Mn(III)-desferrioxamine superoxide dismutase-mimic: Alternative modes of action

Various low-molecular-weight copper chelates have been synthesized to mimic superoxide dismutase (SOD) by catalyzing O^{{dot minus}}₂ dismutation. However, in the presence of cellular proteins, such chelates dissociate and thereby lose their SOD-mimetic activity. In contrast, desferrioxamine-Mn(III) 1:1 chelate (DFMn), an SOD-mimic that affords protection from oxidative damage, reportedly is stable in the presence of serum albumin. DFMn, unlike SOD, is reported to permeate the membrane of at least one cell type and can protect cells by detoxifying intracellular O^{{dot minus}}₂. Recently DFMn was shown to protect hypoxic cells from H₂O₂-induced damage. Such results suggest that DFMn can protect cells from O^{{dot minus}}₂ -independent damage by alternative mechanisms. This study examines such possibilities. To avoid O^{{dot minus}}₂ participation in the damaging process, killing of monolayered V79 Chinese hamster cells was induced in a hypoxic environment by t-butyl hydroperoxide (t-BHP). Damage induced by t-BHP was inhibitable by DFMn. DFMn was also found to rapidly oxidize iron(II)-bound DNA. Additionally, once DFMn oxidizes Fe(II) or Cu(I), the DF moiety of DFMn dissociates and rapidly binds to Fe(III) or Cu(II). Without excluding the possibility that DFMn protects cells by facilitating the removal of O^{{dot minus}}₂, the present results show that this SOD-mimic can confer protection from cytotoxic processes independent of O^{{dot minus}}₂ or of O^{{dot minus}}₂-derived active species.