Excess release of ferriheme in G6PD-deficient erythrocytes: possible cause
of hemolysis and resistance to malaria
SK Janney, JJ Joist and CD Fitch
Hemoglobin in glucose-6-phosphate dehydrogenase (G6PD)-deficient
erythrocytes is abnormally vulnerable to oxidative denaturation, which may
release ferriheme, a known cytolytic agent. We found 13.3 nmol of ferriheme
in G6PD-deficient erythrocyte membranes (per gram of total erythrocyte
hemoglobin) using a spectrophotometric assay, as compared to 9.8 in normal
membranes (P less than .05). After incubation of erythrocytes with 250
mumol/L menadione, an oxidant drug, the values increased by 37.4 nmol in
G6PD-deficient membranes and by 26 in normal membranes (P less than .005),
indicating increased hemoglobin denaturation. To verify that hemoglobin
denaturation in G6PD-deficient erythrocytes releases ferriheme in a form
available to interact with other ligands, [14C]-chloroquine binding to
intact erythrocytes was measured. With an initial concentration of 5
mumol/L chloroquine in a medium containing no menadione, an excess of 14.8
nmol of chloroquine was bound in G6PD-deficient erythrocytes (per gram of
hemoglobin) as compared to normal erythrocytes (P less than .005). In the
presence of 250 mumol/L menadione, chloroquine binding increased by 17.9
nmol in G6PD-deficient and by 7.2 in normal erythrocytes (P less than
.005). These results indicate that ferriheme becomes available to interact
with endogenous ligands and, thus, to mediate menadione-induced hemolysis
in patients with G6PD deficiency. Furthermore, the increase in ferriheme
may mediate the selective toxicity of menadione for Plasmodium falciparum
parasites growing in G6PD-deficient erythrocytes. Ferriheme release in
response to the intraerythrocytic oxidant stress introduced by malaria
parasites also may account for the resistance to malaria afforded by G6PD
deficiency. This is a US government work. There are no restrictions on its
use.
Volume 67,
Issue 2,
pp. 331-333,
02/01/1986
Copyright © 1986 by The American Society of Hematology
