Chloroquine-(14)C was used to study the processes which concentrate
chloroquine in mouse red blood cells infected with
chloroquine-sensitive or with
chloroquine-resistant Plasmodium berghei. The initial rates of uptake and exchange of chloroquine-(14)C were both too fast to measure, yet large concentration gradients were maintained by the cells. When red blood cells were exposed to 10(-8)M
chloroquine at 22 degrees C, with pH between 7.2 and 7.4, steady-state gradients of chloroquine-(14)C were approximately 600:1 (cells:medium) for cells infected with
chloroquine-sensitive parasites, 100:1 for cells comparably infected with
chloroquine-resistant parasites, and 14:1 for uninfected cells. The processes responsible for these gradients were saturable, in agreement with the proposal of
chloroquine binding to cellular constituents. No degradation of
chloroquine was detected. The major difference between the
chloroquine-sensitive and -resistant parasites was deficiency of high-affinity binding of
chloroquine by cells infected with
chloroquine-resistant parasites. This deficiency explains the reduced ability of
chloroquine-resistant parasites to concentrate
chloroquine, and it suggests that
chloroquine resistance is due to a decrease in the number, affinity, or accessibility of
chloroquine receptor sites on a constituent of the
malaria parasite.