Metal specificity in DNA damage prevention by sulfur antioxidants

Metals such as Cu-I and Fe-II generate hydroxyl radical ((OH)-O-center dot) by reducing endogenous hydrogen peroxide (H2O2). Because antioxidants can ameliorate metal-mediated oxidative damage, we have quantified the ability of glutathione, a primary intracellular antioxidant, and other biological sulfur-containing compounds to inhibit metal-mediated DNA damage caused hydroxyl radical. In the CuI/H2O2 system, six sulfur compounds, including both reduced and oxidized glutathione, inhibited DNA damage with IC50 values ranging from 3.4 to 12.4 mu M. Glutathione and 3-carboxypropyl disulfide also demonstrated significant antioxidant activity with Fell and H2O2. Additional gel electrophoresis and UV-vis spectroscopy studies confirm that antioxidant activity for sulfur compounds in the Cu-I system is attributed to metal coordination, a previously unexplored mechanism. The antioxidant mechanism for sulfur compounds in the Fe-II system, however, is unlike that of Cu-I. Our results demonstrate that glutathione and other sulfur compounds are potent antioxidants capable of preventing metal-mediated oxidative DNA damage at well below their biological concentrations. This novel metal-binding antioxidant mechanism may play a significant role in the antioxidant behavior of these sulfur compounds and help refine understanding of glutathione function in vivo. (C) 2008 Elsevier Inc. All rights reserved.