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 blue cation radical. It has been proposed that the mechanism by which hypochlorous acid oxidizes aminopyrine to a cation radical involves N-chlorination followed by loss of a chlorine radical. Another possible mechanism is loss of HCl to form an iminium ion and subsequent reaction with another molecule of aminopyrine and a hydrogen ion to form two radical 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 reaction between aminopyrine and hypochlorous acid, an intermediate with a lambda max at approximately 420 nm was observed in the formation of the cation radical. We propose that this represents a dication formed by the loss of chloride ion from N-chloroaminopyrine. This intermediate is very reactive, with a half-life of approximately 15 ms, and in addition to being the precursor of the cation radical, it also appears to react with two molecules of water to form several other products that were observed and are consistent with the proposed dication intermediate. Similar stable products were formed when amino-pyrine was oxidized by the combination of myeloperoxidase, hydrogen peroxide, and chloride or activated neutrophils. The reactive dication formed by neutrophil-derived hypochlorous acid could be responsible for aminopyrine-induced agranulocytosis.
Uetrecht
J P
JP
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Ma
H M
HM
MacKnight
E
E
McClelland
R
R
D000380:Agranulocytosis / Q000139:chemically induced*; D000632:Aminopyrine / Q000737:chemistry* / Q000633:toxicity; D002412:Cations; D003903:Deuterium; D006801:Humans; D006997:Hypochlorous Acid / Q000737:chemistry*; D007554:Isotopes; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009504:Neutrophils / Q000187:drug effects; D010084:Oxidation-Reduction
D002412:Cations; D007554:Isotopes; D000632:Aminopyrine; D006997:Hypochlorous Acid; D003903:Deuterium