Oxidation Reactions of Cytosine DNA Components by Hydroxyl Radical and One-Electron Oxidants in Aerated Aqueous Solutions

Indirect evidence strongly suggests that oxidation reactions of cytosine and its minor derivative 5-methylcytosine play a major role in mutagenesis and cancer. final oxidation products of these reactions, to search for their formation in cellular DNA, and to assess their mutagenic features. In this Account, we report and discuss the main (OH)-O-center dot and one-electron-mediated oxidation reactions, two of the most potent sources of DNA damage, of cytosine and 5-methylcytosine nucleosides that have been recently characterized. The addition of (OH)-O-center dot to the 5,6-unsaturated double bond of cytosine and Therefore, there is an emerging necessity to identify the 5-methylcytosine generates final degradation products that resemble those observed for uracil and thymine. The main product from the oxidation of cytosine, cytosine glycol, has been shown to undergo dehydration at a much faster rate as a free nucleoside than when inserted into double-stranded DNA. On the other hand, the predominant (OH)-O-center dot addition at C5 of cytosine or 5-methylcytosine leads to the formation of 5-hydroxy-5,6-dihydro radicals that give rise to novel products with an imidazolidine structure. The mechanism of the formation of imidazolidine products is accounted for by rearrangement reactions that in the presence of molecular oxygen likely involve an intermediate pyrimidine endoperoxide. The reactions of the radical cations of cytosine and 5-methylcytosine are governed by competitive hydration, mainly at C6 of the pyrimidine ring, and deprotonation from the exocyclic amino and methyl group, leading in most cases to products similar to those generated by (OH)-O-center dot. 5-Hydroxypyrimidines, the dehydration products of cytosine and uracil glycols, have a low oxidation potential, and their one-electron oxidation results in a cascade of decomposition reactions involving the formation of isodialuric acid, dialuric acid, 5-hydroxyhydantoin, and its hydrontketone isomer. In biology, GC -> T transitions are the most common mutations in the genome of aerobic organisms, including the lad gene in bacteria, lad transgenes in rodents, and the HPRT gene in rodents and humans, so a more complete understanding of cytosine oxidation is an essential research goal. The data and insights presented here shed new light on oxidation reactions of cytosine and 5-methylcytosine and should facilitate their validation in cellular DNA.