Regulation of heme polymerizing activity and the antimalarial action of chloroquine.
Mice infected with Plasmodium berghei served as donors of erythrocytes with a high level of parasitemia for the study of ferriprotoporphyrin IX (FP) polymerization. Six hours after treatment of these mice with 3 micromol of chloroquine per 25 g of body weight, there were significant losses of heme polymerase I (HPA I). For chloroquine-susceptible (CS) P. berghei, the rate of FP polymerization decreased from 541 +/- 42 (mean +/- standard deviation; n = 12) to 51 +/- 19 (n = 8) nmol of FP polymerized per h per ml of packed erythrocytes (normalized to represent 1,000 parasites per 1,000 erythrocytes). For chloroquine-resistant (CR) P. berghei, the rate decreased from 284 +/- 19 (n = 16) to 124 +/- 11 (n = 6) nmol per h per ml. The chloroquine-induced loss of HPA I was accompanied by the accumulation of unpolymerized FP in CS P. berghei but not in CR P. berghei, which is consistent with the hypothesis that FP mediates the antimalarial action of chloroquine. Quinine treatment partially reversed the effects of chloroquine in CS P. berghei but not in CR P. berghei. Cycloheximide treatment antagonized the effects of chloroquine in both lines of parasites. To explain these findings, we propose that chloroquine, quinine, and cycloheximide perturb a regulatory process for HPA I. Furthermore, we propose that when chloroquine engages its target in the regulatory process, it initiates a chain of events which culminates in increased production, accessibility, or reactivity of a regulator (inactivator) of HPA I.
Fitch
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CD
Department of Internal Medicine, Saint Louis University School of Medicine, Missouri 63104, USA. fitchcd@wpogate.slu.edu
Chou
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AC
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006427:Hemin / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D010962:Plasmodium berghei / Q000187:drug effects* / Q000201:enzymology*; D011108:Polymers; D011803:Quinine / Q000494:pharmacology; D014166:Transferases / Q000187:drug effects* / Q000378:metabolism
D000962:Antimalarials; D011108:Polymers; D006427:Hemin; D002738:Chloroquine; D003513:Cycloheximide; D011803:Quinine; D014166:Transferases; C072176:heme polymerase