Redox properties of iron–dithiocarbamates and their nitrosyl derivatives: implications for their use as traps of nitric oxide in biological systems

Abstract

While the Fe 2+–dithiocarbamate complexes have been commonly used as NO traps to estimate NO production in biological systems, these complexes can undergo complex redox chemistry. Characterization of this redox chemistry is of critical importance for the use of this method as a quantitative assay of NO generation. We observe that the commonly used Fe 2+ complexes of N-methyl- D-glucamine dithiocarbamate (MGD) or diethyldithiocarbamate (DETC) are rapidly oxidized under aerobic conditions to form Fe 3+ complexes. Following exposure to NO, diamagnetic NO–Fe 3+ complexes are formed as demonstrated by the optical, electron paramagnetic resonance and gamma-resonance spectroscopy, chemiluminescence and electrochemical methods. Under anaerobic conditions the aqueous NO–Fe 3+–MGD and lipid soluble NO–Fe 2+–DETC complexes gradually self transform by reductive nitrosylation into paramagnetic NO–Fe 2+–MGD complexes with yield of up to 50% and the balance is converted to Fe 3+–MGD and nitrite. In dimethylsulfoxide this process is greatly accelerated. More efficient transformation of NO–Fe 3+–MGD into NO–Fe 2+–MGD (60–90% levels) was observed after addition of reducing equivalents such as ascorbate, hydroquinone or cysteine or with addition of excess Fe 2+–MGD. With isotope labeling of the NO–Fe 3+–MGD with 57Fe, it was shown that these complexes donate NO to Fe 2+–MGD. NO–Fe 3+–MGD complexes were also formed by reversible oxidation of NO–Fe 2+–MGD in air. The stability of NO–Fe 3+–MGD and NO–Fe 2+–MGD complexes increased with increasing the ratio of MGD to Fe. Thus, the iron–dithiocarbamate complexes and their NO derivatives exhibit complex redox chemistry that should be considered in their application for detection of NO in biological systems.