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Nature and nurture – lessons from chemical carcinogenesis

Key Points

  • Associations between cancer and occupational exposures can be dated back into the sixteenth century.

  • Today, about 200 different chemical compounds and mixtures are known or anticipated to be human carcinogens.

  • The great majority of human chemical carcinogens require metabolic activation to elicit detrimental effects. The activity of 'xenobiotic metabolizing enzymes' such as cytochrome-P450-dependent monooxygenases, glutathione S-transferases, sulphotransferases and others are required for activation (toxication) of important carcinogens.

  • Human carcinogens act through a variety of genotoxic and non-genotoxic mechanisms. DNA binding and induction of mutations in cancer-susceptibility genes, such as TP53 and KRAS, are import mechanisms of tumour initiation. In addition, the accompanying ability of many compounds to promote the outgrowth of transformed cell clones has been acknowledged.

  • The preferential formation of certain stereoisomers during metabolic activation of genotoxic carcinogens can determine the level of DNA damage, the efficiency of DNA repair, and the carcinogenic potency of a compound.

  • Humans are exposed to mixtures of compounds with different degrees of biological activity. Analysis of compound-specific mutational patterns provides valuable clues on the contribution of individual chemicals (or single classes of chemicals) to the overall biological response to these mixtures observed in certain tissues.

Abstract

The roles of genetic constitution versus environmental factors in cancer development have been a matter of debate even long before the discovery of 'oncogenes'. Evidence from epidemiological, occupational and migration studies has consistently pointed to environmental factors as the major contributing factors to cancer, so it seems reasonable to discuss the importance of chemical carcinogenesis in the present 'age of cancer genetics'.

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Figure 1: Sir Ernest Laurence Kennaway (1881–1958) and his co-workers.
Figure 2: Enzymatic conversion of some selected human carcinogens towards their ultimate DNA-reactive metabolites.
Figure 3: Overview of genotoxic and non-genotoxic effects of carcinogens.
Figure 4: Tumour promotion and tumour initiation.

References

  1. 1

    Doll, R. & Peto, R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J. Natl Cancer Inst. 66, 1191–1308 (1981). A landmark paper that compiled epidemiological evidence for a predominant role of environmental factors in human cancer.

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Kolonel, L. N., Altshuler, D. & Henderson, B. E. The multiethic cohort study: exploring genes, lifestyle and cancer risk. Nature Rev. Cancer 4, 519–527 (2004).

    CAS  Article  Google Scholar 

  3. 3

    Peto, J. Cancer epidemiology in the last century and the next decade. Nature 411, 390–395 (2001).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Lichtenstein, P. et al. Environmental and heritable factors in the causation of cancer. N. Engl. J. Med. 343, 78–85 (2000). Combined data on 44,788 pairs of twins indicate that the environment has the prinicpal role in causing sporadic human cancer.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5

    Czene, K., Lichtenstein, P. & Hemminki, K. Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish family-cancer database. Int. J. Cancer 99, 260–266 (2002).

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Theophrasti Paracelsi von Hohenheim. Von der Bergsucht oder Bergkrankheiten drey Bücher (Sebaldum Mayer, Dilingen, Germany, 1567).

  7. 7

    Rostoski, Saupe & Schmorl . Die Bergkrankheit der Erzbergleute in Schneeberg in Sachsen ('Schneeberger Lungenkrebs'). Z. Krebsforsch. 23, 360–384 (1926).

    Article  Google Scholar 

  8. 8

    Pirchan, A. & Sikl, H. Cancer of the lung in the miners of Jáchymov (Joachimstal). Report of cases observed in 1929–1930. Am. J. Cancer 16, 681–722 (1932).

    Google Scholar 

  9. 9

    Ramazzini, B. De Morbis Artificum Diatriba (Typis Antonii Capponi, Impressoris Episcopalis Supriorum Consensu, 1700).

    Google Scholar 

  10. 10

    Hill, J. 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, 1761).

    Google Scholar 

  11. 11

    Pott, P. The Chirurgical Works. 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 Ch. III 60–68 (Hawes, W. Clarke, and R. Collins, London, 1775). Original work of Percivall Pott, who was a surgeon at St. Bartholomew's Hospital London, that contains his seminal report on scrotal cancer in chimney sweeps. This observation raised the first possibility of cancer prevention.

    Google Scholar 

  12. 12

    Paris, J. A. Pharmacologica; or the History of Medicinal Substances, with a View to Establish the Art of Prescribing and of Composing Extemporaneous Formulae upon Fixed and Scientific Principles 206–217 (F. & R. Lockwood, New York, 1822).

    Google Scholar 

  13. 13

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

    Google Scholar 

  14. 14

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

    PubMed  PubMed Central  Google Scholar 

  15. 15

    Hutchinson, J. On some examples of arsenic-keratosis of the skin and of arsenic-cancer. Trans. Path. Soc. London 39, 352–393 (1888).

    Google Scholar 

  16. 16

    Rehn, L. Blasengeschwülste bei Fuchsin-Arbeitern. Arch. Klin. Chir. 50, 588–600 (1895). Report of three cases of urinary bladder tumours in the production of 'fuchsin' (magenta), a complex red dyestuff made from aniline and other aromatic amines.

    Google Scholar 

  17. 17

    Henry, S. A. Occupational cutaneous cancer attributable to certain chemicals in industry. Br. Med. Bull. 4, 389–401 (1947). Compilation of about 4,000 cases of cutaneous cancer observed in certain factories of Great Britain. Provides interesting insights on the conditions and exposures at work during the first half of the twentieth century.

    CAS  Article  Google Scholar 

  18. 18

    Yamagiwa, K. & Ichikawa, K. Experimentelle Studie über die Pathogenese der Epithelialgeschwülste. Mitt. Med. Fak. Kaiserl. Univ. Tokio 15, 295–344 (1915).

    Google Scholar 

  19. 19

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20

    Cook, J. W. et al. Chemical compounds as carcinogenic agents. Am. J. Cancer 29, 219–259 (1937).

    CAS  Article  Google Scholar 

  21. 21

    Cook, J. W., Hewett, C. L. & Hieger, I. The isolation of a cancer-producing hydrocarbon from coal tar. J. Chem. Soc. 395–405 (1933).

  22. 22

    Berenblum, I. & Bonser, G. M. Experimental investigation of 'aniline cancer'. J. Ind. Hyg. Toxicol. 19, 86–92 (1937).

    CAS  Google Scholar 

  23. 23

    Hueper, W. C. et al. Experimental production of bladder tumors in dogs by administration of beta-naphthylamine. J. Ind. Hyg. Toxicol. 20, 46–84 (1938).

    CAS  Google Scholar 

  24. 24

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

    Article  Google Scholar 

  25. 25

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

    Google Scholar 

  26. 26

    Kinosita, R. Researches on the carcinogenesis of the various chemical substances. (In Japanese). Gann 30, 423–426 (1936).

    Google Scholar 

  27. 27

    Wilson, R. H., DeEds, F. & Cox, A. J. Jr. The toxicity and carcinogenic activity of 2-acetaminofluorene. Cancer Res. 1, 595–608 (1941).

    CAS  Google Scholar 

  28. 28

    U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. 10th Report on Carcinogens [online], <http://ehp.niehs.nih.gov/roc/toc10.html> (Research Triangle Park, North Carolina, USA, 2004).

  29. 29

    Miller, E. C. & Miller, J. A. The presence and significance of bound amino azodyes in the livers of rats fed p-dimethylaminoazobenzene. Cancer Res. 7, 468–480 (1947). First demonstration of the covalent binding of a chemical carcinogen to cellular macromolecules such as proteins.

    CAS  Google Scholar 

  30. 30

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

    CAS  PubMed  Google Scholar 

  31. 31

    Miller, E. C. & Miller, J. A. In vivo combinations between carcinogens and tissue constituents and their possible role in carcinogenesis. Cancer Res. 12, 547–556 (1952).

    CAS  PubMed  Google Scholar 

  32. 32

    Wheeler, G. P. & Skipper, H. E. 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 (1957). Early paper describing the binding of a carcinogen to DNA in vivo.

    CAS  PubMed  Article  Google Scholar 

  33. 33

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34

    Brookes, P. & Lawley, P. D. 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 (1964). Seminal paper on the correlation between DNA-binding level and carcinogenicity of six selected polycyclic aromatic hydrocarbons.

    CAS  PubMed  Article  Google Scholar 

  35. 35

    Sporn, M. B. & Dingman, C. W. 2-Acetamidofluorene and 3-methylcholanthrene: differences in binding to rat liver deoxyribonucleic acid in vivo. Nature 210, 531–532 (1966).

    CAS  PubMed  Article  Google Scholar 

  36. 36

    Dingman, C. W. & Sporn, M. B. The binding of metabolites of aminoazo dyes to rat liver DNA in vivo. Cancer Res. 27, 938–944 (1967).

    CAS  PubMed  Google Scholar 

  37. 37

    Auerbach, C. & Robson, J. M. Chemical production of mutations. Nature 157, 302 (1946). The carcinogen 'mustard gas' induced mutations in Drosophila.

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Ames, B. N., Durston, W. E., Yamasaki, E. & Lee, F. D. Carcinogens are mutagens: a simple test system combining liver homogenates for activation and bacteria for detection. Proc. Natl Acad. Sci. USA 70, 2281–2285 (1973). Bruce Ames established the 'Ames Assay' for testing chemical-induced genotoxicity.

    CAS  PubMed  Article  Google Scholar 

  39. 39

    Wiley, F. H. The metabolism of β-naphthylamine J. Biol. Chem. 124, 627–630 (1938).

    CAS  Google Scholar 

  40. 40

    Boyland, E., Levi, A. A., Mawson, E. H. & Roe, E. 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 (1941).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41

    Stevenson, E. S., Dobriner, K. & Rhoads, C. P. The metabolism of dimethylaminoazobenzene (Butter Yellow) in rats. Cancer Res. 2, 160–167 (1942).

    CAS  Google Scholar 

  42. 42

    Mueller, G. C. & Miller, J. A. The metabolism of 4-dimethylaminoazobenzene by rat liver homogenates. J. Biol. Chem. 176, 535–544 (1948). First demonstration of microsome-catalysed biotransformation of a chemical carcinogen in vitro.

    CAS  PubMed  Google Scholar 

  43. 43

    Conney, A. H., Miller, E. C. & Miller, J. A. The metabolism of methylated aminoazo dyes. V. Evidence for induction of enzyme synthesis in the rat by 3-methylcholanthrene. Cancer Res. 16, 450–459 (1956).

    CAS  PubMed  Google Scholar 

  44. 44

    Brodie, B. B. et al. Detoxication of drugs and other foreign compounds by liver microsomes. Science 121, 603–604 (1955).

    CAS  PubMed  Article  Google Scholar 

  45. 45

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

    CAS  PubMed  Google Scholar 

  46. 46

    Lu, A. Y. H. & Coon, M. J. Role of hemoprotein P-450 in fatty acid ω-hydroxylation in a soluble enzyme system from liver microsomes. J. Biol. Chem. 243, 1331–1332 (1968).

    CAS  PubMed  Google Scholar 

  47. 47

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

    CAS  PubMed  Article  Google Scholar 

  48. 48

    Shimada, T., Oda, Y., Gillam, E. M. J., Guengerich, F. P. & Inoue, K. Metabolic activation of polycyclic aromatic hydrocarbons and other procarcinogens by cytochromes P450 1A1 and P450 1B1 allelic variants and other human cytochromes P450 in Salmonella typhimurium NM2009. Drug Metab. Disp. 29, 1176–1182 (2001).

    CAS  Google Scholar 

  49. 49

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

    CAS  PubMed  Article  Google Scholar 

  50. 50

    Cramer, J. W., Miller, J. A. & Miller, J. C. N-Hydroxylation: a new metabolic reaction observed in the rat with the carcinogen 2-acetylaminofluorene. J. Biol. Chem. 235, 885–888 (1960).

    CAS  PubMed  Google Scholar 

  51. 51

    Miller, E. C., Miller, J. A. & Hartmann, H. A. N-Hydroxy-2-acetylaminofluorene: a metabolite of 2-acetylaminofluorene with increased carcinogenic activity in the rat. Cancer Res. 21, 815–824 (1961).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    DeBraun, J. R., Smith, J. Y. R., Miller, E. C. & Miller, J. A. Reactivity in vivo of the carcinogen N-hydroxy-2-acetylaminofluorene: increase by sulfate ion. Science 167, 184–186 (1970). First evidence that sulphate esters of N -hydroxyarylamines or -amides are the ultimate carcinogenic metabolites of the corresponding parent compounds formed in vivo.

    Article  Google Scholar 

  53. 53

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

    CAS  PubMed  Article  Google Scholar 

  54. 54

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55

    Wartenberg, D, Reyner, D. & Scott, C. S. Trichloroethylene and cancer: epidemiological evidence. Environ. Health Perspect. 108 (Suppl. 2), 161–176 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    Guengerich, F. P. Activations of dihaloalkanes by thiol-dependent mechanisms. J. Biochem. Mol. Biol. 36, 20–27 (2003).

    CAS  PubMed  Google Scholar 

  57. 57

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

    CAS  PubMed  Article  Google Scholar 

  58. 58

    McGregor, D. B., Partensky, C., Wilbourn, J. & Rice, J. M. 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 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

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

    CAS  PubMed  Article  Google Scholar 

  60. 60

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

    CAS  PubMed  Article  Google Scholar 

  61. 61

    Conney, A. H., Miller, E. C. & Miller, J. A Substrate-induced synthesis and other properties of benzpyrene hydroxylase in rat liver. J. Biol. Chem. 228, 753–766 (1957). Describes BP-mediated induction of arylhydrocarbon hydroxylase in rat liver.

    CAS  PubMed  Google Scholar 

  62. 62

    Poland, A., Glover, E. & Kende, A. S. 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 (1976).

    CAS  PubMed  Google Scholar 

  63. 63

    Gu, Y. Z., Hogenesch, J. B. & Bradfield, C. A. The PAS superfamily: sensors of environmental and developmental signals. Annu. Rev. Pharmacol. Toxicol. 40, 519–561 (2000).

    CAS  PubMed  Article  Google Scholar 

  64. 64

    Nebert, D. W., Puga, A. & Vasiliou, V. 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 (1993).

    CAS  PubMed  Article  Google Scholar 

  65. 65

    Gonzalez, F. J. & Fernandez-Salguero, P. The arylhydrocarbon receptor. Studies using the AhR-null mice. Drug Metab. Dispos. 26, 1194–1198 (1998).

    CAS  PubMed  Google Scholar 

  66. 66

    Fernandez-Salguero, P. M., Hilbert, D. M., Rudikoff, S., Ward, J. M. & Gonzalez, F. J. Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity. Toxicol. Appl. Pharmacol. 140, 173–179 (1996). Reports that mice deficient for the AhR are fully protected against the toxic effects of TCDD in the liver, thymus, heart, kidney, pancreas, spleen, lymph nodes and uterus.

    CAS  PubMed  Article  Google Scholar 

  67. 67

    Andersson, P. et al. A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors. Proc. Natl Acad. Sci. USA 99, 9990–9995 (2002).

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Moennikes, O. et al. A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice. Cancer Res. 64, 4707–4710 (2004). Unequivocal proof that the AhR is crucial in mediating the tumour-promoting activities of receptor agonists such as TCDD, polycyclic aromatic hydrocarbons and polychlorinated biphenyls.

    CAS  PubMed  Article  Google Scholar 

  69. 69

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

    CAS  PubMed  Article  Google Scholar 

  70. 70

    Frueh, F. W., Hayashibara, K. C., Brown, P. O. & Whitlock, J. P. Jr. Use of cDNA microarrays to analyze dioxin-induced changes in human liver gene expression. Toxicol. Lett. 122, 189–203 (2001).

    CAS  PubMed  Article  Google Scholar 

  71. 71

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

    CAS  PubMed  Article  Google Scholar 

  72. 72

    Carlson, D. B. & Perdew, G. H. 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 (2002).

    CAS  PubMed  Article  Google Scholar 

  73. 73

    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. Biochem. Pharmacol. 52, 1599–1612 (1996). The protein kinase SRC is activated in cytosolic liver preparations through attachment to the AhR and upon binding to TCDD.

    CAS  PubMed  Article  Google Scholar 

  74. 74

    Luch, A. in The Carcinogenic Effects of Polycyclic Aromatic Hydrocarbons (ed. Luch, A.) 1–18 (Imperial College, London, in the press).

  75. 75

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76

    Boyland, E. & Sims, P. 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 (1960).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77

    Sims, P., Grover, P. L., Swaisland, A., Pal, K. & Hewer, A. Metabolic activation of benzo[a]pyrene proceeds by a diol-epoxide. Nature 252, 326–328 (1974). First experimental evidence that the vicinal 'bay-region' 7,8-dihydrodiol 9,10-epoxide is the ultimate DNA-binding metabolite of the aromatic hydrocarbon BP.

    CAS  PubMed  Article  Google Scholar 

  78. 78

    Luch, A. & Baird, W. M. in The Carcinogenic Effects of Polycyclic Aromatic Hydrocarbons (ed. Luch, A.) 19–96 (Imperial College, London, in the press).

  79. 79

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

    CAS  PubMed  Article  Google Scholar 

  80. 80

    Balmain, A. & Pragnell, I. B. Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene. Nature 303, 72–74 (1983). Genomic DNA from skin carcinomas of mice sequentially treated with a chemical initiator (7,12-dimethylbenz[ a ]anthracene) and a promotor (12- O -tetradecanoylphorbol-13–acetate) of carcinogenesis contained an activated RAS oncogene and morphologically transformed fibroblasts.

    CAS  PubMed  Article  Google Scholar 

  81. 81

    Shimizu, Y. et al. Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proc. Natl Acad. Sci. USA 97, 779–782 (2000). Demonstrates that BP-mediated tumorigenesis in subcutaneous or epidermal mouse tissue requires the presence of a functional AhR.

    CAS  PubMed  Article  Google Scholar 

  82. 82

    Klaunig, J. E. & Kamendulis, L. M. The role of oxidative stress in carcinogenesis. Annu. Rev. Pharmacol. Toxicol. 44, 239–267 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83

    Freudenthal, R. I., Stephens, E. & Anderson, D. P. Determining the potential of aromatic amines to induce cancer in the urinary bladder. Int. J. Toxicol. 18, 353–359 (1999).

    CAS  Article  Google Scholar 

  84. 84

    Beland, F. A. & Kadlubar, F. F. Formation and persistance of arylamine DNA adducts in vivo. Environ. Health Perspect. 62, 19–33 (1985).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85

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

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Klöhn, P. C. et al. 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 (2003).

    PubMed  Article  CAS  Google Scholar 

  87. 87

    Van Delft, J. H. M. et al. Discrimination of genotoxic from non-genotoxic carcinogens by gene expression profiling. Carcinogenesis 25, 1265–1276 (2004).

    CAS  PubMed  Article  Google Scholar 

  88. 88

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

    CAS  PubMed  Article  Google Scholar 

  89. 89

    Hartwig, A. et al. Interference by toxic metal ions with DNA repair processes and cell cycle control: molecular mechanisms. Environ. Health Perspect. 110 (Suppl. 5), 797–799 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90

    McMurray, C. T. & Tainer, J. A. Cancer, cadmium and genome integrity. Nature Genet. 34, 239–241 (2003).

    CAS  PubMed  Article  Google Scholar 

  91. 91

    Hughes, M. F. Arsenic toxicity and potential mechanisms of action. Toxicol. Lett. 133, 1–16 (2002).

    CAS  PubMed  Article  Google Scholar 

  92. 92

    Kawanishi, S., Hiraku, Y., Murata, M. & Oikawa S. Oxidative damage and repair: the role of metals in site-specific DNA damage with reference to carcinogenesis. Free Radic. Biol. Med. 32, 822–832 (2002).

    CAS  PubMed  Article  Google Scholar 

  93. 93

    Beyersmann, D. & Hechtenberg, S. Cadmium, gene regulation, and cellular signalling in mammalian cells. Toxicol. Appl. Pharmacol. 144, 247–261 (1997).

    CAS  PubMed  Article  Google Scholar 

  94. 94

    Qian, Y., Castranova, V. & Shi, X. New perspectives in arsenic-induced cell signal transduction. J. Inorg. Biochem. 96, 271–278 (2003).

    CAS  PubMed  Article  Google Scholar 

  95. 95

    Kasprzak, K. S., Sunderman, F. W. Jr. & Salnikow, K. Nickel carcinogenesis. Mutat. Res. 533, 67–97 (2003).

    CAS  PubMed  Article  Google Scholar 

  96. 96

    Lee, Y. W. et al. Carcinogenic nickel silences gene expression by chromatin condensation and DNA methylation: a new model for epigenetic carcinogens. Mol. Cell. Biol. 15, 2547–2557 (1995).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97

    Zhang, Q. et al. Inhibition and reversal of nickel-induced transformation by the histone deacetylase inhibitor trichostatin A. Toxicol. Appl. Pharmacol. 192, 201–211 (2003).

    CAS  PubMed  Article  Google Scholar 

  98. 98

    Govindarajan, B. et al. Reactive oxygen-induced carcinogenesis causes hypermethylation of p16Ink4a and activation of MAP kinase. Mol. Med. 8, 1–8 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99

    Kowara, R. et al. Reduced Fhit protein expression in nickel-transformed mouse cells and in nickel-induced murine sarcomas. Mol. Cell. Biochem. 255, 195–202 (2004).

    CAS  PubMed  Article  Google Scholar 

  100. 100

    Chen, H. et al. Association of c-myc oncogene overexpression and hyperproliferation with arsenite-induced malignant transformation. Toxicol. Appl. Pharmacol. 175, 260–268 (2001).

    CAS  PubMed  Article  Google Scholar 

  101. 101

    Zhao, C. Q., Young, M. R., Diwan, B. A., Coogan, T. P. & Waalkes, M. P. Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc. Natl Acad. Sci. USA 94, 10907–10912 (1997).

    CAS  PubMed  Article  Google Scholar 

  102. 102

    Glatt, H. R. in The Carcinogenic Effects of Polycyclic Aromatic Hydrocarbons. (ed. Luch, A.) 283–314 (Imperial College, London, in the press).

  103. 103

    Ross, J. A. et al. Adenomas induced by polycyclic aromatic hydrocarbons in strain A/J mouse lung correlate with time-integrated DNA adduct levels. Cancer Res 55, 1039–1044 (1995).

    CAS  PubMed  Google Scholar 

  104. 104

    Poirier, M. C. Chemical-induced DNA damage and human cancer risk. Nature Rev. Cancer 4, 630–637 (2004).

    CAS  Article  Google Scholar 

  105. 105

    Kensler, T. W., Qian, G. S., Chen, J. G. & Groopman, J. D. Translational strategies for cancer prevention in liver. Nature Rev. Cancer 3, 321–329 (2003).

    CAS  Article  Google Scholar 

  106. 106

    Baertschi, S. W., Raney, K. D., Stone, M. P. & Harris, T. M. Preparation of the 8,9-epoxide of the mycotoxin aflatoxin B1: the ultimate carcinogenic species. J. Am. Chem. Soc. 110, 7929–7931 (1988). Key experiment with chemically synthesized AFB 1 exo -8,9-oxide that provided an unequivocal proof that this epoxide is the DNA-binding metabolite of the mycotoxin.

    CAS  Article  Google Scholar 

  107. 107

    Guengerich, F. P. et al. Activation and detoxification of aflatoxin B1 . Mutat. Res. 402, 121–128 (1998).

    CAS  PubMed  Article  Google Scholar 

  108. 108

    Iyer, R. S. et al. DNA adduction by the potent carcinogen aflatoxin B1: mechanistic studies. J. Am. Chem. Soc. 116, 1603–1609 (1994).

    CAS  Article  Google Scholar 

  109. 109

    Yang, S. K., McCourt, D. W., Roller, P. P. & Gelboin, H. V. 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, 2594–2598 (1976).

    CAS  PubMed  Article  Google Scholar 

  110. 110

    Koreeda, M. et al. 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 (1978).

    CAS  PubMed  Article  Google Scholar 

  111. 111

    Cheng, S. C., Hilton, B. D., Roman, J. M. & Dipple, A. DNA adducts from carcinogenic and noncarcinogenic enantiomers of benzo[a]pyrene dihydrodiol epoxides. Chem. Res. Toxicol. 2, 334–340 (1989).

    CAS  PubMed  Article  Google Scholar 

  112. 112

    Friedberg, E. C. How nucleotide excision repair protects against cancer. Nature Rev. Cancer 1, 22–33 (2001).

    CAS  Article  Google Scholar 

  113. 113

    Hess, M. T., Gunz, D., Luneva, N., Geacintov, N. E. & Naegeli, H. 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 (1997). Indicates that the efficiency of NER of bulky aromatic hydrocarbon–DNA adducts greatly depends on the stereochemistry and the conformation of the lesion induced.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114

    Geacintov, N. E. et al. NMR solution structures of stereoisomeric covalent polycyclic aromatic carcinogen-DNA adducts: principles, patterns, and diversity. Chem. Res. Toxicol. 10, 111–146 (1997).

    CAS  PubMed  Article  Google Scholar 

  115. 115

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

    CAS  PubMed  Google Scholar 

  116. 116

    Wang, A. et al. Response of human mammary epithelial cells to DNA damage induced by BPDE: involvement of novel reulatory pathways. Carcinogenesis 24, 225–234 (2003).

    PubMed  Article  Google Scholar 

  117. 117

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

    CAS  PubMed  Article  Google Scholar 

  118. 118

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

    CAS  PubMed  Article  Google Scholar 

  119. 119

    Malumbres, M. & Barbacid, M. RAS oncogenes: the first 30 years. Nature Rev. Cancer 3, 459–465 (2003).

    CAS  Article  Google Scholar 

  120. 120

    Feng, Z. et al. Preferential DNA damage and poor repair determine ras gene mutational hotspot in human cancer. J. Natl Cancer Inst. 94, 1527–1536 (2002). Codon 12 of KRAS in bronchial epithelial cells is a DNA-binding 'hot spot' of the cigarette smoke carcinogen BP, due to both a preferential binding of anti -BPDE at the first dG in this codon and the inefficient DNA repair that follows.

    CAS  PubMed  Article  Google Scholar 

  121. 121

    Bos, J. L. Ras oncogenes in human cancer: a review. Cancer Res. 49, 4682–4689 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

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

    CAS  PubMed  Article  Google Scholar 

  123. 123

    Chen, J. X., Zheng, Y., West, M. & Tang, M. S. Carcinogens preferentially bind at methylated CpG in the p53 mutational hot spots. Cancer Res. 58, 2070–2075 (1998).

    CAS  PubMed  Google Scholar 

  124. 124

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

    CAS  PubMed  Article  Google Scholar 

  125. 125

    Denissenko, M. F., Chen, J. X., Tang, M. S. & Pfeifer, G. P. Cytosine methylation determines hot spots of DNA damage in the human p53 gene. Proc. Natl Acad. Sci. USA 94, 3893–3898 (1997).

    CAS  PubMed  Article  Google Scholar 

  126. 126

    Feng, Z., Hu, W., Rom, W. N., Beland, F. A. & Tang, M. S. 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 (2002).

    CAS  Article  PubMed  Google Scholar 

  127. 127

    Denissenko, M. F., Pao, A., Tang, M. S. & Pfeifer, G. P. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in p53. Science 274, 430–432 (1996). Landmark paper in molecular epidemiology that provides an aetiological link between BP exposure and human lung cancer based on mutations at codons 157, 248 and 273 of cellular TP53.

    CAS  PubMed  Article  Google Scholar 

  128. 128

    Denissenko, M. F., Pao, A., Pfeifer, G. P. & Tang, M. S. 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 (1998).

    CAS  PubMed  Article  Google Scholar 

  129. 129

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

    CAS  Article  Google Scholar 

  130. 130

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

  131. 131

    Hu, W., Feng, Z. & Tang, M. S. 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 (2004).

    CAS  PubMed  Article  Google Scholar 

  132. 132

    Buterin, T. et al. Trapping of DNA nucleotide excision repair factors by nonrepairable carcinogen adducts. Cancer Res. 62, 4229–4235 (2002). Demonstrates that the NER-catalysed excision of (+)- trans-anti -BPDE-dG fails when its deoxycytosine base pair is deleted. This is known as the 'prototypic decoy adduct'. Bulky lesions opposite deoxycytosine deletion are also normally present in cells as an intermediate after replicative bypass of AAF or BP adducts.

    CAS  PubMed  Google Scholar 

  133. 133

    Lewtas, J. et al. in Methods for Genetic Risk Assessment (ed. Brusick, D. J.) 125–169 (Lewis Publishers, Boca Raton, Florida, 1994).

    Google Scholar 

  134. 134

    Calabrese, E. J. & Baldwin, L. A. Toxicology rethinks its central belief. Nature 421, 691–692 (2003).

    CAS  PubMed  Article  Google Scholar 

  135. 135

    Farmer, P. B. & Shuker, D. E. G. 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 (1999).

    CAS  PubMed  Article  Google Scholar 

  136. 136

    Wiltse, J. A. & Dellarco, V. L. U. S. Environmental Protection Agency's revised guidelines for carcinogen risk assessment: evaluating a postulated mode of carcinogen action in guiding dose–response extrapolation. Mutat. Res. 464, 105–115 (2000).

    CAS  PubMed  Article  Google Scholar 

  137. 137

    Henderson, L., Albertini, S. & Aardema, M. Thresholds in genotoxicity responses. Mutat. Res. 464, 123–128 (2000).

    CAS  PubMed  Article  Google Scholar 

  138. 138

    Nuwaysir, E. F., Bittner, M., Trent, J., Barrett, J. C. & Afshari, C. A. Microarrays and toxicology: the advent of toxicogenomics. Mol. Carcinog. 24, 153–159 (1999). Discussion of the advantages of cDNA microarray-based expression profiling as a highly sensitive marker for detection, monitoring and characterization of biohazardous compounds in the human environment ('ToxChip' technology).

    CAS  PubMed  Article  Google Scholar 

  139. 139

    Hamadeh, H. K. et al. Prediction of compound signature using high density gene expression profiling. Toxicol. Sci. 67, 232–240 (2002).

    CAS  Article  PubMed  Google Scholar 

  140. 140

    Gonzalez, F. J. The role of carcinogen-metabolizing enzyme polymorphism in cancer susceptibility. Reprod. Toxicol. 11, 397–412 (1997).

    CAS  PubMed  Article  Google Scholar 

  141. 141

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

    CAS  PubMed  Article  Google Scholar 

  142. 142

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

    Google Scholar 

  143. 143

    Boyland, E. History and future of chemical carcinogenesis. Br. Med. Bull. 36, 5–10 (1980).

    CAS  PubMed  Article  Google Scholar 

  144. 144

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

    Google Scholar 

  145. 145

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

    Google Scholar 

  146. 146

    Leitch, A. & Kennaway, E. L. Experimental production of cancer by arsenic. Br. Med. J. II, 1107–1108 (1922).

    Google Scholar 

  147. 147

    Friedewald, W. F. & Rous, P. 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 (1944).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

I am very grateful to my colleague and friend G. P. Tochtrop for his critical reading of the manuscript. I also want to acknowledge the help and kind advice from J. Eckert in the 'Rare Books and Special Collections' department of the Francis A. Countway Library of Medicine, Harvard Medical School, Boston, Massachusetts. I wish to thank the staff of the Houghton Library, Harvard University, Cambridge, Massachusetts, for their help with Paracelsus' books. The work of the author was supported by the German Research Foundation.

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DATABASES

Entrez Gene

COT

CYP1A1

CYP1A2

CYP1B1

CYP2A6

CYP2E1

CYP3A4

KRAS

NEK2

TP53

FURTHER INFORMATION

Agency for Toxic Substances and Disease Registry

Cytochrome P450 Homepage

General National Institutes of Health web site on Toxicology and Environmental Health

Genetic polymorphisms of cytochrome P450 enzymes

Genetic polymorphisms of N-acetyltransferases

International Agency for Research on Cancer (IARC) Monographs Programme on the Evaluation of Carcinogenic Risks to Humans

IARC web site on polychlorinated dibenzo-p–dioxins

National Toxicology Program

Toxicology Data Network of National Institutes of Health

United States Environmental Protection Agency Integrated Risk Information System

World Health Organization air quality guidelines

Glossary

ELECTROPHILIC

Having an affinity for negative charge; molecules that behave as electron acceptors.

NUCLEOPHILIC

Having an affinity for positive charge; molecules that behave as electron donors.

OLEFINS

Hydrocarbons containing a carbon–carbon double bond; also known as alkenes.

MICROSOMES

Vesicles formed from the endoplasmatic reticulum when cells are disrupted; used in cell-free in vitro studies of biotransformation.

MIXED-FUNCTION OXIDASES

Enzymes that catalyse oxidation–reduction reactions in which one atom of the oxygen molecule is incorporated into the organic substrate; the other oxygen atom is reduced and combined with hydrogen ions to form water. Also known as monooxygenases or hydroxylases.

CYTOCHROME P450

Haem-containing protein involved in electron-transfer reactions.

XENOBIOTICS

Chemical compounds that are foreign to the biological system.

BIOTRANSFORMATION

Enzymatically catalysed chemical alterations of a compound that occur within living organisms or cells.

VICINAL DIHALOALKANES

Saturated hydrocarbons containing two halogen atoms (for example, chlorine) that are bonded to adjacent carbon atoms.

PLANAR

Molecules that have two-dimensional structures.

EPOXIDATION

A chemical reaction in which an oxygen is joined to an olefinic molecule to form a cyclic, three-membered ether. The products are known as oxiranes, epoxides or simply oxides.

GENOTOXIC CARCINOGENS

Chemical carcinogens that are capable of causing damage to DNA. These can be mutagenic, clastogenic or aneugenic.

ADDUCTS

Covalent reaction products between chemicals and proteins or DNA.

DIASTEREOMERS

Stereoisomers that are not related as mirror images to each other.

ENANTIOMER

One of the two non-superimposable mirror image forms of an optically active molecule.

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Luch, A. Nature and nurture – lessons from chemical carcinogenesis. Nat Rev Cancer 5, 113–125 (2005). https://doi.org/10.1038/nrc1546

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