Antigenotoxic and Anticarcinogenic Effects of Thiols. In Vitro Inhibition of the Mutagenicity of Drug Nitrosation Products and Protection of Rat Liver ADP-Ribosyl Transferase Activity

  • Silvio De Flora
  • Carmelo F. Cesarone
  • Carlo Bennicelli
  • Anna Camoirano
  • Domizio Serra
  • Monia Bagnasco
  • Anna I. Scovassi
  • Linda Scarabelli
  • Umberto Bertazzoni


Reduced glutathione (GSH) is well-known to play a fundamental role in the protection of the organism against toxic, mutagenic and/or carcinogenic agents (see e.g. refs. 1–3 for reviews). Among synthetic aminothiols, acting as analogs and precursors of GSH, N-acetyl-L-cysteine (NAC) is of particular interest, because this molecule is already extensively used in the treatment of chronic respiratory diseases, and is extremely well tolerated in humans4. In addition, NAC is known to possess various antitoxic and antioxidant properties3–5.


Ascorbic Acid Sodium Nitrite Diethyl Maleate Sodium Dichromate Blue Tetrazolium Chloride 
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. 1.
    D. J. Jollow, Glutathione thresholds in reactive metabolite toxicity, in: “Quantitative Aspects of Risk Assessment in Chemical Carcinogenesis”, J. Clemmesen, D. M. Conning and F. Oesch, eds., Springer-Verlag, Berlin/Heidelberg/New York, Arch. Toxicol. suppl. 3:95 (1980).CrossRefGoogle Scholar
  2. 2.
    A. Meister, Selective modification of glutathione metabolism, Science 220:470 (1983).CrossRefGoogle Scholar
  3. 3.
    S. De Flora, C. Bennicelli, D. Serra, A. Izzotti and C. F. Cesarone, Role of glutathione and N-acetylcysteine as inhibitor of mutagenesis and carcinogenesis, in: “Absorption and Utilization of Amino Acids”, M. Friedman, ed., CRC Press, Boca Raton, Florida, in press (1988).Google Scholar
  4. 4.
    J. W. Yarbro, R. S. Bornstein and M. J. Mastrangelo, eds., N-acetylcysteine (NAC): a significant chemoprotective adjunct, Seminars in Oncology 10:1 (1983).Google Scholar
  5. 5.
    P. Moldéus, I. A. Cotgreave and M. Berggren, Lung protection by thiolcontaining antioxidant: N-acetylcysteine, Respiration 50:31 (1986).PubMedGoogle Scholar
  6. 6.
    S. De Flora, C. Bennicelli, P. Zanacchi, A. Camoirano, A. Morelli and A. De Flora, In vitro effects of N-acetylcysteine on the mutagenicity of direct-acting compounds and procarcinogens, Carcinogenesis 5:505 (1984).PubMedCrossRefGoogle Scholar
  7. 7.
    S. De Flora, C. Bennicelli, A. Camoirano, D. Serra, C. Basso, P. Zanacchi and C. F. Cesarone, Inhibition of mutagenesis and carcinogenesis by N-acetylcysteine, in: “Anticarcinogenesis and Radiation Protection”, P. A. Cerutti, O. Nygaard and M. G. Simic, eds., Plenum Press, New York, in press (1988).Google Scholar
  8. 8.
    S. De Flora, Detoxification of genotoxic compounds as a threshold mechanism limiting their carcinogenicity, Toxicol. Pathol. 12:337 (1984).PubMedCrossRefGoogle Scholar
  9. 9.
    A. Camoirano, G. S. Badolati, P. Zannachi, M. Bagnasco and S. De Flora, Dual role of thiols in N-methyl-N-nitro-N-nitrosoguanidine genotoxicity, Life Science Advances-Exp. Cell Genetics 6: in press (1987).Google Scholar
  10. 10.
    S. De Flora, C. Bennicelli, A. Camoirano, D. Serra, M. Romano, G. A. Rossi, A. Morelli and A. De Flora, In vivo effects of N-acetylcysteine on glutathione metabolism and on the biotransformation of carcinogenic and/or mutagenic compounds, Carcinogenesis 6:1735 (1985).PubMedCrossRefGoogle Scholar
  11. 11.
    S. De Flora, M. Romano, C. Basso, M. Bagnasco, C. F. Cesarone, G. A. Rossi and A. Morelli, Detoxifying activities in alveolar macrophages of rats treated with acetylcysteine, diethyl maleate and/or Aroclor, Anticancer Res. 6:1009 (1986).PubMedGoogle Scholar
  12. 12.
    C. F. Cesarone, M. Romano, D. Serra, L. Scarabelli and S. De Flora, Effects of aminothiols in 2-acetylaminofluorene-treated rats. II. Glutathione cycle and liver cytosolic activities, In Vivo 1:93 (1987).Google Scholar
  13. 13.
    S. De Flora, M. Astengo, D. Serra and C. Bennicelli, Inhibition of urethan-induced lung tumors in mice by dietary N-acetyl-cysteine, Cancer Lett. 32:235 (1986).PubMedCrossRefGoogle Scholar
  14. 14.
    C. F. Cesarone, L. Scarabelli and M. Orunesu, Effect of glutathione on alterations of liver DNA structure and metabolic activities induced in vivo by 2-acetylaminofluorene, Anticancer Res. 6:1283 (1986).PubMedGoogle Scholar
  15. 15.
    C. F. Cesarone, L. Scarabelli, M. Orunesu, M. Bagnasco and S. De Flora, Effects of aminothiols in 2-acetylaminofluorene-treated rats. I. Damage and repair of liver DNA, hyperplastic foci, and Zymbal gland tumors, In Vivo 1:85 (1987).Google Scholar
  16. 16.
    S. De Flora and A. Picciotto, Mutagenicity of cimetidine in nitrite-enriched human gastric juice, Carcinogenesis 1:925 (1980).PubMedCrossRefGoogle Scholar
  17. 17.
    S. De Flora, Cimetidine, ranitidine and their mutagenic nitroso-derivatives, Lancet ii:993 (1981).CrossRefGoogle Scholar
  18. 18.
    S. De Flora, C. Bennicelli, A. Camoirano and P. Zanacchi, Genotoxicity of nitrosated ranitidine, Carcinogenesis 1A:255 (1983).CrossRefGoogle Scholar
  19. 19.
    S. De Flora, A. Camoirano, C. Basso, M. Astengo, P. Zanacchi and C. Bennicelli, Bacterial genotoxicity of nitrosated famotidine, Mutagenesis 1:125 (1986).PubMedCrossRefGoogle Scholar
  20. 20.
    S. De Flora, A. Picciotto, V. Savarino, C. Bennicelli, A. Camoirano, G. Garibotto and G. Celle, Circadian monitoring of gastric juice mutagenicity, Mutagenesis 2:115 (1987).PubMedCrossRefGoogle Scholar
  21. 21.
    G. W. Teebor and F. F. Becker, Regression and persistence of hyper-plastic nodules induced by N-2-fluorenylacetamide and their relationship to hepatocarcinogenesis, Cancer Res. 31:1 (1971).PubMedGoogle Scholar
  22. 22.
    S. Shall, ADP-ribose in DNA repair: A new component of DNA excision repair, Adv. Rad. Biol. 11:1 (1984).Google Scholar
  23. 23.
    K. Ueda, ADP-ribosylation, Ann. Rev. Biochem. 54:73 (1985).PubMedCrossRefGoogle Scholar
  24. 24.
    A. I. Scovassi, M. Stefanini, P. Lagomarsini, R. Izzo and U. Bertazzoni, Response of mammalian ADP-ribosyl transferase to lymphocyte stimulation, mutagen treatment and cell cycling, Carcinogenesis 8:1295 (1987).PubMedCrossRefGoogle Scholar
  25. 25.
    C. F. Cesarone, A. I. Scovassi, L. Scarabelli, R. Izzo, M. Orunesu and U. Bertazzoni, Loss of ADP-ribosyl transferase activity in liver of rats treated with 2-acetylaminofluorene, in: “Proceedings of the 8th International Symposium on ADP-Ribosylation: Niacin Nutrition, ADP-Ribosylation and Cancer”, Ft. Worth, Texas, USA, May 30-June 3 (1987).Google Scholar
  26. 26.
    A. I. Scovassi, M. Stefanini and U. Bertazzoni, Catalytic activities of human poly(ADP-ribose) polymerase from normal and mutagenized cells detected after sodium dodecyl sulfate polyacrylamide gel electro-phoresis, JL Biol. Chem. 259:10973 (1984).Google Scholar
  27. 27.
    D. M. Maron and B. N. Ames, Revised methods for the Salmonella utagenicity test, Mutat. Res. 113:173 (1983).PubMedCrossRefGoogle Scholar
  28. 28.
    C. Bennicelli, A. Camoirano, S. Petruzzelli, P. Zanacchi and S. De Flora, High sensitivity of Salmonella TA102 in detecting hexa-valent chromium mutagenicity and its reversal by liver and lung preparations, Mutat. Res. 122:1 (1983).PubMedCrossRefGoogle Scholar
  29. 29.
    H. Towbin, T. Staehelin and J. Gordon, Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications, Proc. Natl. Acad. Sci. USA 76:4350 (1979).PubMedCrossRefGoogle Scholar
  30. 30.
    S. S. Mirvish, Ascorbic acid inhibition of N-nitroso compound formation in chemical, food and biological systems, in: “Inhibition of Tumor Induction and Development”, M. S. Zedek and M. Lipken, eds., Plenum Press, New York (1981).Google Scholar
  31. 31.
    H. Bartsh, H. Ohshima, J. Nair, B. Pignatelli and S. Calmels, Modifiers of endogenous nitrosamine synthesis and metabolism, in: “Antimutagenesis and Anticarcinogenesis Mechanisms”, D. M. Shankel, P. E. Hartman, T. Kada and A. Hollaender, eds., Plenum Press, New York (1986).Google Scholar
  32. 32.
    J. B. Guttenplan, Mechanisms of inhibition by ascorbate of microbial mutagenesis induced by N-nitroso compounds, Cancer Res. 38:2018 (1978).PubMedGoogle Scholar
  33. 33.
    P. Sen, Formation and occurrence of nitrosamines in food, in: “Diet, Nutrition and Cancer: a Critical Evaluation”, Vol.11. Micronutrients, Nonnutritive Dietary Factors, and Cancer, B. S. Reddy and L. A. Cohen, eds., CRC Press, Boca Raton, Florida (1986).Google Scholar
  34. 34.
    S. De Flora, A. Camoirano, C. Bennicelli, M. Orunesu and C. F. Cesarone, Effects of aminothiols in 2-acetylaminofluorene-treated rats. III. Metabolic activation of aromatic amines, In Vivo 1:101 (1987).PubMedGoogle Scholar
  35. 35.
    E. Farber, S. Parker and M. Gruenstein, The resistance of putative premalignant liver cell populations, hyperplastic nodules, to the acute cytotoxic effects of some hepatocarcinogens, Cancer Res. 36:3879 (1976).PubMedGoogle Scholar
  36. 36.
    M. H. Hanigan and H. C. Pitot, Gamma-glutamyl transpeptidase. Its role in hepatocarcinogenesis, Carcinogenesis 6:165 (1985).PubMedCrossRefGoogle Scholar
  37. 37.
    L. Roy Morgan, M. R. Holdiness and L. E. Gillen, N-acetylcysteine: its bioavailability and interaction with isofosfamide metabolites, Seminars in Oncology, suppl. 1, 10:56 (1983).Google Scholar
  38. 38.
    D. Reed, A. Brodie and M. Meredith, Cellular heterogeneity in the status and function of cysteine and glutathione, in: “Function of Glutathione”, A. Larsson, A. Holmgren, S. Orrenius and B. Mannervik, eds., Raven Press, New York (1983).Google Scholar

Copyright information

© Springer Science+Business Media New York 1988

Authors and Affiliations

  • Silvio De Flora
    • 1
  • Carmelo F. Cesarone
    • 1
    • 2
  • Carlo Bennicelli
    • 1
  • Anna Camoirano
    • 1
  • Domizio Serra
    • 1
  • Monia Bagnasco
    • 1
  • Anna I. Scovassi
    • 1
    • 3
  • Linda Scarabelli
    • 1
    • 2
  • Umberto Bertazzoni
    • 1
    • 3
  1. 1.Institute of Hygiene and Preventive MedicineUniversity of GenoaGenoaItaly
  2. 2.Institute of General PhysiologyUniversity of GenoaGenoaItaly
  3. 3.CNR Institute of Biochemical and Evolutionary GeneticsPaviaItaly

Personalised recommendations