Nitroxide Species Derived From Hydroxamate-Based Drugs as Reductants of Ferryl (and Perferryl) Heme, SOD-Mimetics, and "Catalase Activity Augmenters"

This article [Atamna et al., 2000: (http://www.jbc.org/content/275/10/6741.full.pdf+html)(http://www.ncbi.nlm.nih.gov/pubmed/10702229?dopt=Abstract); Krishna et al., 1996: (http://www.jbc.org/content/271/42/26018.full.pdf+html)(http://www.ncbi.nlm.nih.gov/pubmed/8824241)] is useful and shows that nitroxide compounds can exert antioxidant effects by serving as one-electron reductants of ferryl heme to ferric heme, and a key point is that the ferryl-to-ferric step can be rate-limiting in the maintenance of the catalase activity of protein-bound hemes. Drugs that contain hydroxamate groups are oxidized to their nitroxide radical species by their reactions with peroxyl radicals, and then the nitroxide form of the drug could reduce ferryl heme to ferric heme, without generating the superoxide that would usually be formed through the reduction of ferryl heme by hydrogen peroxide, and yield the oxo-ammonium cation form of the hydroxamate-containing drug. The oxo-ammonium cation species generally tend to exert superoxide-dismutase-mimetic effects by (reacting with superoxide and) forming O2, and that regenerates the nitroxide species that is likely to be the key species, in the absence of free iron, for example. But the acceleration of the rate of reduction of ferryl heme to ferric heme, via the reduction of ferryl heme by the nitroxide species, can, evidently, accelerate the two-electron catalase or "hydroperoxidase" activity of the perferryl-to-ferric heme reduction step. The redox cycling, via the reduction of the oxoammonium species by reduced glutathione, for example, of nitroxide-oxoammonium-hydroxylamine species is actually thought to be necessary for the so-called "catalytic" antioxidant mechanisms (as opposed to stoichiometric antioxidant mechanisms) by which nitroxides or hydroxamate-based drugs that are serving as "nitroxide prodrugs" can act. The nitroxide-oxoammonium cycling is "catalytic" because the species aren't consumed or inactivated through the cycling. And the SOD-mimetic effect may also be an important element, particularly since that mechanism can regenerate the nitroxide species. Anyway, it's too late to put up a sketch, but one reduction mechanism (for the reduction of ferryl heme to ferric heme by a nitroxide radical) is very similar to the reduction by H2O2.