Desferrioxamine inhibits protein tyrosine nitration: Mechanisms and implications

作者：Adgent Margaret A; Squadrito Giuseppe L; Ballinger Carol A; Krzywanski David M; Lancaster Jack R Jr; Postlethwait Edward M^*

来源：Free Radical Biology and Medicine, 2012, 53(4): 951-961.

DOI：10.1016/j.freeradbiomed.2012.06.003

• Desferrioxamine
• Nitrogen dioxide
• Membrane proteins
• Hydroxamic acids
• Epithelial lining fluid
• Nitration
• Tyrosine
• Tyrosyl radicals
• Repair
• Reduction

Tissues are exposed to exogenous and endogenous nitrogen dioxide ((NO2)-N-center dot), 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 (NO2)-N-center dot 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 (NO2)-N-center dot 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 (NO2)-N-center dot compared to ascorbate, assessed via (NO2)-N-center dot 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 %26quot;bound%26quot; to RCM. Per the above and kinetic analyses suggesting preferential DFO versus (NO2)-N-center dot reaction within membranes, we conclude that DFO inhibits 3-NT formation predominantly by facile repair of the tyrosyl radical intermediate, which prevents (NO2)-N-center dot addition, and thus nitration, and potentially influences biochemical functionalities.

• 出版日期2012-8-15