Hemozoin production by Plasmodium falciparum: variation with strain and exposure to chloroquine.
Synchronized Plasmodium falciparum parasites were grown in erythrocytic culture for measurement of malaria pigment (hemozoin) production using a simple method based on the insolubility of beta-hematin, the principal pigment of hemozoin. In the last 44 h of the life cycle, one strain (chloroquine-susceptible) incorporated an average of 960 pmol of ferriprotoporphyrin IX (FP) from hemoglobin into beta-hematin per 10(6) parasitized erythrocytes. By comparison, another strain (chloroquine-resistant) incorporated 515 pmol of FP into beta-hematin. When exposed to 25 ng of chloroquine per ml of culture medium, chloroquine-susceptible P. falciparum incorporated 240 pmol of FP into beta-hematin per 10(6) parasitized erythrocytes in one intraerythrocytic life cycle. In contrast chloroquine-resistant P. falciparum exposed to 100 ng of chloroquine per ml incorporated 630 pmol of FP into beta-hematin. Thus, chloroquine inhibits hemozoin production in chloroquine-susceptible P. falciparum but not in chloroquine-resistant P. falciparum. On the contrary, sublethal concentrations of chloroquine partially reverse a deficiency of hemozoin production in chloroquine-resistant P. falciparum. These results indicate that the adaptation responsible for chloroquine resistance in P. falciparum prevents the accumulation of toxic FP by preventing chloroquine from uncoupling the processes of hemoglobin degradation and hemozoin production.
Orjih
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Department of Internal Medicine, Saint Louis University School of Medicine, MO 63104.
Fitch
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D000818:Animals; D002738:Chloroquine / Q000494:pharmacology*; D004351:Drug Resistance; D004912:Erythrocytes / Q000469:parasitology*; D006420:Hemeproteins / Q000096:biosynthesis*; D006427:Hemin / Q000032:analysis / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014166:Transferases / Q000037:antagonists & inhibitors
D006420:Hemeproteins; C020753:hemozoin; D006427:Hemin; D002738:Chloroquine; D014166:Transferases; C072176:heme polymerase