Antioxidants as Blocking Agents Against Nitrosamine Formation

  • William J. Mergens
  • Harold L. Newmark

Abstract

N-nitroso compounds have been known since they were first synthesized in Germany in the mid-nineteenth century. They have been extensively used in organic synthesis, analytical chemistry and 1 research for over a century. However, in 1954, Barnes and Magee found that dimethylnitrosamine (DMN) produced liver toxicity in two men in the UK. Similarly, an outbreak of acute liver toxicity in sheep in Norway was traced to the formation of DMN in fish meal preserved by nitrite.2 These events prompted the early synthetic investigations of the N-nitroso compounds, particularly by groups headed by Magee in the UK and US, and Druckrey in Germany. Their work, and that of others, rapidly showed that the N-nitroso compounds, as a group, had enormous potential for carcinogenesis. This, in turn, has led to the current deep scientific interest in the analysis, formation, and occurrence of carcinogenic N-nitroso compounds in our food supply, polluted atmosphere, drinking water, beverages, cigarette smoke, cosmetics, industrial waste and by-products, and more recently to their formation in vivo.3,4,5 It is the intention of this paper to survey several aspects of these studies and address the use of ascorbic acid and alpha-tocopherol as blocking agents to prevent the formation of these potential human carcinogens.

Keywords

Tertiary Amine Sodium Nitrite Propyl Gallate Ascorbyl Palmitate Nitroso Compound 
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.

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References

  1. 1.
    J. M. Barnes and P. N. Magee, Some toxic properties of dimethylnitrosamine, Brit. J. Industrial Med. 11:167 (1954).Google Scholar
  2. 2.
    F. Ender, G. Havre, A. Helgebostad, N. Koppang, R. Madsen, and L. Ceh, Insolation and identification of a hepatotoxic factor in herring meal produced from sodium nitrite preserved herring, Naturwissenschaften 24: 637 (1964).Google Scholar
  3. 3.
    D. H. Fine, R. Ross, D. P. Rounbehler, A. Silvergleid, and L. Song, Formation in vivo of volatile N-nitrosamines, Nature 265: 753 (1977).Google Scholar
  4. 4.
    R. M. Hicks, T. A. Gough, and C. L. Walters, Demonstration of the presence of nitrosamines in human urine: preliminary observations on a possible etiology for bladder cancer in association with chronic urinary tract infection, in: “Environmental Aspects of N-Nitroso Compounds,” E. A. Walker, M. Castegnaro, L. Griciute, R. E. Lyle, eds., IARC Publication #19, Lyon (1978).Google Scholar
  5. 5.
    L. Lakritz, A. Wasserman, R. Gates, and A. Spinelli, Preliminary observations on amines and nitrosamines in non-normal human gastric contents, in: “Environmental Aspects of N-Nitroso Compounds,” E. A. Walker, M. Castegnaro, L. Griciute, R. E. Lyle, eds., IARC Publication #19, Lyon (1978).Google Scholar
  6. 6.
    P. N. Magee and J. M. Barnes, Carcinogenic N-nitroso compounds, Adv. Cancer Res. 10:163 (1967).Google Scholar
  7. 7.
    B. Terracini, P. N. Magee, and J. M. Barnes, Hepatic pathology in rats on low dietary levels of dimethylnitrosamine, Br. J. Cancer 21:559 (1967).Google Scholar
  8. 8.
    D. Fine, F. Rufeh, and B. Gunther, A group specific procedure for the analysis of both volatile and non-volatile Nnitroso compounds in picogram amounts, Anal. Letters 6(8): 731 (1973).Google Scholar
  9. 9.
    H. Druckrey, R. Freissman, S. Ivankovic and D. Schmaehl, Organotropic carcinogenic effects of 65 different N-nitroso compounds on BD rats, Z. Krebsforschung 64:103 (1967).Google Scholar
  10. 10.
    H. Marquardt, F. Rufino, and J. H. Weisburger, Mutagenic activity of nitrite-treated foods: Human stomach cancer may be related to dietary factors, Science 196: 1000 (1977).Google Scholar
  11. 11.
    M. L. Douglas, B. L. Kabacoff, G. A. Anderson, and M. C. Cheng, The chemistry of nitrosamine formation, inhibition, and destruction, J. Soc. Cosmet. Chem. 29:581 (1978).Google Scholar
  12. 12.
    S. S. Mirvish, Formation of N-nitroso compounds. Chemistry, kinetics, and in vivo occurrence, Tox. Appl. Pharmacol.31:325 (1975).Google Scholar
  13. 13.
    J. H. Ridd, Nitrosation, Diazotization, and Deamination, Q. Rev. Chem. Soc. 15:418 (1961).Google Scholar
  14. 14.
    P. A. S. Smith and H. G. Pars, Nitrosative cleavage of N’, N’-dialkylhydrazides and tertiary amines, J. Org. Chem.24:1325 (1959).Google Scholar
  15. 15.
    P. A. S. Smith and R. N. Leoppky, Nitrosative cleavage of tertiary amines, J. Amer. Chem. Soc. 89:1147 (1967).Google Scholar
  16. 16.
    W. Fiddler, J. W. Pensabene, R. C. Doerr, and A. E. Wasserman, Formation of N-nitrosodimethylamine from naturally occurring quaternary ammonium compounds and tertiary amines, Nature 236: 307 (1972).Google Scholar
  17. S. S. Mirvish, Kinetics of Nitrosamide Formation from alkylureas, N-alkylurethans, and alkylguanidines. Possible implications for the etiology of human gastric cancer, J. Nat. Cancer Inst. 46:1183 (1971).Google Scholar
  18. 18.
    S. S. Mirvish, Kinetics of N-nitrosation reactions in relation to tumorigenesis experiments with nitrite plus amines or urea, in: “N-Nitroso Compounds: Analysis and Formation,” P. Bogovski, R. Preussmann, E. A. Walker, eds., IARC Scientific Publications No. 3, Lyon (1974).Google Scholar
  19. 19.
    E. H. White, The chemistry of N-alkyl-N-nitrosamides. I. Methods of preparation, J. Amer. Chem. Soc. 77: 6008 (1955).CrossRefGoogle Scholar
  20. 20.
    J. D. Okun and M. C. Archer, Kinetics of nitrosamine formation in the presence of micelle forming surfactants, J. Natl. Cancer Inst. 58(2):409 (1977).Google Scholar
  21. 21.
    J. J. Kamm, T. Dashman, A. H. Conney, and J. J. Burns, Protective effect of ascorbic acid on hepatotoxicity caused by sodium nitrite plus aminopyrine, Proc. Nat. Acad. Sci. USA 70(5):747 (1973).Google Scholar
  22. 22.
    M. Greenblatt, Ascorbic acid blocking of aminopyrine nitrosation in NZO/BL mice, J. Natl. Cancer Inst. 50:1055 (1973).Google Scholar
  23. 23.
    E. A. Walker, B. Pignatelli, and M. Castegnaro, Catalytic effect of p-nitrosophenol on the nitrosation of diethyl-amine, J. Agric. Food Chem. 27(2):393 (1979).Google Scholar
  24. 24.
    S. Singer, Kinetics and mechanism of aliphatic transnitrosation, J. Org. Chem. 43(24):4612 (1978).Google Scholar
  25. 25.
    W. J. Mergens, J. J. Kamm, H. L. Newmark, W. Fiddler, and J. Pensabene, Alpha-tocopherol: uses in preventing nitrosamine formation, in: “Environmental Aspects of N-Nitroso Compounds,” E. A. Walker, M. Castegnaro, L. Griciute, R. E. Lyle, eds., IARC Publication No. 19, Lyon (1978).Google Scholar
  26. J. J. Kamm, T. Dashman, H. Newmark, and W. J. Mergens, Inhibition of amine-nitrite hepatotoxicity by alpha-tocopherol, Tox. and Appl. Pharm. 41:575 (1977).Google Scholar
  27. 27.
    B. Astill, Phenolic antioxidants and the inhibition of hepatotoxicity from dimethylnitrosamine found in situ in the rat stomach, Food Cosmet. Toxicol. 15:167 (1977).Google Scholar
  28. 28.
    J. S. Patton and M. C. Carey, Watching fat digestion, Science 204: 145 (1979).Google Scholar
  29. 29.
    W. Fiddler, J. Pensabene and A. Wasserman, The role of lean and adipose tissue on the formation of nitrosopyrrolidine in fried bacon, J. Food Sci. 59:1070 (1974).Google Scholar
  30. 30.
    W. J. Mergens and W. Fiddler, unpublished work (1979).Google Scholar
  31. 31.
    J. H. Weisburger, L. A. Cohen, and E. L. Wynder, On the Etiology and metabolic epidemiology of the main human cancers, in: “Origins of Human Cancer,” H. H. Hiatt, J. D. Watson, J. A. Winsten, eds., Cold Spring Harbor, New York (1977).Google Scholar
  32. 32.
    S. S. Mirvish, Blocking the formation of N-nitroso compounds with ascorbic acid in vitro and in vivo, Ann. NY Acad. Sci. 258:175 (1975).Google Scholar
  33. 33.
    S. R. Tannenbaum, D. Fett, V. R. Young, P. Land and W. R. Bruce, Nitrite and nitrate are formed by endogenous synthesis in the human intestine, Science 200: 1487 (1978).Google Scholar
  34. 34.
    T. Wang, T. Kakizoe, P. Dion, R. Furrer, A. J. Varghese, and W. R. Bruce, Volatile nitrosamines in normal human feces, Nature 276: 280 (1978).Google Scholar
  35. 35.
    D. Fine, An assessment of human exposure to N-nitroso compounds, in: “Environmental Aspects of N-Nitroso Compounds,” E. A. Walker, M. Castegnaro, L. Griciute, R. E. Lyle, eds., IARC Scientific Publication No. 19, Lyon (1978).Google Scholar
  36. 36.
    T. A. Gough, K. S. Webb, and R. F. Coleman, Occurrence of volatile nitrosamines, Nature 272: 162 (1978).Google Scholar
  37. 37.
    E. Boyland, E. Nice, and K. Williams, The catalysis of nitrosation by thiocyanate from saliva, Fd. Cosmet. Toxicol. 9:639 (1971).Google Scholar
  38. 38.
    L. K. Keefer and P. P. Roller, N-nitrosation by nitrite ion in neutral and basic medium, Science 18: 1245 (1973).Google Scholar
  39. 39.
    P. N. Magee, R. Montesano, and R. Preussmann, N-nitroso compounds and related carcinogens, in: “Chemical Carcinogens,” C. Searle, ed., ACS Monograph 173, (1976).Google Scholar
  40. 40.
    J. Sander, Nitrosaminsynthese durch bakterien, Hopper Seyler’s, Z. Physiol. Chem. 349:429 (1968).Google Scholar
  41. 41.
    P. Klubes and W. R. Jondurf, Dimethylnitrosamine formation from sodium nitrite and dimethylamine by bacterial flora of rat intestine, Chem. Path. Pharmac. 2:24 (1971).Google Scholar
  42. 42.
    P. Klubes, I. Cerna, A. D. Rabinowitz, and W. R. Jondurf, Factors affecting dimethylnitrosamine formation from simple precursors by rat intestinal bacteria, Fd. Cosmet. Toxicol. 10:757 (1972).Google Scholar
  43. 43.
    A. J. Varghese, P. C. Land, R. Furrer, and W. R. Bruce, Nonvolatile N-nitroso compounds in human feces, in: “Environmental Aspects of N-Nitroso Compounds,” E. A. Walker, M. Castegnaro, L. Griciute, R. E. Lyle, eds., IARC Scientific Publication No. 19, Lyon (1978).Google Scholar
  44. 44.
    W. R. Bruce, A. J. Varghese, S. Wang, and P. Dion, The endogenous production of nitroso compounds in the colon and cancer at that site, in: “Naturally Occurring Carcinogens-Mutagens and Modulators of Carcinogenesis,” E. C. Miller, J. A. Miller, I. Hirono, T. Sugimura, and S. Takayama, eds., University Park Press, Baltimore (1979).Google Scholar
  45. 45.
    V. G. Bowen and R. H. Kiebel, Effects of nitrite and ascorbate on botulinal toxin formation in weiners and bacon, Proc. Meat Industry Research Conf. pp. 63–68 (1974).Google Scholar
  46. 46.
    W. Fiddler, J. Pensabene, E. H. Piotrowski, J. G. Phillips, J. Keating, W. J. Mergens, and H. L. Newmark, Inhibition of formation of volatile nitrosamines in fried bacon by the use of cure-solubilized alpha-tocopherol, J. Agric. Food Chem. 26(3):653 (1978).Google Scholar
  47. 47.
    N. P. Sen, B. Donaldson, S. Seaman, J. R. Iyengar, and W. F. Miles, Inhibition of nitrosamine formation in fried bacon by propyl gallate and L-ascorbyl palmitate, J. Agric. Food Chem. 24:397 (1976).Google Scholar
  48. 48.
    C. L. Walters, M. W. Edwards, T. S. Elsey, and M. Martin, The effect of antioxidants on the production of volatile nitrosamines during the frying of bacon, Z. Lebensm. Unters.-Forsch. 162:377 (1976).Google Scholar
  49. 49.
    L. J. Rubin and K. R. Bharucha, Long chain acetals of ascorbic acid, Paper presented at the Expert Panel on Nitrite and Nitrosamines, Washington, D.C., August 17, 1977.Google Scholar
  50. 50.
    American Meat Institute in collaboration with Hoffmann-La Roche Inc., unpublished study (1978).Google Scholar
  51. 51.
    R. Bonnett, A. Charalambides, M. Hursthouse, K. Malik, P. Nicolaidou, and G. Sheldrick, The reaction of ethoxyquin (6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline) with nitrous acid, J. Chem. Soc. Perkin trans I 2:488 (1979).Google Scholar

Copyright information

© Springer Science+Business Media New York 1980

Authors and Affiliations

  • William J. Mergens
    • 1
  • Harold L. Newmark
    • 1
  1. 1.Hoffmann-La Roche Inc.NutleyUSA

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