Peroxy Radical Oxidation of Thymidine

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Abstract
The peroxy radical (ROO•) is unique among reactive oxygen species implicated in the production of DNA damage in that it possesses an extremely long half-life (order of seconds) and is predicted to have a relatively greater chemical selectivity in its reactions relative to other radical intermediates. Yet no product studies of the reactions of ROO• with bases, nucleosides, or DNA have appeared, and thus no meaningful predictions can be made regarding its potential involvement in the production of DNA base damage and the mutagenic process. We report here on the reaction products formed by peroxy radical with thymidine, a major target of oxidative base damage. ROO• reacts with thymine to yield predominantly 5-Me oxidation products. The highly mutagenic 5-(hydroperoxymethyl)-2‘-deoxyuridine, 5-formyl-2‘-deoxyuridine, and 5-(hydroxymethyl)-2‘-deoxyuridine are produced by peroxy radical oxidation. In contrast, 5-Me oxidation products are minor products of thymidine oxidation by •OH, which yields predominantly saturated derivatives via addition to the 5,6 double bond. A plausible mechanistic scheme for the formation of the base oxidation products of thymidine by peroxy radicals is presented. Attack at the deoxyribose moiety resulting in oxidative depyrimidination is also found to occur, as indicated by free base release. Phosphodiester backbone cleavage resulting in single and double strand breaks is also catalyzed by peroxy radical, as demonstrated using a plasmid nicking assay.

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