Abstract
2,3-Dimercaptosuccinic acid (DMSA) has been widely used in the treatment of lead, arsenic and other heavy metal poisoning in clinic because of its low toxicity, safe and convenient administration. However, it is not clear whether DMSA can provide protection against copper-induced oxidative damage; and if so, what is its underlying molecular mechanism. In this study, we investigated the role of DMSA in copper-induced oxidative damage to DNA, using copper-containing system Cu(II)/ascorbate. Oxidative damage to DNA was measured as stand breakage and the formation of 8-oxodG. DMSA (0.1-1.0 mM) provided strong and dose-dependent protection against oxidation of DNA by Cu(II)/ascorbate system. In contrast, only limited protection was observed with the typical ●OH scavenger dimethyl sulfoxide, even at concentrations as high as 500 mM. DMSA also significantly inhibited copper-catalyzed oxidation of ascorbate and competed effectively with histidine and 1,10-phenanthroline for binding of cuprous copper, but not cupric copper, as demonstrated by UV-visible and low-temperature electron spin resonance techniques. We conclude that the protection by DMSA against copper-mediated oxidative damage to DNA is through the formation of a redox-inactive DMSA-cuprous complex.
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