Promotion of iron-induced rat liver microsomal lipid peroxidation by copper

Although copper has been demonstrated to promote lipid peroxidation in a number of systems, the mechanisms involved have not been fully defined. In this study, the role of copper in modifying lipid peroxidation has been explored in rat hepatic microsomes. In an in vitro system containing reduced glutathione (GSH, 200 microM) and Tris buffer, pH 7.4, cupric sulfate (1-50 microM) potentiated lipid peroxidation induced by ferrous sulfate (10 microM) but was unable to elicit peroxidation in the absence of iron. Higher levels of cupric sulfate (100 microM or greater) were inhibitory. The nature as well as the extent of the peroxidative response of microsomes to cupric sulfate were dependent on glutathione levels in addition to those of iron. Cupric sulfate (100 microM) strongly potentiated ferrous ion-induced lipid peroxidation in the presence of 400-800 microM GSH, while it inhibited peroxidation at lower levels of GSH (0-200 microM) and did not affect ferrous ion-induced peroxidation with glutathione levels of 3-10 mM. The potentiating effect of copper on ferrous ion-induced lipid peroxidation was further explored by investigating: (1) potential GSH-mediated reduction of cupric ions; (2) potential copper/GSH-mediated reduction of ferric ions (formed by oxidation during incubation); and (3) possible promotion of propagation reactions by copper/GSH. Our results indicate that cupric ions are reduced by GSH and thus are converted from an inhibitor to an enhancer of iron-induced lipid peroxidation. Cuprous ions appear to potentiate lipid peroxidation by reduction of ferric ions, rather than by promoting propagation reactions. Iron (in a specific Fe+2/Fe+3 ratio) is then an effective promoter of initiation reactions.