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The pro-oxidative activity of SOD and nitroxide SOD mimics

Molecular Biology, Hebrew University - Hadassah Medical School, Jerusalem, 91120, Israel; and
^* Radiation Biology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA

¹Correspondence: Molecular Biology, Faculty of Medicine, Hebrew University-Hadassah Medical School, Jerusalem, 91120, Israel. E-mail: talof{at}md2.huji.ac.il

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.—Offer, T., Russo, A., Samuni, A. The pro-oxidative activity of SOD and nitroxide SOD mimics.

Key Words: papain • hydrogen peroxide • superoxide • oxidative damage • thiol

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