文摘
The mechanism underpinning chloroquine drug resistance in the human malarial parasitePlasmodium falciparum has remained controversial. Currently considered models to explain the resistancephenotype include acquisition of a chloroquine efflux pump, changes in intracellular chloroquinepartitioning, diminished binding affinity of chloroquine to its intracellular target, heme, and changes inheme crystallization. To challenge these different models, we have investigated chloroquine accumulationunder trans-stimulation conditions and in the presence and absence of glucose. We show that, in chloroquine-sensitive strains, labeled chloroquine accumulation is steadily reduced as the pre-equilibrated chloroquineconcentration is raised. In the resistant cells, the extent of accumulation is, strikingly, raised at the lowerlevels of preloading, in comparison with resistant controls in the absence of chloroquine. The trans-stimulation effect observed in chloroquine-resistant cells is strictly energy-dependent. The data areinterpreted in terms of a model in which chloroquine is bound to intracellular binding sites, not differentas between sensitive and resistant cells, but where, in resistant cells, there exists an energy-dependentcarrier that moves chloroquine out of this intracellular compartment. A mathematical model describingthe kinetics of these processes is presented.