Chloroquine resistance in malaria: variations of substrate-stimulated chloroquine accumulation

The response of [14C]chloroquine accumulation to the provision of substrate was evaluated using washed erythrocytes infected with Plasmodium berghei CS (chloroquine-susceptible), with P. berghei CR (chloroquine-resistant), with Plasmodium vinckei CS, with P. vinckei CR, or with a strain of P. berghei spontaneously resistant to chloroquine, Plasmodium berghei yoelii 17X. Erythrocytes infected with chloroquine-resistant parasites had a blunted response, particularly to low glucose concentrations. In the presence of 0.5 mM glucose in one set of experiments, for example, chloroquine accumulation increased by a factor of 8 in erythrocytes infected with P. berghei CS whereas there was no increase in erythrocytes infected with P. berghei CR or with P. berghei yoelii 17X; the difference between P. vinckei CS and P. vinckei CR was less dramatic. In every case except for P. berghei CR, the process of chloroquine accumulation in the presence of 5 mM glucose exhibited a component which became saturated at low concentrations of chloroquine in the medium. For P. berghei CR, plotting steady-state accumulation of chloroquine as a function of the concentration of chloroquine in the medium yielded a sigmoid curve, revealing that higher concentrations of chloroquine (above 100 mM) somehow relieve the blunted response to glucose and suggesting that the variation is in the process of accumulation rather than in substrate utilization.