Hemoglobin catabolism and the killing of intraerythrocytic Plasmodium falciparum by chloroquine.
To evaluate how chloroquine kills malaria parasites, hemoglobin catabolism was studied at the various stages of intraerythrocytic parasite development. We found that hemoglobin catabolism is switched off when Plasmodium 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 parasites failed to mature in the presence of chloroquine, some of them switched on hemoglobin ingestion and became stuffed with hemoglobin-filled vesicles, indicating a distal block in catabolism. In fact, we demonstrated a high-grade block in hemozoin production during a 22 h incubation of synchronized ring forms; ferriprotoporphyrin IX (FP) incorporation into the beta-hematin of hemozoin decreased from 900 to 50 pmol/10(6) parasitized erythrocytes. We propose that the primary effect of chloroquine on hemoglobin catabolism is to block FP polymerization to beta-hematin. Secondarily, toxic FP and FP-chloroquine complexes accumulate 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.
Orjih
A U
AU
Department of Internal Medicine, Saint Louis University School of Medicine, Missouri 63104.
Ryerse
J S
JS
Fitch
C D
CD
D000818:Animals; D002738:Chloroquine / Q000494:pharmacology*; D004912:Erythrocytes / Q000469:parasitology*; D006420:Hemeproteins / Q000096:biosynthesis; D006427:Hemin / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism*; D006790:Host-Parasite Interactions; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development* / Q000648:ultrastructure
D006420:Hemeproteins; D006454:Hemoglobins; C020753:hemozoin; D006427:Hemin; D002738:Chloroquine