Sulfhydryl groups of the erythrocyte membrane and their relation to glycolysis and drug-induced hemolytic anemia.

Hemolytic anemia caused by oxidative drugs is thought to result from the oxidation of intracellular and membrane sulfhydryl groups of the erythrocyte. This process is more likely to occur in those erythrocytes in which the intracellular mechanism for reduction of disulfides is abnormal (e.g., glucose-6-phosphate dehydrogenase deficiency). If a membrane sulfhydryl group is critical in the pathogenesis of druginduced hemolytic anemia, it follows that this specific group must be dependent on intracellular reductive mechanisms for maintenance of the reduced state. This report describes a sulfhydryl group(s), involved in membrane structure, which is (are) dependent on intracellular metabolism for maintenance of the reduced state. It is postulated that this metabolically dependent membrane sulfhydryl group may play a role in the pathogenesis of drug-induced hemolytic anemia. Membrane sulfhydryl groups were studied by observing the effect of sulfhydryl blocking agents, e.g., N-ethyl-maleimide (NEM), on the recovery of erythrocyte ghosts after osmotic lysis. It was shown that NEM interfered with ghost recovery by reacting with membrane sulfhydryl groups. The concentration of NEM (as determined by [(14)C] NEM binding) necessary to cause this effect was lower than that necessary to produce changes in osmotic fragility or cation permeability, or to cause Heinz body formation. In the absence of glucose, these sulfhydryl groups became disulfides, but could be returned to the reduced state by restoring glycolysis or by adding dithiothreitol. Phenylhydrazine hemolytic anemia was induced in pigs, and membrane changes of the type described above occurred early in the pathogenesis of the disease.