Trans Stimulation Provides Evidence for a Drug Efflux Carrier as the Mechanism of Chloroquine Resistance in Plasmodium falciparum

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• 作者：Cecilia P. Sanchez ; Wilfred Stein ; and Michael Lanzer
• 刊名：Biochemistry
• 出版年：2003
• 出版时间：August 12, 2003
• 年：2003
• 卷：42
• 期：31
• 页码：9383 - 9394
• 全文大小：139K
• 年卷期：v.42,no.31(August 12, 2003)
• ISSN：1520-4995

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.