Desferrioxamine inhibits protein tyrosine nitration: mechanisms and implications.
Tissues are exposed to exogenous and endogenous nitrogen dioxide ((·)NO(2)), which is the terminal agent in protein tyrosine nitration. Besides iron chelation, the hydroxamic acid (HA) desferrioxamine (DFO) shows multiple functionalities including nitration inhibition. To investigate mechanisms whereby DFO affects 3-nitrotyrosine (3-NT) formation, we utilized gas-phase (·)NO(2) exposures, to limit introduction of other reactive species, and a lung surface model wherein red cell membranes (RCM) were immobilized under a defined aqueous film. When RCM were exposed to ()NO(2) covered by +/- DFO: (i) DFO inhibited 3-NT formation more effectively than other HA and non-HA chelators; (ii) 3-NT inhibition occurred at very low[DFO] for prolonged times; and (iii) 3-NT formation was iron independent but inhibition required DFO present. DFO poorly reacted with (·)NO(2) compared to ascorbate, assessed via (·)NO(2) reactive absorption and aqueous-phase oxidation rates, yet limited 3-NT formation at far lower concentrations. DFO also inhibited nitration under aqueous bulk-phase conditions, and inhibited 3-NT generated by active myeloperoxidase "bound" to RCM. Per the above and kinetic analyses suggesting preferential DFO versus (·)NO(2) reaction within membranes, we conclude that DFO inhibits 3-NT formation predominantly by facile repair of the tyrosyl radical intermediate, which prevents (·)NO(2) addition, and thus nitration, and potentially influences biochemical functionalities.
Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Margaret A
MA
Adgent
Giuseppe L
GL
Squadrito
Carol A
CA
Ballinger
David M
DM
Krzywanski
Jack R
JR
Lancaster
Edward M
EM
Postlethwait
D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D003676:Deferoxamine / Q000737:chemistry / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000502:physiology; D009585:Nitrogen Dioxide / Q000737:chemistry / Q000494:pharmacology; D010083:Oxidants, Photochemical / Q000737:chemistry / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D017262:Siderophores / Q000737:chemistry / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
D016166:Free Radical Scavengers; D010083:Oxidants, Photochemical; D011506:Proteins; D017262:Siderophores; C002744:3-nitrotyrosine; D014443:Tyrosine; D009195:Peroxidase; D003676:Deferoxamine; D009585:Nitrogen Dioxide