Modulation of sulfur mustard toxicity by arginine analogues and related nitric oxide synthase inhibitors in vitro

The modulating effects of a series of arginine analogues and related nitric oxide synthase inhibitors against the toxicity of sulfur mustard (HD) in p rimary cultures of chick embryo forebrain neurons were examined. In additio n to the previously identified protective compounds, D- and L-nitroarginine methyl ester, eight additional arginine analogues were shown to have signi ficant, concentration-dependent protective characteristics against HD toxic ity. Of these, L-nitroarginine was the most potent, increasing the LC50 of vehicle-pretreated HD-treated control cultures by similar to 350%. In addit ion to these protective agents, five compounds related to arginine were als o identified that potentiated the toxicity of HD in the neuron cultures in a concentration-dependent manner. This action occurred at concentrations wh ere these chemicals alone exhibited no toxicity. Characterization of the ac tive compounds in this study showed that it was likely that the protective agents, as well as those compounds that potentiated HD toxicity, were exert ing their effects at the same biochemical target, but not through the inhib ition of nitric oxide synthase, Although the identity of this target site i s as yet unknown, these studies demonstrate that subtle alterations to the arginine structure can yield compounds that differentially modulate the tox icity of HD through their activity at a common target site, (C) 1998 Societ y of Toxicology.