HEMOGLOBIN CATABOLISM AND THE KILLING OF INTRAERYTHROCYTIC PLASMODIUM-FALCIPARUM BY CHLOROQUINE

To evaluate how chloroquine kills malaria parasites, hemoglobin catabo lism was studied at the various stages of intraerythrocytic parasite d evelopment. We found that hemoglobin catabolism is switched off when P lasmodium falciparum parasites mature to the late trophozoite or early schizont stages and is switched on again during the ring stage. When hemoglobin catabolism is switched off, the parasites are resistant to the morphologic effects of chloroquine. Although the ring stage parasi tes failed to mature in the presence of chloroquine, some of them swit ched on hemoglobin ingestion and became stuffed with hemoglobin-filled vesicles, indicating a distal block in catabolism. In fact, we demons trated a high-grade block in hemozoin production during a 22 h incubat ion of synchronized ring forms; ferriprotoporphyrin IX (FP) incorporat ion into the beta-hematin of hemozoin decreased from 900 to 50 pmol/10 (6) parasitized erythrocytes. We propose that the primary effect of ch loroquine on hemoglobin catabolism is to block FP polymerization to be ta-hematin. Secondarily, toxic FP and FP-chloroquine complexes accumul ate and are available to exert their several toxicities, which include inhibition of hemoglobin-degrading proteases and membrane damage. As a consequence, maturation is arrested and eventually the parasites die and lyse.