Nitrosamine metabolites

C. A. Reynolds and C. Thomson, Int. J. Quantum Chem., 30, 751 (1986). A Theoretical Study of N-Nitrosamine Metabolites Possible Alkylating Species in Carcinogenesis by N,N -Dimethylnitrosamine. 

Nitrosamines are not carcinogenic at the point of application. They require bioactivation. One possible mechanism of biotransformation is by enzymatic transformation to a carbonium ion. Activation is known to proceed first by hydroxylation of an a-carbon. The resulting hydroxyalkyl moiety is eliminated as an aldehyde, and an unstable primary nitrosamine is formed. The unstable nitrosamine ultimately tautomerizes to a carbonium ion. The highly reactive carbonium ion readily alkylates with the nearby cellular macromolecules. Cancer and mutagenicity develop when reactive nitrosamine metabolites alkylate to genetic macromolecules. 

Relative Stability of alcohol, primary, secondary and tertiary models for possible cyclic nitrosamine metabolites as proposed in figure 2. All energies are in kcal/mole. 

Fig. 18.2. Mutations in DNA caused by nitrosamines. Nitrosamines are consumed in many natural products and are produced in the stomach from nitrites used as preservatives and secondary amines found in foods such as fish. They are believed to be responsible for the high incidence of gastric cancer found in Japan and Iceland, where salt-preserved fish was a major dietary item. Nitrosamine metabolites methylate guanine (the transferred methyl group is shown in blue).

Duncan, R.H., Davies, G.S. Alkylation of DNA bases by carcinogenic N-nitrosamine metabolites A theoretical study. International Journal of Quantum Chemistry 35, 665-677 (1989)... 

All of these results support the o-hydroxylation hypothesis, but they do not prove it. No o-hydroxy nitrosamine or a derivative of one has ever been isolated as a metabolite of any nitrosamine. Nevertheless, a-hydroxylation is an attractive working hypothesis and it seems to account for... 

It is known that nitrosamines with side-chains longer than methyl are metabolically hydroxylated on virtually every carbon. For example, the urinary metabolites in the rat of di-n-butylnitrosamine include the glucuronides of the following hydroxylated nitrosamines (42). 

We have developed a quantitative structure-activity model for the variations in potency among the nitrosamines and, more recently, a related model for the variation in target organ for a smaller set of nitrosamines. We are currently developing a model for interspecies variation in susceptibility toward carcinogenic nitrosamines. The model for organ selectivity requires terms for the parent nitrosamine as well as for the hypothesized metabolites while the model for potency variations contains terms only for the unmetabolized parent compound. 

In recent years greater attention has been given to nitrogen containing pesticides and the possibility of their nitrosation in soil. The N-nitrosamines that form may arise from the parent pesticide or from a pesticide metabolite. The reaction calls for favourable pH conditions (pH 3-4) and excess nitrite. Under field conditions, the nitrosable residues are usually present in traces and only small quantities of these will actually be nitrosated in soils. However, the possibility exists that the small amounts of N-nitrosamines could be assimilated by plants. 

The importance of the stereochemistry of the nitrosamine function in the mutagenicity and carcinogenicity of these compounds has not been demonstrated and yet there is considerable indirect evidence that such a stereochemical dependence may be important. It is evident that the metabolism can be related to a stereochemical factor for unsyrametrical nitrosamines. These, of course, give either of two oxygenated metabolites, and there is evidence that only one of these is mutagenic in some cases (23, 24). Thus, the metabolism may be at least regiospecific, if not stereospecific, relative to the nitrosamine function. 

Roller, P.P., Shimp, D.R. and Keefer, L.K., "Synthesis and Solvolysis of Methyl (acetoxymethy 1) nitrosamine. Solution Chemistry of the Presumed Carcinogenic Metabolite of Dimethylnitros-amine". Tetrahedron Letters, 1975, 2065-2068. 

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