Involvement of Radicals in Chemical Carcinogenesis

  • Paul O. P. Ts’o
  • James C. Barrett
  • William J. Caspary
  • Stephen A. Lesko
  • Ronald J. Lorentzen
  • Leonard M. Schechtman


Chemical carcinogens comprise a large and structurally diverse group of synthetic and naturally occurring compounds. It appears almost axiomatic that such compounds must react with tissue components in order to induce neoplastic transformation. With the exception of the carcinogenic alkylating agents, most chemical carcinogens are not reactive per se and must be converted to reactive forms either chemically or metabolically. Data are emerging to indicate that electrophilic reactants are the ultimate form of most, if not all, chemical carcinogens (Miller, 1970). The proximate forms of a number of chemical carcinogens might be convertible to free radicals, i.e., electrophilic reactants, and suggest a possible role for the free radical in carcinogenesis. The presence of free radicals in tobacco smoke has been demonstrated (Lyons and Spence, 1960; Bluhm et al., 1971) and the increased incidence of lung cancer in cigarette smokers based on epidemiological studies is well known. The chemical and metabolic conversion of a number of chemical carcinogens to free radicals and the interaction of these radicals with DNA will be described in this communication.


Chemical Carcinogen Electron Spin Resonance Study Covalent Linkage Chemical Carcinogenesis Polycyclic Hydrocarbon 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bartsch, H., and Hecker, E., 1970, On the metabolic activation of the carcinogen N-hydroxy-N-2-acetylaminofluorene. III. Oxidation with horseradish peroxidase to yield 2-nitrosof1uorene and N-acetoxy-N-2-acetyl aminofluorene, Biochim. Biophys. Acta 237: 567–578.CrossRefGoogle Scholar
  2. Bartsch, H., Traut, M., and Hecker, E., 1970, On the metabolic activation of N-hydroxy-N-2-acetylaminofluorene. II. Simultaneous formation of 2-nitrosofluorene and N-acetoxy-N-2acetyl aminofluorene from N-hydroxy-N-2-acetyl aminofluorene via a free radical intermediate, Biochim. Biophys. Acta 237: 556–566.CrossRefGoogle Scholar
  3. Blackburn, G., and Will, J., 1974, Bonding of benzo(a)pyrene to nitrogen heterocycles by anodic oxidation, J.C.S. Chem. Commun. 1974: 67–68.CrossRefGoogle Scholar
  4. Bluhm, A., Weinstein, J., and Sousa, J., 1971, Free radicals in tobacco smoke, Nature 229: 500.PubMedCrossRefGoogle Scholar
  5. Brookes, P., and Lawley, P., 1964, Evidence for the binding of polynuclear aromatic hydrocarbons to the nucleic acids of mouse skin: Relation between carcinogenic power of hydrocarbons and their binding to deoxyribonucleic acid, Nature 202: 781–784.PubMedCrossRefGoogle Scholar
  6. Carlassare, F., Antonello, C., Baccichetti, F., and Malfer, P., 1972, On the binding of benzo(a)pyrene to DNA “in vivo”, Z. Naturforsch. 27b: 200–202.Google Scholar
  7. Caspary, W., Cohen, B., Lesko, S., and Ts’o, P., 1973, Electron paramagnetic resonance study on iodine induced radicals of benzo(a)pyrene and other polycyclic hydrocarbons, Biochemistry 12: 2649–2656.PubMedCrossRefGoogle Scholar
  8. Cavalieri, E., and Calvin, M., 1971, Molecular characteristics of some carcinogenic hydrocarbons, Proc. Nat. Acad. Sci. USA 68: 1251–1253.PubMedCrossRefGoogle Scholar
  9. Falk, H.L., Kotin, P., Lee, S., and Nathan, A., 1962, Intermediary metabolism of benzo(a)pyrene in the rat, J. Nat. Cancer Inst. 28: 699–724.Google Scholar
  10. Fieser, L., and Hershberg, E., 1939, The orientation of 3, 4-benzpyrene in substitution reactions, J. Amer. Chem. Soc. 61: 1565–1574.CrossRefGoogle Scholar
  11. Forbes, W., and Robinson, J., 1968, Possible formation of an azuline-type radical obtained on heating 3, 4-benzpyrene, Nature 217: 550–551.PubMedCrossRefGoogle Scholar
  12. Fried, J., 1974, One-electron oxidation of polycyclic aromatics as a model for the metabolic activation of carcinogenic hydrocarbons, in “Chemical Carcinogenesis,” Part A (P. Ts’o and J. DiPaolo, eds.), pp. 197–215, Marcel Dekker, New York.Google Scholar
  13. Gelboin, H., 1969, A microsome-dependent binding of benzo(a)pyrene to DNA, Cancer Res. 29: 1272–1276.PubMedGoogle Scholar
  14. Goshman, L., and Heidelberger, C., 1967, Binding of tritium labeled polycyclic hydrocarbons to DNA of mouse skin, Cancer Res. 27: 1678–1688.PubMedGoogle Scholar
  15. Grover, P., and Sims, P., 1968, Enzyme-catalyzed reactions of poly- cyclic hydrocarbons with deoxyribonucleic acid and protein in vitro, Biochem. J. 110: 159–160.PubMedGoogle Scholar
  16. Hayakawa, T., and Udenfriend, S., 1972, A simple radioisotope assay for microsomal aryl hydroxylase, Anal. Biochem. 51: 501–509.CrossRefGoogle Scholar
  17. Hoffmann, H., Lesko, S., and Ts’o, P., 1970, Chemical linkage of polycyclic hydrocarbons to DNA and polynucleotides in aqueous solution and in a buffer-ethanol solvent system, Biochemistry 9: 2594–2604.PubMedCrossRefGoogle Scholar
  18. Holder, G., Yagi, H., Dansette, P., Jerina, D., Levin, W., Lu, A., and Conney, A., 1974, Effects of inducers and epoxide hydrase on the metabolism of benzo(a)pyrene by liver microsomes and a reconstituted system: analysis by high pressure liquid chromatography, Proc. Nat. Acad. Sci. USA 71: 4356–4360.PubMedCrossRefGoogle Scholar
  19. Hutchinson, F., 1973, The lesions produced by ultraviolet light 396 P.O.P. TS’O ET AL. in DNA containing 5-bromouracil, Quart. Rev. Biophys. 6: 201–246.CrossRefGoogle Scholar
  20. Inomata, M., and Nagata, C., 1972, Photoinduced phenoxy radical of 3,4-benzopyrene, Gann 63: 119–130.PubMedGoogle Scholar
  21. Ioki, Y., Kodama, M., Tagashira, Y., and Nagata, C., 1974, Oxygenation of benzo(a)pyrene in a model system using trifluoroacetic acid and hydrogen peroxide, Gann 65: 379–380.PubMedGoogle Scholar
  22. Jeftic, L., and Adams, R., 1970, Electrochemical oxidation pathways of benzo(a)pyrene, J. Amer. Chem. Soc. 92: 1332–1337.CrossRefGoogle Scholar
  23. Lesko, S., Caspary, W., Lorentzen, R., and Ts’o, P., 1975, Enzymic formation of 6-oxo-benzo(a)pyrene radical in rat liver homo-genates from carcinogenic benzo(a)pyrene, Biochemistry 14: 3978–3984.CrossRefGoogle Scholar
  24. Lesko, S., Ts’o, P., and Umans, R., 1969, Interaction of nucleic acids. V. Chemical linkage of 3,4-benzpyrene to deoxyribonucleic acid in aqueous solution, Biochemistry 8: 2291–2298.PubMedCrossRefGoogle Scholar
  25. Lorentzen, R., Caspary, W., Lesko, S., and Ts’o, P., 1975, The autoxidation of 6-hydroxylbenzo(a)pyrene and 6-oxo-benzo(a)pyrene radical, reactive metabolites of benzo(a)pyrene, Biochemistry 14: 3970–3977.CrossRefGoogle Scholar
  26. Lyons, M., and Spence, J., 1960, Environmental free radicals, Brit. J. Cancer 14: 703–708.PubMedCrossRefGoogle Scholar
  27. Maher, V., Lesko, S., Straat, P., and Ts’o, P., 1971, Mutagenic action, loss of transforming activity and inhibition of DNA template activity in vitro caused by the chemical linkage of carcinogenic polycyclic hydrocarbons to DNA, J. Bacteriol. 108: 202–212.PubMedGoogle Scholar
  28. Marquardt, H., Sapozink, M., and Zedeck, M., 1974, Inhibition by cysteamine-HC1 of oncogenesis induced by 7,12-dimethylbenz(a)anthracene without affecting toxicity, Cancer Res. 34: 3387–3390.Google Scholar
  29. Massie, H., Samis, H., and Baird, M., 1972, The kinetics of degradation of DNA by H202, Biochim. Biophys. Acta 272: 539–548.PubMedCrossRefGoogle Scholar
  30. Miller, J., 1970, Carcinogenesis by chemicals: an overview, G.H.A. Clowes Memorial Lecture, Cancer Res. 30: 559–576.PubMedGoogle Scholar
  31. Miller, J., and Miller, E., 1969, Metabolic activiation of carcinogenic aromatic and N-hydroxy-esterification and its relationship to ultimate carcinogens as electrophilic reactants, in “The Jerusalem Symposia on Quantum Chemistry and Biochemistry. Physiochemical Mechanisms of Carcinogenesis,” Vol. I (E. Bergman and B. Pullman, eds.), pp. 237–261, Israel Academy of Sciences and Humanities, Jerusalem.Google Scholar
  32. Mullinix, K., and Rosenkrantz, H., 1971, Effects of N-hydroxyurethan on viability and metabolism of Escherichia coll, J. Bacteriol. 105: 556–564.PubMedGoogle Scholar
  33. Mullinix, K., Rosenkrantz, S., Carr, H., and Rosenkrantz, H., 1973, Reaction between DNA and N-hydroxyurethan, Biochim. Biophys. Acta 312: 1–13.PubMedCrossRefGoogle Scholar
  34. Nagata, C., Inomata, M., Kodama, M., and Tagashira, Y., 1968, Electron spin resonance study on the interaction between the chemical carcinogens and tissue components. III. Determination of the structure of the free radical produced either by stirring 3,4-benzopyrene with albumin or incubating it with liver homogenates, Gann 59: 289–298.PubMedGoogle Scholar
  35. Nagata, C., Ioki, Y., Inomata, M., and Imamura, A., 1969, Electron spin resonance study on the free radicals produced from carcinogenic aminonaphthaols and N-hydroxyaminonaphthalenes, Gann 60: 509–522.PubMedGoogle Scholar
  36. Nagata, C., Kataoka, N., Imamura, A., Kawazoe, Y., and Chihara, G., 1966, Electron spin resonance study on the free radical produced from 4-hydroxyaminoquinoline-1-oxide and its significance in carcinogenesis, Gann 57: 323–335.PubMedGoogle Scholar
  37. Nagata, C., Nakadate, M., Ioki, Y., and Imamura, A., 1972, Electron spin resonance study on the free radical production from Nmethyl-N’-nitro-N-nitrosoguanidine, Gann 63: 471–481.PubMedGoogle Scholar
  38. Nagata, C., Tagashira, Y., and Kodama, M., 1974, Metabolic activation of benzo(a)pyrene: significance of the free radical, in “Chemical Carcinogenesis,” Part A (P. Ts’o and J. DiPaolo, eds.), pp. 87–111, Marcel Dekker, New York.Google Scholar
  39. Pascal, Y., Pochon, F., and Michelson, A., 1971, Free radical mediated linkage of carcinogenic hydrocarbons to polynucleotides, Biochimie 53: 365–368.PubMedCrossRefGoogle Scholar
  40. Prodi, G., Rocchi, P., and Grilli, S., 1970, Binding of 7,12dimethylbenz (a) anthracene and benzo(a)pyrene to nucleic acids and proteins of organs of rats, Cancer Res. 30: 1020–1023.PubMedGoogle Scholar
  41. Rapaport, S., and Ts’o, P., 1966, Interaction of nucleic acids. III. Chemical linkage of the carcinogen 3,4-benzpyrene to DNA induced by X-ray irradiation, Proc. Nat. Acad. Sci. USA 55: 381–387.PubMedCrossRefGoogle Scholar
  42. Rasmussen, R., and Wang, I., 1974, Dependence of specific metabolism of benzo(a)pyrene on the inducer of hydroxylase activity, Cancer Res. 34: 2290–2295.PubMedGoogle Scholar
  43. Rhaese, H., and Freese, E., 1968, Chemical analysis of DNA alterations. I. Base liberation and backbond breakage of DNA and oligodeoxyadenylic acid induced by hydrogen peroxide and hydroxylamine, Biochim. Biophys. Acta 155: 476–490.PubMedCrossRefGoogle Scholar
  44. Rochlitz, J., 1967, Neue reaktionen der carcinogenen kohlenwasserstoffe. II, Tetrahedron 23: 3043–3048.PubMedCrossRefGoogle Scholar
  45. Schechtman, L., Lesko, S., Lorentzen, R., and Ts’o, P., 1974, A cellular system for the study of the chemical reactivity and transforming ability of benzo(a)pyrene and its derivatives, Proc. Amer. Assoc. Cancer Res. 15: 66.Google Scholar
  46. Scribner, J., Miller, J., and Miller, E., 1970, Nucleophilic substitution on carcinogenic N-acetoxy-N-arylacetamides, Cancer Res. 30: 1570–1579.PubMedGoogle Scholar
  47. Scribner, J., and Naimy, W., 1973, Reactions of esters of N-hydroxy2-acetamidophenanthrene with cellular nucleophiles and the formation of free radicals upon decomposition of N-acetoxy N-arylacetamides, Cancer Res. 33: 1159–1164.PubMedGoogle Scholar
  48. Selkirk, J., Croy, R., Roller, P., and Gelboin, H., 1974, High-pressure liquid chromatographic analysis of benzo(a)pyrene metabolism and covalent binding and the mechanism of action of 7,8-benzoflavone and 1,2-epoxy-3,3,3-trichloropropane, Cancer Res. 34: 3474–3480.PubMedGoogle Scholar
  49. Shamberger, R., Baughman, F., Kalchert, S., Willis, C., and Hoffman, I. 1973, Carcinogen-induced chromosomal breakage decreased by antioxidants, Proc. Nat. Acad. Sci. USA 70: 1461–1463.PubMedCrossRefGoogle Scholar
  50. Szent-Gyorgyi, A., Isenberg, I., and Baird, S., 1960, On the electron donating properties of carcinogens, Proc. Nat. Acad. Sci. USA 46: 1444–1449.PubMedCrossRefGoogle Scholar
  51. Ts’o, P., Caspary, W., Cohen, B., Leavitt, J., Lesko, S., Lorentzen, R., and Schechtman, L., 1974, Basic mechanisms in polycyclic hydrocarbon, in “Chemical Carcinogenesis,” Part A (P. Ts’o and J. DiPaolo, eds.), pp. 113–147, Marcel Dekker, New York.Google Scholar
  52. Ts’o, P., and Lu, P., 1964, Interaction of nucleic acids. II. Chemical linkage of the carcinogen 3,4-benzpyrene to DNA induced by photoirradiation, Proc. Nat. Acad. Sci. USA 51: 272–280.CrossRefGoogle Scholar
  53. Wattenberg, L., 1973, Inhibition of chemical carcinogen-induced pulmonary neoplasia by butylated hydroxyanisole, J. Nat. Cancer Inst. 50: 1541–1544.PubMedGoogle Scholar
  54. Wilk, M., and Girke, W., 1969, Radical cations of carcinogenic alternant hydrocarbons, amines and azo dyes, and their reactions with nucleo bases, in “The Jerusalem Symposia on Quantum Chemistry and Biochemistry. Physiochemical Mechanisms of Carcinogenesis,” Vol. I (E. Bergman and B. Pullman, eds.), pp. 91–105, Israel Academy of Sciences and Humanities, Jerusalem.Google Scholar

Copyright information

© Springer Science+Business Media New York 1976

Authors and Affiliations

  • Paul O. P. Ts’o
    • 1
  • James C. Barrett
    • 1
  • William J. Caspary
    • 1
  • Stephen A. Lesko
    • 1
  • Ronald J. Lorentzen
    • 1
  • Leonard M. Schechtman
    • 1
  1. 1.Department of Biochemical and Biophysical Sciences Division of BiophysicsThe Johns Hopkins UniversityBaltimoreUSA

Personalised recommendations