84 - The Critical Role of Quinone-Enoxy Radicals in the Production of the More Mutagenic dIz from DNA by Carcinogenic Halogenated Quinones and Hydroperoxides

Abstract

Halogenated quinones (XQ) are a class of carcinogenic intermediates and newly identified chlorination disinfection byproducts in drinking water. We found recently that XQ could enhance hydroperoxide decomposition and formation of alkoxyl and quinone enoxy/ketoxy radicals metal-independently. However, it is not clear whether XQ/hydroperoxides can oxidize dG to its oxidation products, and if so, what is the underlying molecular mechanism. Here we show that the major oxidation product was dIz when dG was treated with tetrachloro-1,4-benzoquinone (TCBQ) and t-BuOOH, which was markedly inhibited by typical spin-trapping agents. Further ESR and HPLC/MS results showed that the quinone enoxy radicals played a critical role in dIz formation, and O2 was also involved in dIz formation by using oxygen-18-labelled O2. We proposed that the oxidation of dG by TCBQ/t-BuOOH might be through the following mechanism: the quinone enoxy radical may first abstract H from dG, forming dG(-H)• radical, which may combine with O2 to form its corresponding hydroperoxide, resulting in a cascade of decomposition reactions leading to dIz formation. This is the first report that XQ/hydroperoxides can induce potent oxidation of dG to dIz via a quinone-enoxy radical-mediated mechanism, which may partly explain their potential carcinogenicity.