Significance of electrophilic reactivity and especially DNA alkylation in carcinogenesis and mutagenesis.
Alkylating agents have proved useful as models, especially for low molecular weight mutagens and carcinogens, to probe molecular mechanisms of genotoxicity. Results of many studies have indicated that not all DNA substitutions cause mutagenic or carcinogenic responses. Often, quantitatively minor alkylation products are responsible for initiating these biological processes. The factors that influence the distribution of DNA substitution products include: the SN1 reactivity of the electrophilic species; the nucleophilicity and steric accessability of the DNA site; van der Waals or electrostatic interactions that attract the agent to specific DNA sites; and post-alkylation rearrangements. With low molecular weight alkylating agents, a primary determinant of product distribution in DNA, and of genotoxic potential, is the electrophilic reactivity. Agents with high SN1 reactivity (low Swain -Scott s factors) generally have high mutagenic and carcinogenic activity, at equal levels of total DNA alkylkation . This appears to be due to the ability of such agents to cause relatively more alkylation at oxygen sites in DNA, especially at O6 of guanine and at O4 of thymine. Alkylation of DNA alone is insufficient to induce cancer or mutations. Post-alkylation factors such as DNA repair, rate of cell turnover, or presence of tumor promoters can have a profound effect on the biological response to DNA damage (1,5,6,24,42). In this sense, the persistence of a specific miscoding of altered DNA base is significant in carcinogenesis or mutagenesis only to the extent that it remains in DNA long enough to be fixed into the code. This concept necessarily assumes that the altered base has promutagenic potential. Persistence of an alkylated DNA constituent does not, by itself, indicate that the alkylated constituent has biological significance.
D000477:Alkylating Agents / Q000633:toxicity*; D000478:Alkylation; D000818:Animals; D004247:DNA / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D006801:Humans; D009153:Mutagens; D009154:Mutation; D009369:Neoplasms / Q000139:chemically induced*; D010710:Phosphates / Q000378:metabolism; D011687:Purines / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism
D000477:Alkylating Agents; D009153:Mutagens; D010710:Phosphates; D011687:Purines; D011743:Pyrimidines; D004247:DNA