Carcinogenic compounds adducts with nucleic acids

Another source of modified bases in both DNA and RNA is spontaneous or "accidental" alteration. Nucleic acids encounter many highly reactive and mutagenic materials including hydroxyl radicals, formed from 02, and are able to convert guanine rings into 7,8-dihydro-8-oxoguanine.362 Other reactive and carcinogenic compounds can form adducts with nucleic acid bases.363 See Eq. 5-18 and also Chapter 27. 

The reactive nitrenium or carbonium ions postulated to be produced will react with nucleophilic groups in nucleic acids, proteins, and sulfydryl compounds such as glutathione (GSH) and methionine. The arylation of DNA by acetylaminofluorene has been demonstrated in vivo and in vitro. The involvement of sulfate conjugation brings other factors into play. Depletion of body sulfate reduces, and supplementation with organic sulfate increases the carcinogenicity of acetylaminofluorene. The production of covalent adducts between acetylaminofluorene and cellular macromolecules in vivo can be shown to be correspondingly decreased and increased by manipulation of body sulfate levels. 

N,0-Acyltransferase. The /V-acyl transferase enzyme is believed to be involved in the carcinogenicity of arylamines. These compounds are first V-oxidized, and then, in species capable of their A-acetylation, acetylated to arylhydroxamic acids. The effect of N, O-transacetylation is shown in Figure 7.22. The A/-acyl group of the hydroxamic acid is first removed and is then transferred, either to an amine to yield a stable amide or to the oxygen of the hydroxylamine to yield a reactive N-acyloxyarylaminc. These compounds are highly reactive in the formation of adducts with both proteins and nucleic acids, and N, O -acy I Iransfcrasc, added to the medium in the Ames test, increases the mutagenicity of compounds such as A-hydroxy-2-acetylaminofluorine. 

As discussed above, the majority of ultimate chemical mutagens and chemical carcinogens and also many cytotoxic agents possess electrophilic reactivity. It is generally believed that reaction between electrophilic centres in such toxicants with nucleophilic centres in informational or important structural or functional macromolecules is the key event in the toxicity of such compounds. Furthermore the determination of covalent adducts with proteins and nucleic acids may provide the basis of a valuable approach not only for the detection of cytotoxic and genotoxic activities but also in discriminating between these activities. 

---