Suppl 2: 755–760

    CAS  PubMed  Google Scholar 

  60. Huff J, Lucier G, Tritscher A (1994) Carcinogenicity of TCDD: experimental, mechanistic, and epidemiologic evidence. Annu Rev Pharmacol Toxicol 34: 343–372

    CAS  PubMed  Google Scholar 

  61. Piskorska-Pliszczynska J, Keys B, Safe S, Newman MS (1986) The cytosolic receptor binding affinities and AHH induction potencies of 29 polynuclear aromatic hydrocarbons. Toxicol Lett 34: 67–74

    Article  CAS  PubMed  Google Scholar 

  62. Conney AH, Miller EC, Miller JA (1957) Substrate-induced synthesis and other properties of benzpyrene hydroxylase in rat liver. J Biol Chem 228: 753–766

    CAS  PubMed  Google Scholar 

  63. Nebert DW, Gelboin HV (1968) Substrate-inducible microsomal aryl hydroxylase in mammalian cell culture. I. Assay and properties of induced enzyme and II. Cellular responses during enzyme induction. J Biol Chem 243: 6242–6261

    CAS  PubMed  Google Scholar 

  64. Poland A, Glover E, Kende AS (1976) Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J Biol Chem 251: 4936–4946

    CAS  PubMed  Google Scholar 

  65. Gu YZ, Hogenesch JB, Bradfield CA (2000) The PAS superfamily: sensors of environmental and developmental signals. Annu Rev Pharmacol Toxicol 40: 519–561

    Article  CAS  PubMed  Google Scholar 

  66. Nebert DW, Puga A, Vasiliou V (1993) Role of the Ah receptor and the dioxin-inducible [Ah] gene battery in toxicity, cancer, and signal transduction. Ann NY Acad Sci 685: 624–640

    CAS  PubMed  Google Scholar 

  67. Gonzalez FJ, Fernandez-Salguero P (1998) The arylhydrocarbon receptor. Studies using the AHRnull mice. Drug Metab Dispos 26: 1194–1198

    CAS  PubMed  Google Scholar 

  68. Fernandez-Salguero PM, Hilbert DM, Rudikoff S, Ward JM, Gonzalez FJ (1996) Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetradibenzo-p-dioxin-induced toxicity. Toxicol Appl Pharmacol 140: 173–179

    Article  CAS  PubMed  Google Scholar 

  69. Andersson P, McGuire J, Rubio C, Gradin K, Whitelaw ML, Pettersson S, Hanberg A, Poellinger L (2002) A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors. Proc Natl Acad Sci USA 99: 9990–9995

    Article  CAS  PubMed  Google Scholar 

  70. Moennikes O, Loeppen S, Buchmann A, Andersson P, Ittrich C, Poellinger L, Schwarz M (2004) A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice. Cancer Res 64: 4707–4710

    Article  CAS  PubMed  Google Scholar 

  71. Mimura J, Fujii-Kuriyama Y (2003) Functional role of AHR in the expression of toxic effects by TCDD. Biochim Biophys Acta 1619: 263–268

    CAS  PubMed  Google Scholar 

  72. Puga A, Maier A, Medvedovic M (2000) The transcriptional signature of dioxin in human hepatoma HepG2 cells. Biochem Pharmacol 60: 1129–1142

    Article  CAS  PubMed  Google Scholar 

  73. Frueh FW, Hayashibara KC, Brown PO, Whitlock JP Jr, (2001) Use of cDNA microarrays to analyze dioxin-induced changes in human liver gene expression. Toxicol Lett 122: 189–203

    Article  CAS  PubMed  Google Scholar 

  74. Carlson DB, Perdew GH (2002) A dynamic role for the Ah receptor in cell signaling? Insights from a diverse group of Ah receptor interacting proteins. J Biochem Mol Toxicol 16: 317–325

    Article  CAS  PubMed  Google Scholar 

  75. Enan E, Matsumura F (1996) 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. Biochem Pharmacol 52: 1599–1612

    Article  CAS  PubMed  Google Scholar 

  76. Johnson CD, Balagurunathan Y, Tadesse MG, Falahatpisheh MH, Brun M, Walker MK, Dougherty ER, Ramos KS (2004) Unraveling gene-gene interactions regulated by ligands of the aryl hydrocarbon receptor. Environ Health Perspect 112: 403–412

    CAS  PubMed  Google Scholar 

  77. Boyland E, Levi AA (1935) Metabolism of polycyclic compounds. I. Production of dihydroxydihydroanthracene from anthracene. Biochem J 29: 2679–2683

    CAS  Google Scholar 

  78. a) Boyland E, Sims P (1960) Metabolism of polycyclic compounds. 16. The metabolism of 1:2-dihydronaphthalene and 1:2-epoxy-1:2:3:4-tetrahydronaphthalene. Biochem J 77: 175–181; b) Booth J, Boyland E, Sato T, Sims P (1960) Metabolism of polycyclic compounds. 17. The reaction of 1:2-dihydronaphthalene and 1:2-epoxy-1:2:3:4-tetrahydronaphthalene with glutathione catalysed by tissue preparations. Biochem J 77: 182–186

    CAS  Google Scholar 

  79. Sims P, Grover PL, Swaisland A, Pal K, Hewer A (1974) Metabolic activation of benzo[a]pyrene proceeds by a diol-epoxide. Nature 252: 326–328

    Article  CAS  PubMed  Google Scholar 

  80. Luch A, Baird WM (2005) Metabolic activation of polycyclic aromatic hydrocarbons. In: A Luch (ed.): The Carcinogenic Effects of Polycyclic Aromatic Hydrocarbons. Imperial College Press, London, 19–96

    Google Scholar 

  81. Shimizu Y, Nakatsuru Y, Ichinose M, Takahashi Y, Kume H, Mimura J, Fujii-Kuriyama Y, Ishikawa T (2000) Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proc Natl Acad Sci USA 97: 779–782

    CAS  PubMed  Google Scholar 

  82. Gonzalez FJ (2001) The use of gene knockout mice to unravel the mechanisms of toxicity and chemical carcinogenesis. Toxicol Lett 120: 199–208

    Article  CAS  PubMed  Google Scholar 

  83. Nakatsuru Y, Wakabayashi K, Fujii-Kuriyama Y, Ishikawa T, Kusama K, Ide F (2004) Dibenzo[a,l]pyrene-induced genotoxic and carcinogenic responses are dramatically suppressed in aryl hydrocarbon receptor-deficient mice. Int J Cancer 112: 179–183

    Article  CAS  PubMed  Google Scholar 

  84. Berenblum I, Shubik P (1947) A new, quantitative, approach to the study of the stages of chemical carcinogenesis in the mouse’s skin. Br J Cancer 1: 383–391

    Google Scholar 

  85. Luch A (2005) Polycyclic aromatic hydrocarbon-induced carcinogenesis — an introduction. In: A Luch (ed.): The Carcinogenic Effects of Polycyclic Aromatic Hydrocarbons. Imperial College Press, London, 1–18

    Google Scholar 

  86. Friedewald WF, Rous P (1944) The initiating and promoting elements in tumor production. An analysis of the effects of tar, benzpyrene, and methylcholanthrene on rabbit skin. J Exp Med 80: 101–126

    CAS  Google Scholar 

  87. Balmain A, Pragnell IB (1983) Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene. Nature 303: 72–74

    Article  CAS  PubMed  Google Scholar 

  88. Robles AI, Rodriquez-Puebla ML, Glick AB, Trempus C, Hansen L, Sicinski P, Tennant RW, Weinberg RA, Yuspa SH, Conti CJ (1998) Reduced skin tumor development in cyclin D1-deficient mice highlights the oncogenic ras pathway in vivo. Genes Dev 12: 2469–2474

    CAS  PubMed  Google Scholar 

  89. Campbell SL, Khosravi-Far R, Rossman KL, Clark GJ, Der CJ (1998) Increasing complexity of Ras signaling. Oncogene 17: 1395–1413

    Article  CAS  PubMed  Google Scholar 

  90. Freudenthal RI, Stephens E, Anderson DP (1999) Determining the potential of aromatic amines to induce cancer in the urinary bladder. Int J Toxicol 18: 353–359

    CAS  Google Scholar 

  91. Tsuneoka Y, Dalton TP, Miller ML, Clay CD, Shertzer HG, Talaska G, Medvedovic M, Nebert DW (2003) 4-Aminobiphenyl-induced liver and urinary bladder DNA adduct formation in Cyp1a2(-/-) and Cyp1a2(+/+) mice. J Natl Cancer Inst 95: 1227–1237

    CAS  PubMed  Google Scholar 

  92. Beland FA, Kadlubar FF (1985) Formation and persistance of arylamine DNA adducts in vivo. Environ Health Perspect 62: 19–33

    CAS  PubMed  Google Scholar 

  93. Neumann HG, Ambs S, Bitsch A (1994) The role of nongenotoxic mechanisms in arylamine carcinogenesis. Environ Health Perspect 102,Suppl 6: 173–176

    CAS  PubMed  Google Scholar 

  94. Klöhn PC, Soriano ME, Irwin W, Penzo D, Scorrano L, Bitsch A, Neumann HG, Bernardi P (2003) Early resistance to cell death and to onset of the mitochondrial permeability transition during hepatocarcinogenesis with 2-acetylaminofluorene. Proc Natl Acad Sci USA 100: 10014–10019

    PubMed  Google Scholar 

  95. 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: 1265–1276

    PubMed  Google Scholar 

  96. Skorski T (2002) Oncogenic tyrosine kinases and the DNA-damage response. Nat Rev Cancer 2: 351–360

    Article  CAS  PubMed  Google Scholar 

  97. Bombail V, Moggs JG, Orphanides G (2004) Perturbation of epigenetic status by toxicants. Toxicol Lett 149: 51–58

    Article  CAS  PubMed  Google Scholar 

  98. Newbold RR (2004) Lessons learned from perinatal exposure to diethylstilbestrol. Toxicol Appl Pharmacol 199: 142–150

    Article  CAS  PubMed  Google Scholar 

  99. Herbst AL, Ulfelder H, Poskanzer DC (1971) Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young woman. N Engl J Med 284: 878–881

    CAS  PubMed  Google Scholar 

  100. Miller KP, Borgeest C, Greenfield C, Tomic D, Flaws JA (2004) In utero effects of chemicals on reproductive tissues in females. Toxicol Appl Pharmacol 198: 111–131

    CAS  PubMed  Google Scholar 

  101. Li S, Hursting SD, Davis BJ, McLachlan JA, Barrett JC (2003) Environmental exposure, DNA methylation, and gene regulation. Lessons from diethylstilbestrol-induced cancers. Ann NY Acad Sci 983: 161–169

    CAS  PubMed  Google Scholar 

  102. Li S, Washburn KA, Moore R, Uno T, Teng C, Newbold RR, McLachlan JA, Negishi M (1997) Developmental exposure to diethylstilbestrol elicits demethylation of estrogen-responsive lactoferrin gene in mouse uterus. Cancer Res 57: 4356–4359

    CAS  PubMed  Google Scholar 

  103. Li S, Hansman R, Newbold R, Davis B, McLachlan JA, Barrett JC (2003) Neonatal diethylstilbestrol exposure induces persistent elevation of c-fos expression and hypomethylation in its exon-4 in mouse uterus. Mol Carcinog 38: 78–84

    Article  CAS  PubMed  Google Scholar 

  104. Block K, Kardana A, Igarashi P, Taylor HS (2000) In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing mullerian system. FASEB J 14: 1101–1108

    CAS  PubMed  Google Scholar 

  105. Li S, Ma L, Chiang TC, Burow M, Newbold RR, Negishi M, Barrett JC, McLachlan JA (2001) Promotor CpG methylation of Hox-a10 and Hox-a11 in mouse uterus not altered upon neonatal diethylstilbestrol exposure. Mol Carcinog 32: 213–219

    Article  CAS  PubMed  Google Scholar 

  106. Iball J (1939) The relative potency of carcinogenic compounds. Am J Cancer 35: 188–190

    CAS  Google Scholar 

  107. 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, 283–314

    Google Scholar 

  108. 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: 1039–1044

    CAS  PubMed  Google Scholar 

  109. Poirier MC (2004) Chemical-induced DNA damage and human cancer risk. Nat Rev Cancer 4: 630–637

    CAS  PubMed  Google Scholar 

  110. Greim H (2001) Use of covalent binding in risk assessment. Adv Exp Med Biol 500: 715–722

    CAS  PubMed  Google Scholar 

  111. Kensler TW, Qian GS, Chen JG, Groopman JD (2003) Translational strategies for cancer prevention in liver. Nat Rev Cancer 3: 321–329

    Article  CAS  PubMed  Google Scholar 

  112. Baertschi SW, Raney KD, Stone MP, Harris TM (1988) Preparation of the 8,9-epoxide of the mycotoxin aflatoxin B1: the ultimate carcinogenic species. J Am Chem Soc 110: 7929–7931

    Article  CAS  Google Scholar 

  113. Guengerich FP, Johnson WW, Shimada T, Ueng YF, Yamazaki H, Langouët S (1998) Activation and detoxication of aflatoxin B1. Mutat Res 402: 121–128

    CAS  PubMed  Google Scholar 

  114. Iyer RS, Coles BF, Raney KD, Thier R, Guengerich FP, Harris TM (1994) DNA adduction by the potent carcinogen aflatoxin B1: mechanistic studies. J Am Chem Soc 116: 1603–1609

    CAS  Google Scholar 

  115. Guengerich FP (2003) Cytochrome P450 oxidations in the generation of reactive electrophiles: epoxidation and related reactions. Arch Biochem Biophys 409: 59–71

    PubMed  Google Scholar 

  116. 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: 778–780

    CAS  PubMed  Google Scholar 

  117. 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: 202–210

    Article  CAS  PubMed  Google Scholar 

  118. 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: 7069–7076

    CAS  PubMed  Google Scholar 

  119. 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: 111–146

    Article  CAS  PubMed  Google Scholar 

  120. Khan QA, Dipple A (2000) Diverse chemical carcinogens fail to induce G1 arrest in MCF-7 cells. Carcinogenesis 21: 1611–1618

    CAS  PubMed  Google Scholar 

  121. Lehmann AR (2002) Replication of damaged DNA in mammalian cells: new solutions to an old problem. Mutat Res 509: 23–34

    CAS  PubMed  Google Scholar 

  122. Wang A, Gu J, Judson-Kremer K, Powell KL, Mistry H, Simhambhatla P, Aldaz CM, Gaddis S, MacLeod MC (2003) Response of human mammary epithelial cells to DNA damage induced by BPDE: involvement of novel reulatory pathways. Carcinogenesis 24: 225–234

    PubMed  Google Scholar 

  123. Jeffy BD, Chirnomas RB, Chen EJ, Gudas JM, Romagnolo DF (2002) Activation of the aromatic hydrocarbon receptor pathway is not sufficient for transcriptional repression of BRCA-1: requirements for metabolism of benzo[a]pyrene to 7r,8t-dihydroxy-9t,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. Cancer Res 62: 113–121

    CAS  PubMed  Google Scholar 

  124. Narod SA, Foulkes WD (2004) BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 4: 665–676

    Article  CAS  PubMed  Google Scholar 

  125. Ross JA, Nesnow S (1999) Polycyclic aromatic hydrocarbons: correlation between DNA adducts and ras oncogene mutations. Mutat Res 424: 155–166

    CAS  PubMed  Google Scholar 

  126. Bos JL (1989) Ras oncogenes in human cancer: a review. Cancer Res 49: 4682–4689

    CAS  PubMed  Google Scholar 

  127. Feng Z, Hu W, Chen JX, Pao A, Li H, Rom W, Hung MC, Tang MS (2002) Preferential DNA damage and poor repair determine ras gene mutational hotspot in human cancer. J Natl Cancer Inst 94: 1527–1536

    CAS  PubMed  Google Scholar 

  128. Hu W, Feng Z, Tang MS (2003) Preferential carcinogen-DNA adduct formation at codons 12 and 14 in human K-ras gene and their possible mechanisms. Biochemistry 42: 10012–10023

    CAS  PubMed  Google Scholar 

  129. Denissenko MF, Chen JX, Tang MS, Pfeifer GP (1997) Cytosine methylation determines hot spots of DNA damage in the human p53 gene. Proc Natl Acad Sci USA 94: 3893–3898

    Article  CAS  PubMed  Google Scholar 

  130. Chen JX, Zheng Y, West M, Tang MS (1998) Carcinogens preferentially bind at methylated CpG in the p53 mutational hot spots. Cancer Res 58: 2070–2075

    CAS  PubMed  Google Scholar 

  131. Feng Z, Hu W, Rom WN, Beland FA, Tang MS (2002) N-hydroxy-4-aminobiphenyl-DNA binding in human p53 gene: sequence preference and the effect of C5 cytosine methylation. Biochemistry 41: 6414–6421

    CAS  PubMed  Google Scholar 

  132. Feng Z, Hu W, Rom WN, Beland FA, Tang MS (2002) 4-Aminobiphenyl is a major etiological agent of human bladder cancer: evidence from its DNA binding spectrum in human p53 gene. Carcinogenesis 23: 1721–1727

    Article  CAS  PubMed  Google Scholar 

  133. Denissenko MF, Pao A, Tang MS, Pfeifer GP (1996) Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in p53. Science 274: 430–432

    Article  CAS  PubMed  Google Scholar 

  134. Denissenko MF, Pao A, Pfeifer GP, Tang MS (1998) Slow repair of bulky DNA adducts along the nontranscribed strand of the human p53 gene may explain the strand bias of transversion mutations in cancers. Oncogene 16: 1241–1247

    Article  CAS  PubMed  Google Scholar 

  135. Denissenko MF, Koudriakova TB, Smith L, O’Connor TR, Riggs AD, Pfeifer GP (1998) The p53 codon 249 mutational hotspot in hepatocellular carcinoma is not related to selective formation or persistance of aflatoxin B1 adducts. Oncogene 17: 3007–3014

    Article  CAS  PubMed  Google Scholar 

  136. Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC (1991) Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 350: 427–428

    Article  CAS  PubMed  Google Scholar 

  137. Olivier M, Hussain SP, Caron de Fromentel C, Hainaut P, Harris CC (2004) TP53 mutation spectra and load: a tool for generating hypotheses on the etiology of cancer. IARC Sci Publ 157: 247–270

    PubMed  Google Scholar 

  138. Smela ME, Hamm ML, Henderson PT, Harris CM, Harris TM, Essigmann JM (2002) The aflatoxin B1 formamidopyrimidine adduct plays a major role in causing the types of mutations observed in human hepatocellular carcinoma. Proc Natl Acad Sci USA 99: 6655–6660

    Article  CAS  PubMed  Google Scholar 

  139. Zhang YJ, Ahsan H, Chen Y, Lunn RM, Wang LY, Chen SY, Lee PH, Chen CJ, Santella RM (2002) High frequency of promotor hypermethylation of RASSF1A and p16 and its relationship to aflatoxin B1-DNA adduct levels in human hepatocellular carcinomas. Mol Carcinog 35: 85–92

    Article  CAS  PubMed  Google Scholar 

  140. Uno S, Dalton TP, Derkenne S, Curran CP, Miller ML, Shertzer HG, Nebert DW (2004) Oral exposure to benzo[a]pyrene in the mouse: detoxication by inducible cytochrome P450 is more important than metabolic activation. Mol Pharmacol 65: 1225–1237

    Article  CAS  PubMed  Google Scholar 

  141. 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: 23847–23850

    Article  CAS  PubMed  Google Scholar 

  142. Lee ML, Novotny M, Bartle KD (1978) Gas chromatography/mass spectrometry and nuclear magnetic resonance determination of polynuclear aromatic hydrocarbons in airborne particulates. Anal Chem 48: 1566–1572

    Google Scholar 

  143. IARC (2004) Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Volume 83: Tobacco Smoke and Involuntary Smoking. International Agency for Research on Cancer, Lyon, France

    Google Scholar 

  144. Hu W, Feng Z, Tang MS (2004) Nickel (II) enhances benzo[a]pyrene diol epoxide-induced mutagenesis through inhibition of nucleotide excision repair in human cells: a possible mechanism for nickel (II)-induced carcinogenesis. Carcinogenesis 25: 455–462

    Article  CAS  PubMed  Google Scholar 

  145. Schwerdtle T, Walter I, Hartwig A (2003) Arsenite and its biomethylated metabolites interfere with the formation and repair of stable BPDE-induced DNA adducts in human cells and impair XPAzf and Fpg. DNA Repair 2: 1449–1463

    Article  CAS  PubMed  Google Scholar 

  146. Buterin T, Hess MT, Gunz D, Geacintov NE, Mullenders LH, Naegeli H (2002) Trapping of DNA nucleotide excision repair factors by nonrepairable carcinogen adducts. Cancer Res 62: 4229–4235

    CAS  PubMed  Google Scholar 

  147. Lewtas J, DeMarini D, Favor J, Layton D, MacGregor J, Ashby J, Lohman P, Haynes R, Mendelsohn M (1994) Risk characterization strategies for genotoxic environmental agents. In: DJ Brusick (ed.): Methods for Genetic Risk Assessment. Lewis Publishers, Boca Raton, FL, 125–169

    Google Scholar 

  148. Calabrese EJ, Baldwin LA (2002) Applications of hormesis in toxicology, risk assessment and chemotherapeutics. Trends Pharmacol Sci 23: 331–337

    Article  CAS  PubMed  Google Scholar 

  149. Perera FP, Weinstein IB (2000) Molecular epidemiology: recent advances and future directions. Carcinogenesis 21: 517–524

    CAS  PubMed  Google Scholar 

  150. Gonzalez FJ (1997) The role of carcinogen-metabolizing enzyme polymorphism in cancer susceptibility. Reprod Toxicol 11: 397–412

    Article  CAS  PubMed  Google Scholar 

  151. Wormhoudt LW, Commandeur NM, Vermeulen NPE (1999) Genetic polymorphisms of human N-acetyltransferase, cytochrome P450, glutathione-S-transferase, and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity. Crit Rev Toxicol 29: 59–124

    Article  CAS  PubMed  Google Scholar 

  152. Bartsch H, Nair U, Risch A, Rojas M, Wikman H, Alexandrov K (2000) Genetic polymorphism of CYP genes, alone or in combination, as a risk modifier of tobacco-related cancers. Cancer Epidemiol Biomarkers Prev 9: 3–28

    CAS  PubMed  Google Scholar 

  153. Kellermann G, Shaw CR, Luyten-Kellerman M (1973) Aryl hydrocarbon hydroxylase inducibility and bronchogenic carcinoma. N Engl J Med 289: 934–937

    CAS  PubMed  Google Scholar 

  154. Bartsch H, Castegnaro M, Rojas M, Camus AM, Alexandrov K, Lang M (1992) Expression of pulmonary cytochrome P4501A1 and carcinogen DNA adduct formation in high risk subjects for tobacco-related lung cancer. Toxicol Lett 64/65: 477–483

    Article  PubMed  Google Scholar 

  155. Alexandrov K, Rojas M, Geneste O, Castegnaro M, Camus AM, Petruzzelli S, Giuntini C, Bartsch H (1992) An improved fluorometric assay for dosimetry of benzo[a]pyrene diol-epoxide-DNA adducts in smokers’ lung: comparisons with total bulky adducts and aryl hydrocarbon hydroxylase activity. Cancer Res 52: 6248–6253

    CAS  PubMed  Google Scholar 

  156. Smart J, Daly AK (2000) Variation in induced CYP1A1 levels: relationship to CYP1A1, Ah receptor and GSTM1 polymorphisms. Pharmacogenetics 10: 11–24

    Article  CAS  PubMed  Google Scholar 

  157. Phillips DH (2002) Smoking-related DNA and protein adducts in human tissues. Carcinogenesis 23: 1979–2004

    Article  CAS  PubMed  Google Scholar 

  158. Alexandrov K, Cascorbi I, Rojas M, Bouvier G, Kriek E, Bartsch H (2002) CYP1A1 and GSTM1 genotypes affect benzo[a]pyrene DNA adducts in smokers’ lung: comparison with aromatic/hydrophobic adduct formation. Carcinogenesis 23: 1969–1977

    Article  CAS  PubMed  Google Scholar 

  159. Kawajiri K, Eguchi H, Nakachi K, Sekiya T, Yamamoto M (1996) Association of CYP1A1 germ line polymorphisms with mutations of the p53 gene in lung cancer. Cancer Res 56: 72–76

    CAS  PubMed  Google Scholar 

  160. Greenblatt MS, Bennett WP, Hollstein M, Harris CC (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54: 4855–4878

    CAS  PubMed  Google Scholar 

  161. Hecht SS (2003) Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer 3: 733–744

    Article  CAS  PubMed  Google Scholar 

  162. Hecht SS (1998) Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines. Chem Res Toxicol 11: 559–603

    Article  CAS  PubMed  Google Scholar 

  163. Goldman R, Shields PG (2003) Food mutagens. J Nutr 133,Suppl 3: 965–973

    Google Scholar 

  164. Gao WM, Mady HH, Yu GY, Siegfried JM, Luketich JD, Melhem MF, Keohavong P (2003) Comparison of p53 mutations between adenocarcinoma and squamous cell carcinoma of the lung: unique spectra involving G to A transitions and G to T transversions in both histologic types. Lung Cancer 40: 141–150

    Article  PubMed  Google Scholar 

  165. Wu X, Shi H, Hong J, Kemp B, Hong WK, Delclos GL, Spitz MR (1997) Association between cytochrome P4502E1 genotype, mutagen sensitivity, cigarette smoking and susceptibility to lung cancer. Carcinogenesis 18: 967–973

    CAS  PubMed  Google Scholar 

  166. Ko Y, Abel J, Harth V, Bröde P, Anthony C, Donat S, Fischer HP, Ortiz-Pallardo ME, Thier R, Sachinidis A et al. (2001) Association of CYP1B1 codon 432 mutant allele in head and neck squamous cell cancer is reflected by somatic mutations of p53 in tumor tissue. Cancer Res 61: 4398–4404

    CAS  PubMed  Google Scholar 

  167. Lee WJ, Brennan P, Boffetta P, London SJ, Benhamou S, Rannug A, To-Figueras J, Ingelman-Sundberg M, Shields P, Gaspari L, Taioli E (2002) Microsomal epoxide hydrolase polymorphisms and lung cancer risk: a quantitative review. Biomarkers 7: 230–241

    Article  CAS  PubMed  Google Scholar 

  168. Nebert DW, McKinnon RA, Puga A (1996) Human drug-metabolizing enzyme polymorphisms: effects on risk of toxicity and cancer. DNA Cell Biol 15: 273–280

    CAS  PubMed  Google Scholar 

  169. Scheel J, Hussong R, Schrenk D, Schmitz HJ (2002) Variability of the human aryl hydrocarbon receptor nuclear translocator (ARNT) gene. J Hum Genet 47: 217–224

    Article  CAS  PubMed  Google Scholar 

  170. Glatt H, Boeing H, Engelke CEH, Ma L, Kuhlow A, Pabel U, Pomplun D, Teubner W, Meinl W (2001) Human cytosolic sulphotransferases: genetics, characteristics, toxicological aspects. Mutat Res 482: 27–40

    CAS  PubMed  Google Scholar 

  171. Matullo G, Palli D, Peluso M, Guarrera S, Carturan S, Celentano E, Krogh V, Munnia A, Tumino R, Polidoro S et al. (2001) XRCC1, XRCC3, XPD gene polymorphisms, smoking and 32P-DNA adducts in a sample of healthy subjects. Carcinogenesis 22: 1437–1445

    Article  CAS  PubMed  Google Scholar 

  172. Spitz MR, Wei Q, Dong Q, Amos CI, Wu X (2003) Genetic susceptibility to lung cancer: the role of DNA damage and repair. Cancer Epidemiol Biomarkers Prev 12: 689–698

    CAS  PubMed  Google Scholar 

  173. Kiyohara C, Otsu A, Shirakawa T, Fukuda S, Hopkin JM (2002) Genetic polymorphisms and lung cancer susceptibility. Lung Cancer 37: 241–256

    Article  PubMed  Google Scholar 

  174. Kiyohara C, Shirakawa T, Hopkin JM (2002) Genetic polymorphism of enzymes involved in xenobiotic metabolism and the risk of lung cancer. Environ Health Prev Med 7: 47–59

    Article  CAS  Google Scholar 

  175. Vineis P (2004) Individual susceptibility to carcinogens. Oncogene 23: 6477–6483

    Article  CAS  PubMed  Google Scholar 

  176. Matullo G, Peluso M, Polidoro S, Guarrera S, Munnia A, Krogh V, Masala G, Berrino F, Panico S, Tumino R et al. (2003) Combination of DNA repair gene single nucleotide polymorphisms and increased levels of DNA adducts in a population-based study. Cancer Epidemiol Biomarkers Prev 12: 674–677

    CAS  PubMed  Google Scholar 

  177. Farmer PB, Shuker DEG (1999) What is the significance of increases in background levels of carcinogen-derived protein and DNA adducts? Some considerations for incremental risk assessment. Mutat Res 424: 275–286

    CAS  PubMed  Google Scholar 

  178. Wiltse JA, Dellarco VL (2000) U.S. Environmental Protection Agency’s revised guidelines for carcinogen risk assessment: evaluating a postulated mode of carcinogen action in guiding doseresponse extrapolation. Mutat Res 464: 105–115

    CAS  PubMed  Google Scholar 

  179. Orphanides G, Kimber I (2003) Toxicogenetics: applications and opportunities. Toxicol Sci 75: 1–6

    Article  CAS  PubMed  Google Scholar 

  180. Mohrenweiser HW (2004) Genetic variation and exposure related risk estimation: will toxicology enter a new era? DNA repair and cancer as a paradigm. Toxicol Pathol 32,Suppl 1: 136–145

    CAS  PubMed  Google Scholar 

  181. Balmain A, Gray J, Ponder B (2000) The genetics and genomics of cancer. Nat Genet Suppl 33: 238–244

    Google Scholar 

  182. Frank SA (2004) Genetic predisposition to cancer — insights from population genetics. Nat Rev Genet 5: 764–772

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, E17-132, Cambridge, MA, 02139, USA

    Andreas Luch

Authors
  1. Andreas Luch
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Birkhäuser Verlag/Switzerland

About this chapter

Cite this chapter

Luch, A. (2006). The mode of action of organic carcinogens on cellular structures. In: Cancer: Cell Structures, Carcinogens and Genomic Instability. Experientia Supplementum, vol 96. Birkhäuser Basel. https://doi.org/10.1007/3-7643-7378-4_4

Download citation

Publish with us

Policies and ethics

Search

Navigation