The Involvement of Peroxyl Free Radicals in Tumor Initiation and Promotion

  • Lawrence J. Marnett


In recent years, there has been considerable interest in the involvement of free radicals in carcinogenesis (1–4). Much of the research emphasis has focused on intermediates of oxygen reduction such as superoxide anion and hydroxyl radical (2). Organic analogs of superoxide anion and its protonated form, perhydroxyl radical, have received less attention but may be just as important biologically as reduced oxygen intermediates. Our laboratory is interested in the role of hydroperoxide-dependent oxidations in carcinogenesis and much of our research is concerned with the chemistry and biology of peroxyl radicals generated by metal-catalyzed fragmentations of unsaturated fatty acid hydroperoxides. We believe evidence exists to support the hypothesis that peroxyl free radicals contribute to metabolic activation of chemical carcinogens (e.g., polycyclic hydrocarbons) in the initiation phase of tumorigenesis; circumstantial evidence implicates peroxyl radicals in tumor promotion as well.


Retinoic Acid Benzoyl Peroxide Tumor Promotion Mouse Skin Peroxyl Radical 
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  1. 1.
    Copeland, E. S. (1983) Free radicals in promotion — A chemical pathology study section report. Cancer Res. 43, 5631–5637.PubMedGoogle Scholar
  2. 2.
    Troll, W. and Weisner, R. (1985) The role of oxygen radicals as a possible mechanism of tumor promotion. Ann. Rev. Pharmacol. Toxicol. 25, 509–528.CrossRefGoogle Scholar
  3. 3.
    Cerutti, P. (1985) Prooxidant states and tumor promotion. Science 227, 375–381.PubMedCrossRefGoogle Scholar
  4. 4.
    Kensler, T. W. and Taffe, B. G. (1986) Free radicals in tumor promotion. Adv. in Free Radical Biology and Medicine 2, 347–387.CrossRefGoogle Scholar
  5. 5.
    Porter, N. A. (1986) Mechanisms for the autoxidation of polyunsaturated lipids. Acc. Chem. Res. 19, 262–268.CrossRefGoogle Scholar
  6. 6.
    Pryor, W. A. (1986) Oxy-radicals and related species: their formation, lifetimes, and reactions. Ann. Rev. Physiol. 48, 657–667.CrossRefGoogle Scholar
  7. 7.
    Walling, C. (1957) In Walling, C. (ed) Free Radicals in Solution, John Wiley and Sons, New York, pp 418–427.Google Scholar
  8. 8.
    Mamett, L. J. (1981) Polycyclic hydrocarbon oxidation during prostaglandin biosynthesis. Life Sci., 29, 531–546.CrossRefGoogle Scholar
  9. 9.
    Panthananickal, A. and Mamett, L. J. (1981) Arachidonic acid-dependent metabolism of 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene to polyguanylic acid-binding derivatives. Chem. Biol. Interactions 33, 239–252.CrossRefGoogle Scholar
  10. 10.
    Jerina, D. M., Michaud, D. P., Feldman, R. J., Armstrong, R. N., Vyas, K. P., Thakker, D. R., Yagi, H., Thomas, P. E., Ryan, D. E., and Levin, W. (1982) Steroechemical modeling of the catalytic site of cytochrome P-450c. In Sato, R. and Kato, R. (eds) Microsomes, Drug Oxidations, and Drug Toxicity Wiley-Interscience, New York, pp 195–201.Google Scholar
  11. 11.
    Dix, T. A. and Marnett, L. J. (1983) Metabolism of polycyclic aromatic hydrocarbon derivatives to ultimate carcinogens during lipid peroxidation. Science 221, 77–79.PubMedCrossRefGoogle Scholar
  12. 12.
    Battista, J. R., Dix, T. A., and Marnett, L.J. (1984) The mechanism of hydroperoxide-dependent epoxidation of 7,8-dihydroxy-7,8-dihydro-benzo[a]pyrene by rat liver microsomes. Proc. Amer. Assoc. Cancer Res. 25, 114.Google Scholar
  13. 13.
    Reed, G. A., Brooks, E. A., and Eling, T. E. (1984) Phenylbutazone-dependent epoxidation of 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene. J. Biol. Chem. 259, 5591–5595.PubMedGoogle Scholar
  14. 14.
    Reed, G. A., Curtis, J. F., Mottley, C., Eling, T. E., and Mason, R. P. (1986) Epoxidation of (±)-7, 8-dihydroxy-7, 8-dihydrobenzo [a]pyrene durin (bi)sulfite autoxidation: activation of a procarcinogen by a cocarcinogen. Proc. Natl. Acad. Sci. USA 83, 7499–7502.PubMedCrossRefGoogle Scholar
  15. 15.
    Guthrie, J., Robertson, I. G. C., Zeiger, E., Boyd, J. A., and Eling, T. E. (1982) Selective activation of dihydrodiols of several polycyclic aromatic hydrocarbons to mutagenic products by prostaglandin synthetase. Cancer Res. 42, 1620–1623.PubMedGoogle Scholar
  16. 16.
    Dix, T. A., Buck, J. R., and Mamett, L. J. (1986) Hydroperoxide-dependent epoxidation of of 3,4-dihydroxy-3,4-dihydroben2o[a]anthracene by ram seminal vesicles and by hematin. Biochem. Biophys. Res. Comm. 140, 181–187.PubMedCrossRefGoogle Scholar
  17. 17.
    Eling, T. E., Curtis, J., Battista, J. R., and Marnett, L. J. (1986) Oxidation of (+)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene by mouse keratinocytes: evidence for peroxyl radical- and monooxygenase-dependent metabolism. Carcinogenesis 7, 1957–1963.PubMedCrossRefGoogle Scholar
  18. 18.
    Deutsch, J., Leutz, J. C., Yang, S. K., Gelboin, H. V., Chang, Y. L., Vatsis, K. P., and Coon, M. J. (1978) Regio- and stereoselectivity of various forms of cytochrome P-450 in the metabolism of benzo[a]pyrene and (±)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene as shown by product formation and binding to DNA . Proc. Natl. Acad. Sci. USA 75, 3123–3127.PubMedCrossRefGoogle Scholar
  19. 19.
    Thakker, D. R., Yagi, H., Akagi, H., Koreeda, M., Lu, A. Y. H., Levin, W., Wood, A. W., Conney, A. H., and Jerina, D. M. (1977) Stereoselective metabolism of benzo [a]pyrene and benzo[a]pyrene-7,8-dihydrodiol to diolepoxides. Chem. Biol. Interactions 16, 281–300.CrossRefGoogle Scholar
  20. Preuss-Schwartz, D., Nimesheim, A., and Marnett, L.J., submitted for publication.Google Scholar
  21. 21.
    Levin, W., Wood, A. W., Chang, R. L., Slaga, T. J., Yagi, H., Jerina, D. M., and Conney, A. H. (1977) Marked differences in the tumor-initiating activity of optically pure (+)- and (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene on mouse skin. Cancer Res. 37, 2721–2725.PubMedGoogle Scholar
  22. 22.
    Slaga, T. J., Klein-Szanto, A. J. P., Triplett, L. L., Yotti, L. P., and Trosko, J. E. (1981) Skin tumor promoting activity of benzoyl peroxide, a widely used free radical generating compound. Science 213, 1023–1025.PubMedCrossRefGoogle Scholar
  23. 23.
    Slaga, T. J., Solanki, V., and Logani, M. (1983) Studies on the mechanism of action of antitumor promoting agents: suggestive evidence for the involvement of free radicals in prannotion. In Nygaard, O. and Simic, M. G. (eds) Radioprotectors and Anticarcinogens Academic Press, New York, pp 471–485.Google Scholar
  24. 24.
    Bollag, W. (1972) Prophylaxis of chemically induced benign and malignant epithelial tumors by vitamin A acid (retinoic acid).Eur. J. Cancer 8, 689–693.PubMedCrossRefGoogle Scholar
  25. 25.
    Verma, A. K., Rice, H. M., Shapas, B. G., and Boutwell, R. K. (1978) Cancer Res. 38, 793–801.PubMedGoogle Scholar
  26. 26.
    Verma, A. K., Shapas, B. G., Rice, H. M., and Boutwell, R. K. (1979) Cancer Res. 39, 419–425.PubMedGoogle Scholar
  27. 27.
    Roberts, A. B. and Sporn, M. B. (1984) Cellular biology and biochemistry of the retinoids. In Spom, M. B., Roberts, A. B., and Goodman, D. S. (eds) The Retinoids Vol. 2 Academic Press, New York, pp 210–286.Google Scholar
  28. 28.
    Verma, A.K. and Boutwell, R. K. (1977) Vitamin A acid (retinoic acid), a potent inhibitor of 12-0-tetradecanoyl-phorbol-13-acetate-induced ornithine decarboxylase activity in mouse epidermis. Cancer Res. 37, 2196–2201.PubMedGoogle Scholar
  29. 29.
    Cope, F. O., Howard, B. D., and Boutwell, R. K. (1986) The in vitro characterization of the inhibition of mouse brain protein kinase-C by retinoids and their receptors. Experientia 42, 1023–1027.PubMedCrossRefGoogle Scholar
  30. 30.
    Samokyszyn, V. M., Sloane, B. F., Honn, K. V., and Marnett, L. J. (1984) Cooxidation of 13-cis retinoic acid by prostaglandin H synthase. Biochem. Biophys. Res. Comm. 124, 430–436.PubMedCrossRefGoogle Scholar
  31. 31.
    Samokyszyn, V.M. and Mamett, L.J. (1987) J. Biol. Chem. in press.Google Scholar
  32. Fischer, S. M., Klein-Szanto, A. J. P., Adams, L. M., and Slaga, T. J. (1985) Carcinogenesis 6, 575–578.PubMedCrossRefGoogle Scholar
  33. Forbes, P. D., Urbach, F., and Davies, R. E. (1979) Enhancement of experimental photocarcinogenesis by topical retinoic acid. Cancer Letts. 7, 85–90.CrossRefGoogle Scholar
  34. 34.
    Hennings, H., Wenk, M. L., and Donahoe, R. (1982) Retinoic acid promotion of papillcxna formation in mouse skin. Cancer Letts. 16, 1–5.CrossRefGoogle Scholar
  35. 35.
    Spom, M. B. and Roberts, A. B. (1984) Biological methods of analysis and assay of retinoids — relationships between structure and activity. In Spom, M. B., Roberts, A. B., and Goodman, D. S. (eds) The Retinoids Vol. 2 Academic Press, New York, pp 236–279.Google Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • Lawrence J. Marnett
    • 1
  1. 1.Department of ChemistryWayne State UniversityDetroitUSA

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