Redox dependence of the rate of interaction of hydroxyl radical adducts of DNA nucleobases with oxidants: Consequences for DNA strand breakage

Oxidants and oxygen enhance the sensitivity of cells to radiation. To understand this effect at the mechanistic level, the kinetics of interaction of the OH adducts of pyrimidines and 2'-deoxynucleosides with oxidants (quinones, viologens, nitroarenes) of differing one-electron reduction potentials (-447 to 99 mV) have been determined in aqueous solution at pH 7.5-8 using the technique of pulse radiolysis. With quinones and viologens, this interaction produces the one-electron-reduced species of the oxidants, with rate constants (3.0 x 10(6) to 2.0 x 10(9) dm(3) mol(-1) s(-1)), which depend significantly on the redox potential of the oxidant. This dependence is consistent with an outer-sphere electron-transfer mechanism. In contrast, an addition (nitroxyl) adduct is formed with nitroarenes with rate constants that are weakly if at all dependent on the one-electron redox potentials of the nitroarenes. Using poly C as a probe for strand breakage, the resulting nitroxyl adduct of the nucleobase radical species in the absence of oxygen leads to strand breakage involving a base to sugar transfer of the radical site with a rate constant of 2.7 s(-1). In contrast with benzoquinone, the resulting carbocation of the cytosine moiety of poly C does not result in strand breakage but leads to a decrease in the yield of ssb by similar to 60%. Therefore nitroarenes mimic the effects of oxygen in leading to ssb on interaction with hydroxyl radical damage of nucleobases.