The organic chemistry of nitrosamines is well developed with regard to their syntheses, their structures, and their reactions. They are usually produced by the reaction of nitrous acid and secondary amines. The nitrous acid usually arises from protonation of nitrite. This synthesis method is relevant to the generation of nitrosamines under some biological conditions. With regards to structure, the C2N2O core of nitrosamines is planar, as established by X-ray crystallography. The N-N and N-O distances are 132 and 126 pm, respectively in dimethylnitrosamine. Nitrosamines are not directly carcinogenic. Metabolic activation is required to convert them to the alkylating agents that modify bases in DNA, inducing mutations. The specific alkylating agents vary with the nitrosamine, but all are proposed to feature alkyldiazonium centers.
History and occurrence
In 1956, two British scientists, John Barnes and Peter Magee, reported that dimethylnitrosamine produced liver tumours in rats. Subsequent studies showed that approximately 90% of the 300 nitrosamines tested were carcinogenic in a wide variety of animals. A common way ordinary consumers are exposed to nitrosamines is through cigarette smoke. Tobacco-specific nitrosamines can also be found in American dip snuff, chewing tobacco, and to a much lesser degree, snus. Nitrosamines are produced by the reaction of nitrites and secondary amines. Nitrites are used as food preservatives, e.g. cured meats. Secondary amines arise by the degradation of proteins. Nitrite and nitrosamine intake are associated with risk of gastric cancer and oesophageal cancer. In the 1970s, an elevated frequency of liver cancer was found in Norwegianfarm animals. The farm animals had been fed on herring meal, which was preserved using sodium nitrite. The sodium nitrite had reacted with dimethylamine in the fish and produced dimethylnitrosamine.
Inhibition
Endogenous nitrosamine formation can be inhibited by ascorbic acid. In the case of formation of carcinogenic nitrosamines in the stomach from dietary nitrite, ascorbic acid markedly decreases nitrosamine formation in the absence of fat in the meal; but when 10% fat is present, this reverses the effect such that ascorbic acid then markedly increases nitrosamine formation.
