Drug Resistance in Malaria. Investigation of Mechanisms and Patterns of Drug Resistance and Cross Resistance in Malaria

摘要

Hemoglobin in glucose-6-phosphate dehydrogenase (G6DP)-deficient erythrocytes is abnormally vulnerable to oxidation, which may release ferriprotoporphyrin IX (FP), a potent lytic agent for erythrocytes and malaria parasites. To evaluate this possibility, we measured FP in G6PD-deficient erythrocytes. Because of the biological importance of the interaction of FP with cell membranes, we are evaluating the possibility that FP and certain antimalarial drugs act by altering membrane fluidity. To assess fluidity, 16-DOXYL-stearic acid was incorporated into washed erythrocyte membranes. FP and mefloquine, but not chloroquine, caused significant increases in fluidity as detected by increases in 2T prime, a parameter of the electron paramagnetic resonance (EPR) spectrum of membrane bound 16-DOXYL-stearic acid which is sensitive to changes in fluidity. Treatment of membranes from 1 ml of packed erythrocytes with 1 micromole of FP or 10 micromoles of mefloquine caused increases in 2T prime from 24.27 + or - 0.12 G for control preparations to 24.66 + or - 0.14 G for mefloquine-treated preparations (mean + or - SE for 4 experiments). These effects of FP and mefloquine correlate with the binding of these compounds to membrane phospholipids and with their hemolytic potential. We propose that an increase in membrane fluidity is a primary toxic effect of FP and of mefloquine. Keywords: Drug receptors; Chloroquine; Mefloquine; Quinine; and Heinz body hemolytic anemia.