Kinetics of inhibition of glutathione-mediated degradation of ferriprotoporphyrin IX by antimalarial drugs

We have shown previously that chloroquine and amodiaquine inhibit the gluta thione dependent degradation of ferriprotoporphyrin IX (FP). We have also d emonstrated that treatment of human erythrocytes infected with Plasmodium f alciparum with chloroquine or amodiaquine results in a dose- and time-depen dent accumulation of FP in the membrane fraction of these cells in correlat ion with parasite killing. High levels of membrane FP are known to perturb the barrier properties of cellular membranes, and could thereby irreversibl y disturb the ion homeostasis of the parasite and cause parasite death. We here report on the effect of various 4-aminoquinolines, as well as pyronari dine, halofantrine and some bis-quinolines, on glutathione-mediated. destru ction of FP in aqueous solution, when Fr was bound non-specifically to a pr otein, and when it was dissolved in human erythrocyte ghost membranes. We s howed that all drugs were capable of inhibiting FP degradation in solution. The inhibitory efficacy of some drugs declined when FP was bound non-speci fically to protein. Quinine and mefloquine were unable to inhibit the degra dation of membrane-associated FP, in line with their inability to increase membrane-associated FP levels in malaria-injected cells following drug trea tment. The discrepancy between chloroquine and amodiaquine on the one hand, and quinine and mefloquine on the other, is discussed in terms of the part icular location of drugs and FP in the phospholipid membrane, and may sugge st differences in the mechanistic details of the antimalarial action of the se drugs. BIOCHEM PHARMACOL 58;1: 59-68, 1999 (C) 1999 Elsevier Science Inc .