The pro-oxidative activity of SOD and nitroxide SOD mimics

Native Cu,Zn-SOD and synthetic SOD mimics sometimes demonstrate an apparently anomalous bell-shaped dose-response relationship when protecting various biological systems from oxidative stress. Several mechanisms have been proposed to account for such an effect, including: overproduction of H₂O₂, peroxidative activity of SOD, and opposing roles played by O₂^.- in both initiation and termination of radical chain reactions. In the present study, ferrocyanide and thiols, which are susceptible to one-electron and two-electron 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 O₂^.-/HO₂^. or H₂O₂ alone partially inactivates papain, whereas when combined they act synergistically; 2) nitroxide SOD mimics, but not SOD, exhibit a bell-shaped dose-response relationship in protecting papain from inactivation; 3) SOD, which at low dose inhibits superoxide-induced oxidation of ferrocyanide, loses its antioxidative effect as its concentration increases. These findings offer an additional explanation for the pro- oxidative activity of SOD and SOD mimics without invoking any dual activity of O₂^.- or a combined effect of SOD and H₂O₂. The most significant outcome of an increase in SOD level is a decrease of [O₂^.-](steady state), rather than any notable elevation of [H₂O₂](steady state). As a result, the reaction kinetics of the high oxidation state of each catalyst is altered. In the presence of ultra-low [O₂^.-](steady state), the oxidized form of SOD [Cu(II),Zn-SOD] or SOD mimic (oxo-ammonium cation) does not react with O₂^.- but rather oxidizes the target molecule that it was supposed to have protected. Consequently, these catalysts exert an anti- or pro-oxidative effect depending on their concentration.