Formation and metabolism of alkylated nucleosides: Possible role in carcinogenesis by nitroso compounds and alkylating agents

Alkylation of nucleic acids occurs both physiologically within living cells and after the administration of compounds that are either themselves direct chemical alkylating agents or are converted into alkylating agents by metabolic activation. Some of these compounds are highly potent carcinogens. Carcinogenicity of these agents is due to the alkylation of certain cellular components because no other degradation product nor is the compound itself oncogenic. This chapter deals with the formation and metabolism of alkylated purines in nucleic acids. It briefly discusses other alkylation reactions leading to the alkylphosphate triester production and alkylated pyrimidines. It also presents evidences favoring particular critical targets for the action of alkylating carcinogens. The attack on nucleic acids by carcinogenic alkylating agents is not entirely random and generally leads to the formation of alkylated nucleosides at many different sites distributed throughout the cellular nucleic acids. Carcinogenesis is not necessarily mediated through mutagenesis in somatic cells. However, it is observed that carcinogenic action could be mediated through a distinct action of the electrophilic reactant.