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When the anti-malarial drug primaquine or certain related aniline derivatives, such as sulfanilamide and acetanilid, are administered to sensitive individuals, an acute hemolytic anemia develops (1, 2). Such sensitivity is very rare among Caucasians but occurs in approximately 10 per cent of American Negroes (3). Investigation of this phenomenon by means of red cell survival studies established that sensitivity to the hemolytic action of primaquine was due to an intrinsic abnormality of the red blood cells of sensitive subjects (4). Extensive studies of these erythrocytes demonstrated, however, that sensitivity to these drugs is not merely another manifestation of a previously described red cell abnormality. It was shown, for example, that the defect of drug-sensitive cells is not associated with any alteration in fragility to chemical, osmotic and mechanical lysis, electrophoretic mobility of the hemoglobin, susceptibility to alkali denaturation, antigenic pattern, or Coomb's test (5). When the drug was administered continually to a sensitive individual, hemolysis stopped after the initial hemolytic crisis and the blood counts returned spontaneously to normal (6). By labeling red cells with a limited age span with Fe59 we were able to explain this phenomenon, demonstrating that only the older members of the red cell population were destroyed through the action of drug (7). This finding led us to suggest that primaquine sensitivity might be due to a deficiency in an enzyme system that decreased in activity as the red cell aged, a condition which is known to be met by a number of red cell enzymes (8). Wetherefore examined various enzyme systems in red cells, which for one reason or another might be implicated in drug sensitivity. These studies indicated that sensitivity to these drugs was not due to a defect in catalase, carbonic anhydrase, or cholinesterase activity. They also demonstrated that glycolysis was sufficiently normal to result in normal incorporation of radioactive phosphorus and that blocking glycolysis with sodium fluoride did not cause non-sensitive cells to behave like sensitive cells in the in vitro study system we had developed (8). Measurement of the reduced glutathione (GSH) content of drug-sensitive cells revealed that they were deficient in this compound (8). When the GSH content of sensitive cells was measured during drug administration it was found that an abrupt fall in the average red cell GSH concentration preceded the major portion of the hemolytic episode, but that as hemolysis progressed, the average red cell GSHreturned to pre-treatment levels (9). This suggested that GSHwas destroyed in the older, sensitive red cells and that subsequently the GSH deficient cells were removed from the circulation. Whether the fall in GSHlevel is the direct cause of the in vivo destruction of the red cell or merely one manifestation of a large number of incidental drug-induced alterations in the chemistry of the cell is a question that still requires an answer. However, it seemed reasonable that GSHmight play an important role in drug-induced hemolyis, and that therefore further study of the destruction of red cell glutathione was warranted.

The Mechanism of Glutathione Destruction and Protection in Drug-Sensitive and Non-Sensitive Erythrocytes. In Vitro Studies