A chance insight into the mechanism of phosgene toxicity

Abstract

It has long been known that phosgene, a deadly war gas and industrial reagent, causes intense oxidative stress, but how it does so remains unclear. Here we report an accidental discovery: electron spin resonance spectroscopy (ESR) of live fruit flies reveals that phosgene exposure results in a distinctive manganese (II) hyperfine spectrum. The Mn(II) signal correlates with mitochondrial SOD2 expression. We suggest that phosgene acylates a highly conserved SOD2 active site tyrosine. This prevents the Mn redox cycling between ESR-silent Mn(III) and ESR-active Mn(II) that is required for superoxide dismutation. We propose that mitochondrial SOD2 inactivation is responsible for phosgene toxicity.