Identification of a chloroquine importer in Plasmodium falciparum. Differences in import kinetics are genetically linked with the chloroquine-resistant phenotype.
We demonstrate that uptake of the antimalarial drug chloroquine is temperature-dependent, saturable, and inhibitable in Plasmodium falciparum. These features are indicative of carrier-mediated transport and suggest that a P. falciparum-encoded protein facilitates chloroquine import. Although both chloroquine-resistant and susceptible parasite isolates exhibit facilitated chloroquine uptake, the kinetics differ. Chloroquine-resistant parasite isolates consistently have an import mechanism with a lower transport activity and a reduced affinity for chloroquine. These differences in uptake kinetics are linked with chloroquine resistance in a genetic cross. These data suggest that changes in chloroquine import kinetics constitute a minimal and necessary event in the generation of the resistant phenotype. Competitive inhibition of chloroquine uptake by amiloride derivatives further suggests that chloroquine import is mediated by a plasmodial Na+/H+ exchanger.
Sanchez
C P
CP
Zentrum für Infektionsforschung der Universität Würzburg, Röntgenring 11, D-97070 Würzburg, Federal Republic of Germany.
Wünsch
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S
Lanzer
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M
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D002738:Chloroquine / Q000378:metabolism* / Q000633:toxicity*; D003433:Crosses, Genetic; D004351:Drug Resistance / Q000235:genetics*; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D010641:Phenotype; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013696:Temperature
D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride; D002738:Chloroquine; C039614:ethylisopropylamiloride