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Toxicological Sciences 55, 468-477 (2000)
Copyright © 2000 by the Society of Toxicology

The Effects of Sulfur, Thiol, and Thiol Inhibitor Compounds on Arsine-Induced Toxicity in the Human Erythrocyte Membrane

Leonard T. Rael1, Felix Ayala-Fierro and Dean E. Carter2

Department of Pharmacology and Toxicology, Center for Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721.

The mechanism of arsine (AsH3) toxicity is not completely understood. The first cytotoxic effect of AsH3 is disruption of ion homeostasis, with a subsequent hemolytic action. The only accepted treatment for AsH3 toxicity is exchange transfusion of the blood. In this study the effect of sulfur, sulfur compounds, thiol-containing compounds, and thiol inhibitors on AsH3-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 AsH3. Measuring intracellular ion concentrations tested the effect of NEM on AsH3-induced disruption of membrane transport. AsH3 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 AsH3 treatment. The influx of Ca++ in AsH3-treated erythrocytes is an irreversible 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 membrane sulfhydryl groups are likely targets of AsH3 toxicity, with NEM being able to prevent AsH3-induced hemolysis.

Key Words: arsine; thiols; chelator; human erythrocytes; intracellular ions; membrane disruption.


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L. T. Rael, F. Ayala-Fierro, R. Bar-Or, D. E. Carter, and D. S. Barber
Interaction of Arsine with Hemoglobin in Arsine-Induced Hemolysis
Toxicol. Sci., March 1, 2006; 90(1): 142 - 148.
[Abstract] [Full Text] [PDF]


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