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.