The pro-oxidative activity of SOD and nitroxide SOD mimics

Native Cu,Zn-SOD and synthetic SOD mimics sometimes demonstrate an apparent ly anomalous bell-shaped dose-response relationship when protecting various biological systems from oxidative stress. Several mechanisms have been pro posed to account for such an effect, including: overproduction of H2O2, per oxidative activity of SOD, and opposing roles played by O-2(.-) in both ini tiation and termination of radical chain reactions. In the present study, f errocyanide and thiols, which are susceptible to one-electron and two-elect ron oxidation, respectively, were subjected to a flux of superoxide in the presence and absence of SOD or SOD mimics. The results show that 1) either O-2(.-)/HO2. or H2O2 alone partially inactivates papain, whereas when combi ned they act synergistically; 2) nitroxide SOD mimics, but not SOD, exhibit a bell-shaped dose-response relationship in protecting papain from inactiv ation; 3) SOD, which at low dose inhibits superoxide-induced oxidation of f errocyanide, loses its antioxidative effect as its concentration increases, These findings offer an additional explanation for the pro-oxidative activ ity of SOD and SOD mimics without invoking any dual activity of O-2(.-) or a combined effect of SOD and H2O2. The most significant outcome of an incre ase in SOD level is a decrease of [O-2(.-)](steady state), rather than any notable elevation of [H2O2](steady state). As a result, the reaction kineti cs of the high oxidation state of each catalyst is altered. In the presence of ultra-low [O-2(.-)](steady state), the oxidized form of SOD [Cu(II),Zn- SOD] or SOD mimic (oxoammonium cation) does not react with O-2(.-) but rath er oxidizes the target molecule that it was supposed to have protected. Con sequently, these catalysts exert an anti- or pro-oxidative effect depending on their concentration.-Offer, T., Russo, A., Samuni, A. The pro-oxidative activity of SOD and nitroxide SOD mimics.