THE ROLE OF METAL COORDNATION IN THE INHIBITION OF IRON(II)- AND COPPER(I)-MEDIATED DNA DAMAGE BY ORGANOSELENIUM AND ORGANOSULFUR COMPOUNDS

Copper and iron are two widely-studied transition metals associated with hydroxyl radical (OH) generation: Fe2+/Cu+ + H2O2 = Fe3+/Cu2+ + OH + OH-. Metal-mediated oxidative damage is a major cause of cellular DNA damage and death, and has been implicated in cancer, neurodegenerative, and cardiovascular diseases. Because sulfur and selenium antioxidants ameliorate oxidative damage, the ability of twenty biological sulfur- and selenium-containing compounds to inhibit metal-mediated DNA damage caused by hydroxyl radical has been quantified. In the Cu+/H2O2 system, six sulfur compounds and three selenium compounds inhibited DNA damage with IC50 values ranging from 3.3 to 25.5 μM. Several sulfur and selenium compounds also demonstrated significant antioxidant activity in the Fe2+/H2O2 system. Additional gel electrophoresis and UV-vis spectroscopy studies confirm that metal coordination is required for antioxidant activity of sulfur and selenium compounds with Cu+, a previously unexplored mechanism. The antioxidant mechanism for sulfur and selenium compounds in the Fe2+ system, however, is unlike that of Cu+. Thus, sulfur and selenium compounds are potent antioxidants capable of preventing metal-mediated oxidative DNA damage at or below biological concentrations. Determination of metal coordination as a novel antioxidant mechanism and quantification of a wide range of sulfur and selenium compounds provides a better understanding of the complex nature of sulfur and selenium antioxidant behavior necessary for improved disease treatment and prevention