Sites in nucleic acids reacting with alkylating agents of differing carcinogenicity or mutagenicity

Abstract

The site of alkylation of a nucleic acid, in vivo, is greatly dependent on the type of alkylating agent. Most alkylating agents of low mutagenicity or carcinogenicity (such as dimethylsulfate) react primarily with the ring nitrogens. The carcinogenic N-nitroso compounds have a great affinity for alkylating oxygens and react with all ring oxygens as well as the phosphodiesters and, in the case of RNA, with the 2'-O of ribose. Ethylating agents, though in absolute terms less reactive than the corresponding methylating agents, show even greater affinity toward oxygens. It appears that the ethyl nitroso compounds that are carcinogenic are also the most reactive with oxygens.

Preparation and template activities of polynucleotides containing O2- and O4-alkyluridine.

“…Singer and coworkers have demonstrated in recent years that the highly carcinogenic alkyl nitroso compounds preferentially alkylate the oxygens when acting on nucleic acids (8)(9)(10)(11)(12). One objective of current research is to ascertain the biological consequences of specific modifications of this type.…”

“…More recently, we have found that the highly carcinogenic N-nitroso alkylating agents not only favor the alkylation of the 06 of G, but also react to a high extent with all three pyrimidine oxygens (02 and 04 of U or T, 02 of C) as well as the -0 of the phosphodiesters and, in RNA, the 02' of ribose (8)(9)(10)(11)(12).…”

Chemical and Molecular Biological Aspects of Alkylhydrazine-Induced Carcinogenesis in Human Cells in Vitro. Revised

“…Alkylation of oxygen atoms of purines and pyrimidines of DNA has been suggested to be critical to mutagenesis and carcinogenesis (40) and a positive correlation has been found between tumorigenesis and the formation and persistence of the promutagenic lesion 06 alkylguanine in target tissues (12,(23)(24)(25)31,33 Ci/mmole) were supplied by New England Nuclear Corporation, (Boston, MA). Table 1).…”

Cell specificity in DNA binding and repair of chemical carcinogens.

“…It (24). O-Alkylated pyrimidines, such as O2_ and 04-thymine, occur in greater proportion relative to 06-alkylguanine following exposure to ethylating agents (27). Since the 0-alkylpyrimidines are removed from liver DNA more slowly (28,29)…”

“…Cell specificity in carcinogenesis due to alkylating agents will depend on the ability of different cell populations to activate the carcinogen, their mitogenic response, their capacity to remove promutagenic DNA lesions and the nature of the alkylating agent. For instance, the major promutagenic lesion produced by SN1 methylating agents is O6MG (27). It (24).…”