In Vivo Formation and Persistence of Modified Nucleosides Resulting from Alkylating Agents

Alkylating agents are ubiquitous in the human environment and are continuously synthesized in vivo. Although many classes exist, interest has been focused on the N-nitroso compounds, since many are mutagens for bacteria, phage, and cells, and carcinogens for mammals. In contrast to aromatic amines and polyaromatic hydrocarbons which can react at carbons, simple alkylating agents react with nitrogens and oxygens: 13 sites are possible, including the internucleotide phosphodiester. However, only the N-nitroso compounds react extensively with oxygens. In vivo, most possible derivatives have been found after administration of methyl and ethyl nitroso compounds. The ethylating agents are more reactive toward oxygens than are the methylating agents and are more carcinogenic in terms of total alkylation. This is true regardless of whether or not the compounds require metabolic activation. It has been hypothesized that the level and persistence of specific derivatives in a "target" cell correlates with oncogenesis. However, no single derivative can be solely responsible for this complex process, since correlations cannot be made for even a single carcinogen acting on various species or cell types. Some derivatives are chemically unstable, and the glycosyl bond is broken (3- and 7-alkylpurines), leaving apurinic sites which may be mutagenic. These, as well as most adducts, are recognized by different enzymatic activities which remove/repair at various rates and efficiencies depending on the number of alkyl derivatives, as well as enzyme content in the cell and recognition of the enzyme. Evaluation of human exposure requires early and sensitive methods to detect the initial damage and the extent of repair of each of the many promutagenic adducts.