Metabolic activation of the nitrosamine NDMA, involving its conversion to an alkylating agent.
The organic chemistry of nitrosamines is well developed both with regard to their syntheses, their structures, and their reactions. They are usually produced by the reaction of nitrous acid (HNO2) and secondary amines.
HONO + R2NH -> R2N-NO + H2O
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 1.32 and 1.26 Å, 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.
Endogenous nitrosamine formation can be inhibited by ascorbic acid. In the case of formation of carcinogenic nitrosamines in the stomach from dietary nitrite (used as processed meat preservative), 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.
^Gregory N. Connolly; Howard Saxner (August 21, 2001). "Informational Update Research on Tobacco Specific Nitrosamines (TSNAs) in Oral Snuff and a Request to Tobacco Manufacturers to Voluntarily Set Tolerance Limits For TSNAs in Oral Snuff". Cite journal requires |journal= (help)
^Combet, E; El Mesmari, A; Preston, T; Crozier, A; McColl, K. E. (2010). "Dietary phenolic acids and ascorbic acid: Influence on acid-catalyzed nitrosative chemistry in the presence and absence of lipids". Free Radical Biology and Medicine. 48 (6): 763-71. doi:10.1016/j.freeradbiomed.2009.12.011. PMID20026204.
^Hecht, Steven S.; Borukhova, Anna; Carmella, Steven G. "Tobacco specific nitrosamines" Chapter 7; of "Nicotine safety and toxicity" Society for Research on Nicotine and Tobacco; 1998 - 203 pages