Lt. Rael et al., The effects of sulfur, thiol, and thiol inhibitor compounds on arsine-induced toxicity in the human erythrocyte membrane, TOXICOL SCI, 55(2), 2000, pp. 468-477
The mechanism of arsine (AsH3) toxicity is not completely understood. The f
irst cytotoxic effect of AsH3 is disruption of ion homeostasis, with a subs
equent hemolytic action. The only accepted treatment for AsH3 toxicity is e
xchange transfusion of the blood. In this study the effect of sulfur, sulfu
r compounds, thiol-containing compounds, and thiol inhibitors on AsH3-induc
ed disruption of membrane transport and hemolysis in human erythrocytes was
investigated in vitro. Elemental sulfur, sodium thiosulfate, 5,5'-dithio-b
is(2-nitrobenzoic acid), and meso-2,3-dimercaptosuccinic acid were successf
ul in delaying hemolysis, but the most successful agent was the sulfhydryl
inhibitor, N-ethyl-maleimide (NEM). This indicated that sulfhydryl groups,
possibly membrane sulfhydryls, are major factors in the hemolytic mechanism
of AsH3. Measuring intracellular ion concentrations tested the effect of N
EM on AsH3-induced disruption of membrane transport. AsH3 alone caused all
ions tested to flow with their concentration gradients: Intracellular K+ an
d Mg++ decreased, whereas Na+, Cl-, and Ca++ increased. NEM was unable to p
revent ion loss except for Ca++, whose increase was prevented for 1 h after
AsH3 treatment. The influx of Ca++ in AsH3-treated erythrocytes is an irre
versible event leading to hemolysis. Reduction of oxygenated hemoglobin to
carboxyhemoglobin completely inhibited AsH3-induced hemolysis. In addition,
AsH3 and NEM had no direct chemical interactions. We concluded that membra
ne sulfhydryl groups are likely targets of AsH3 toxicity, with NEM being ab
le to prevent AsH3-induced hemolysis.