The formation of the powerful
oxidant peroxynitrite (PN) from the reaction of
superoxide anion with
nitric oxide has been shown to be a kinetically favored reaction contributing to cellular injury and death at sites of tissue
inflammation. The PN molecule is highly reactive causing lipid peroxidation as well as nitration of both free and
protein-bound
tyrosine. We present evidence for the pharmacological manipulation of PN with decomposition catalysts capable of converting it to
nitrate. In target cells challenged with exogenously added synthetic PN, a series of
metalloporphyrin catalysts (5,10,15,20-tetrakis(2,4,6-trimethyl-3, 3-disulfonatophenyl)porphyrinato
iron (III) (
FeTMPS); 5,10,15, 20-tetrakis(4-sulfonatophenyl)porphyrinato
iron (III) (FeTPPS); 5,10, 15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato
iron (III) (FeTMPyP)) provided protection against PN-mediated injury with EC50 values for each compound 30-50-fold below the final concentration of PN added. Cytoprotection was correlated with a reduction in the level of measurable
nitrotyrosine. In addition, we found our catalysts to be cytoprotective against endogenously generated PN in
endotoxin-stimulated RAW 264.7 cells as well as in dissociated cultures of hippocampal neurons and glia that had been exposed to
cytokines. Our studies thus provide compelling evidence for the involvement of
peroxynitrite in
cytokine-mediated cellular injury and suggest the therapeutic potential of PN decomposition catalysts in reducing cellular damage at sites of
inflammation.