title: The pro-oxidative activity of SOD and nitroxide SOD mimics.
abstract: 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 H(2)O(2), peroxidative activity of SOD, and opposing roles played by O(2)(*-) 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 O(2)(*-)/HO(2)(*) or H(2)O(2) 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 O(2)(*-) or a combined effect of SOD and H(2)O(2). The most significant outcome of an increase in SOD level is a decrease of [O(2)(*-)](steady state), rather than any notable elevation of [H(2)O(2)](steady state). As a result, the reaction kinetics 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 (oxo-ammonium cation) does not react with O(2)(*-) 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.
authors.affiliation: Molecular Biology, Hebrew University - Hadassah Medical School, Jerusalem, 91120, Israel. talof@md2.huji.ac.il
authors.forename: T
authors.initials: T
authors.lastname: Offer
authors.forename: A
authors.initials: A
authors.lastname: Russo
authors.forename: A
authors.initials: A
authors.lastname: Samuni
mesh_terms: D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002254:Carbonates / Q000378:metabolism / Q000494:pharmacology; D002374:Catalase / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004583:Electrons; D005292:Ferricyanides / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008353:Mannitol / Q000378:metabolism / Q000494:pharmacology; D018716:Molecular Mimicry; D009573:Nitrites / Q000378:metabolism / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D016877:Oxidants / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D010084:Oxidation-Reduction / Q000187:drug effects; D010206:Papain / Q000037:antagonists & inhibitors / Q000378:metabolism; D010710:Phosphates / Q000494:pharmacology; D013113:Spin Labels; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D013481:Superoxides / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D002254:Carbonates; D003497:Cyclic N-Oxides; D005292:Ferricyanides; D009573:Nitrites; D009589:Nitrogen Oxides; D016877:Oxidants; D010710:Phosphates; D013113:Spin Labels; D013438:Sulfhydryl Compounds; D013481:Superoxides; C007931:hexacyanoferrate III; D008353:Mannitol; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D010206:Papain; C039900:nitroxyl; C001803:tempol