It has been recognized for a long time that 8-aminoquinoline compounds may cause hemolytic anemia in certain individuals, but until recently the mechanism of such sensitivity has remained obscure. The use of modern hematologic technics for the study of primaquine sensitivity has resulted in the discovery of a new intrinsic red cell defect. Cells with this defect are sensitive to hemolysis by a large number of aromatic amino compounds, including primaquine and other 8-aminoquinoline derivatives.
Administration of primaquine to sensitive subjects results in destruction of the older members of the red cell population. Available evidence suggests that the administration of a hemolytic drug causes oxidative damage to either the hemoglobin and/or the stroma of the sensitive cell. Heinz bodies are visible manifestation of such damage. The damaged red cells are removed from the circulation by in vivo mechanisms, presumably by the reticulo-endothelial system.
Red cell glutathione has been found to be related in some way to sensitivity to these compounds: (1) the glutathione level of sensitive cells is consistently lower than that of nonsensitive cells; (2) poisoning of the sulfhydryl groups of red cells causes nonsensitive cells to react like sensitive cells in vitro with respect to Heinz body formation; (3) a rapid fall in the red cell glutathione level occurs in vivo when primaquine is administered to sensitive individuals but not to nonsensitive ones; and (4) a rapid fall in GSH level occurs in sensitive but not in nonsensitive cells when they are incubated with acetyl phenylhydrazine and many other compounds. These observations indicate that there is a mechanism that protects GSH in the nonsensitive but not in sensitive cells. This mechanism was found to require presence of glucose or inosine. In sensitive cells, this mechanism is defective and the GSH of the older cells is destroyed. The GSH destructive effect appears in vitro, at least, to be exerted through the oxyhemoglobin.
Primaquine-sensitive red cells have been found to be deficient in glucose-6-phosphate dehydrogenase activity. Glucose-6-phosphate dehydrogenase is involved in TPN reduction.45 TPN is a coenzyme for GSH reduction.103 Thus, a deficiency in glucose-6-phosphate dehydrogenase could result in defective GSH reduction and may therefore serve as an explanation of the GSH instability of drug-sensitive red cells.
It is not clear whether GSH serves merely as a convenient indicator of important changes within the cell that actually lead to cell death or whether GSH depletion plays a primary role in cell death and hemolysis. The role of GSH in the red cell is unknown, and evidence that GSH depletion leads to hemolysis has been obtained only by means which may be grossly injurious to the red cell in many other ways.51,75,116 It is entirely possible that another effect of G-6-P.D., such as TPNH deprivation, leads to cell damage in some entirely different way. Inability to reduce TPN might, for example, interfere with lipid synthesis in the red cell.77
It cannot even be considered clearly established that either the GSH instability or G-6-P.D. deficiency of these red cells is the primary defect leading to susceptability to hemolysis. If the level of G-6-P.D. alone governs the red cell’s resistance to hemolysis, one might expect mild enzyme deficiency to result in mild susceptibility to hemolysis. According to preliminary data reported by Alving et al.,2 this is not the case. The possibility must be considered, therefore, that not only GSH changes but even the G-6-P.D. changes in sensitive cells may be associated defects rather than of primary etiologic significance.
Primaquine-sensitive red cells are also uniquely sensitive to the hemolytic effect of many other compounds, including acetanilid, Furadantin and other drugs commonly used in medicine. Yet, it would appear that many of these drugs can also on occasion cause hemolysis of normal red cells. Subjects who are sensitive to the fava bean have also been shown to have the same defect in GSH stability and glucose-6-phosphate dehydrogenase as primaquine-sensitive individuals display, but here other, as yet unknown, predisposing factors would seem to be involved.
The red cell defect of primaquine-sensitivity is genetically transmitted, probably as a sex-linked gene with intermediate penetrance.
It has thus been shown that a drug-sensitivity reaction is intimately related to a genetically transmitted enzyme deficiency. It is entirely possible, as has been pointed out so effectively by Motulsky,95 that other drug sensitivities may have a similar basis.