OXIDATION OF AMINOPYRINE BY HYPOCHLORITE TO A REACTIVE DICATION - POSSIBLE IMPLICATIONS FOR AMINOPYRINE-INDUCED AGRANULOCYTOSIS

Aminopyrine is associated with a high incidence of agranulocytosis. It is known to be oxidized by peroxidases and hypochlorous acid to a blu e cation radical. It has been proposed that the mechanism by which hyp ochlorous acid oxidizes aminopyrine to a cation radical involves N-chl orination followed by loss of a chlorine radical. Another possible mec hanism is loss of HCl to form an iminium ion and subsequent reaction w ith another molecule of aminopyrine and a hydrogen ion to form two rad ical cations. This mechanism would lead to incorporation of a hydrogen from water; however, using a deuterated analog, we found no hydrogen incorporation, thus providing strong evidence against this mechanism. Using a stopped-flow diode array spectrophotometer to study the reacti on between aminopyrine and hypochlorous acid, an intermediate with a l ambda(max) at similar to 420 nm was observed in the formation of the c ation radical. We propose that this represents a dication formed by th e loss of chloride ion from N-chloroaminopyrine. This intermediate is very reactive, with a half-life of approximately 15 ms, and in additio n to being the precursor of the cation radical, it also appears to rea ct with two molecules of water to form several other products that wer e observed and are consistent with the proposed dication intermediate. Similar stable products were formed when aminopyrine was oxidized by the combination of myeloperoxidase, hydrogen peroxide, and chloride or activated neutrophils. The reactive dication formed by neutrophil-der ived hypochlorous acid could be responsible for aminopyrine-induced ag ranulocytosis.