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Title: The effects of sulfur, thiol, and thiol inhibitor compounds on arsine-induced toxicity in the human erythrocyte membrane.

Authors: Rael, L T; Ayala-Fierro, F; Carter, D E

Published In Toxicol Sci, (2000 Jun)

Abstract: The mechanism of arsine (AsH(3)) toxicity is not completely understood. The first cytotoxic effect of AsH(3) is disruption of ion homeostasis, with a subsequent hemolytic action. The only accepted treatment for AsH(3) toxicity is exchange transfusion of the blood. In this study the effect of sulfur, sulfur compounds, thiol-containing compounds, and thiol inhibitors on AsH(3)-induced disruption of membrane transport and hemolysis in human erythrocytes was investigated in vitro. Elemental sulfur, sodium thiosulfate, 5, 5'-dithio-bis(2-nitrobenzoic acid), and meso-2,3-dimercaptosuccinic acid were successful in delaying hemolysis, but the most successful agent was the sulfhydryl inhibitor, N-ethylmaleimide (NEM). This indicated that sulfhydryl groups, possibly membrane sulfhydryls, are major factors in the hemolytic mechanism of AsH(3). Measuring intracellular ion concentrations tested the effect of NEM on AsH(3)-induced disruption of membrane transport. AsH(3) alone caused all ions tested to flow with their concentration gradients: Intracellular K+ and Mg++ decreased, whereas Na+, Cl-, and Ca++ increased. NEM was unable to prevent ion loss except for Ca++, whose increase was prevented for 1 h after AsH(3) treatment. The influx of Ca++ in AsH(3)-treated erythrocytes is an irreversible event leading to hemolysis. Reduction of oxygenated hemoglobin to carboxyhemoglobin completely inhibited AsH(3)-induced hemolysis. In addition, AsH(3) and NEM had no direct chemical interactions. We concluded that membrane sulfhydryl groups are likely targets of AsH(3) toxicity, with NEM being able to prevent AsH(3)-induced hemolysis.

PubMed ID: 10828280 Exiting the NIEHS site

MeSH Terms: Adult; Arsenicals*/adverse effects; Calcium/metabolism; Carbon Monoxide/pharmacology; Chelating Agents/pharmacology; Chlorides/metabolism; Dithionitrobenzoic Acid/pharmacology; Drug Interactions; Erythrocyte Membrane/drug effects*; Ethylmaleimide/pharmacology; Female; Hemolysis/drug effects*; Humans; Magnesium/metabolism; Male; Potassium/metabolism; Sodium/metabolism; Succimer/analogs & derivatives; Succimer/pharmacology; Sulfhydryl Compounds/pharmacology*; Sulfhydryl Reagents/pharmacology*; Sulfur/pharmacology*; Thiosulfates/pharmacology

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