Blood, 1959, Vol. 14, No. 2, pp. 103-139.
© 1959 American Society of Hematology, Inc.
The Hemolytic Effect of Primaquine and Related
Compounds: a Review
ERNEST BEUTLER 1
1 Argonne Cancer Research Hospital, USAEC, and The Department of Medicine, The University of Chicago, Illinois.
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.
Submitted on June 25, 1958
Accepted on August 10, 1958
