Nitrosamine carcinogenicity relationship

Mutagenicity. The AJ-nitrosamines, in general, induce mutations in standard bacterial-tester strains (117). As with carcinogenicity, enzymatic activation, typically with Hver microsomal preparations, is required. Certain substituted A/-nitrosamine derivatives (12) induce mutations without microsomal activation (31,33,34). Because the a-acetoxy derivatives can hydroly2e to the corresponding a-hydroxy compounds, this is consistent with the hypothesis that enzymatic oxidation leads to the formation of such unstable a-hydroxy intermediates (13) (118). However, for simple /V-nitrosamines, no systematic relationship has been found between carcinogenicity and mutagenicity (117,119—123). 

Figure 3. Proposed relationship between metabolic and chemically activated nitrosamines for producing an ultimate carcinogen or mutagen...

Structure-Activity Relationships. More interesting, and -scientifically, at least - more significant, is the question of why one nitrosamine should be more or less carcinogenic than another. In a general sense, the answer is obvious differences in reactivity within a series are, almost by definition, the result of differences in structure. This concept is one of the cornerstones of physical organic chemistry and, more recently, has been applied extensively to drug systems in a systematic and quantitative way following the initial and continued successes of Corwin Hansch and his coworkers (18-25). 

The relationship described by equation 4 indicates that most of the variation in carcinogenicity within the series of acyclic nitrosamines can be associated with water-hexane partition coefficients and electronic inductive effects of substituents on the a-carbons. 

This equation is a fairly typical biological structure-activity relationship with a strong dependence on partition coefficients, and it therefore suggests that the nitrosamines, and perhaps other chemical carcinogens as well, are similar - in the pharmacological sense - to analgesics or toxic agents. 

Nitrosamine is known to be carcinogenic as it leads to liver cancer. Relationships between vitamin E and nitrosamines are attributed to the inhibitory effect of the vitamin on nitrosamine formation, i.e., vitamin E competes for nitrite, a reactant in the formation of nitrosamine. 

Wishnok JS, Archer MC, Edelman AS, Rand WM. Nitrosamine carcinogenicity A quantitative Hansch-Taft structure-activity relationship. Chem Biol Interact 1978 20 43-54. 

Hecht, S.S., A. Castongnay, F.L. Chnng, and D. Hoffmann Carcinogenicity and metahohc activation of tohacco-specific nitrosamines cnrrent statns and future prospects in A-Nitroso compounds Occurrence, biological effects and relationship to human cancer, edited hy I.K. O Neill, R.C. von Borstel, C.T. Miller, J. Long, and F. Bartsch, LARC, Lyon, France, lARC Sci. Publ. No. 57 (1984) 763-768. 

In this article we will outline in vitro metabolic studies which have been performed on representatives of several classes of carcinogens. These studies have been selected from the literature through 1979. Metabolic studies which employed various cellular subfractions, cell culture, or organ culture systems will be compared. The effect of species variations on in vitro metabolism will also be considered. The relationship of these in vitro studies to current concepts on metabolic activation and detoxification will be discussed for aromatic amines, polycyclic aromatic hydrocarbons, nitrosamines, hydrazines, azoxy compounds, halogenated hydrocarbons, and carcinogenic natural products. 

Wishnok, J. S., Archer, M. C., Edelmann, A. S. and Rand, W. M. (1978) Nitrosamine carcinogenicity a quantitative Mansch-Taft structure-activity relationship. Chem. Biol Interact., 20, 43-54. 

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