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 mu mol of chloroquine per 25 g of body weight, there were significan t 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 represe nt 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. bergh ei but not in CR P. berghei, which is consistent with the hypothesis t hat FP mediates the antimalarial action of chloroquine. Quinine treatm ent 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 reg ulatory process for HPA I. Furthermore, we propose that when chloroqui ne 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.