Nucleophilic Sites in DNA

Since the results of our experiments with isolated rat liver fractions supported a reaction sequence Initiated by microsomal oxidation of the nitrosamine leading to formation of a carbonium ion, the results of the animal experiment suggested that in the intact hepatocyte, one of the earlier electrophilic intermediates (II, III or V, Figure 1) is intercepted by nucleophilic sites in DNA (exemplified here by the N7 position of guanine) before a carbocation is formed. 

Nucleophilic Sites in DNA and the Factors that Determine the Sites... 

DNA alkylation has the potential to yield a time-dependent spectrum of adducts, in which initially formed kinetically favored lesions give way to the thermodynamically favored adducts over time. Reversible alkylation has been observed at several of the nucleophilic sites in DNA, including N3A (CC-1065,7, Scheme 8.10, duocarmycin, 8)," " NIA (qui-none methide, 9)," N7G (leinamycin, Schane 8.11, aflatoxin Bj epoxide, 10 and quinone methide, 9),57.ii4.ii8 (quinone methide, 9)," and bPG (ecteinascidin 743,11)." The bidentate Nl/ISPG adduct of malondialdehyde also forms reversibly. ... 

ELECTROPHILE An agent that, having affinity for a pair of electrons, reacts with a substance that offers a pair of electrons in bond formation (i.e., with a nucleophile) because there are many nucleophilic sites in DNA, electrophiles can react with DNA to produce a variety of adducts many mutagens and carcinogens react with DNA as electrophiles. 

The process of initiation by genotoxic carcinogens occurs when the chemical reacts with the DNA molecule. An electrophilic (electron-seeking) compound can bind covalently to certain nucleophilic sites in DNA, forming a carcinogen-DNA adduct. Some binding sites in DNA are shown below ... 

Many chemical carcinogens require metabolic activation to elicit their biological activity. Studies on the metabolism of chemical carcinogens in vivo and in vitro have shown that the formation of electrophiles capable of reacting with nucleophilic sites in DNA, RNA, and protein is a common property among ultimate carcinogens (335, 338). 

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