The possible mode of action of two classes of highly organ- and species-specific carcinogenic N-nitroso compounds, namely the H-nitrosamines and H-nitrosamides, is outlined in this review. Chemical or enzymatic conversion of these agents into active alkylating species is a prerequisite for their biological activity. Although these species are capable of reacting with all cellular macromolecules, there is good evidence that their ability to attack DNA is related to their carcinogenicity. This paper reviews the reasons and experimental support for the hypothesis that it is specifically alkylation of DNA at the O6 position of guanine that initiates malignant transformation, an important factor being the presence of an enzyme system capable of eliminating O6-aikyiguanine from DNA. No such repair reaction appears to exist for this or other alkylation products when they are present in RNA. The activity of this system is enhanced by chronic administration of alkylating agents, and the role that this may play in carcinogenesis is discussed.
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