Dissecting the components of quinine accumulation in Plasmodium falciparum.
Although quinine, the active ingredient of chinchona bark, has been used in the treatment of malaria for several centuries, there is little information regarding the interactions of this drug with the human malaria parasite Plasmodium falciparum. To better understand quinine's mode of action and the mechanism underpinning reduced responsiveness, we have investigated the factors that contribute to quinine accumulation by parasites that differ in their susceptibility to quinine. Interestingly, passive distribution, in accordance with the intracellular pH gradients, and intracellular binding could account for only a small fraction of the high amount of quinine accumulated by the parasites investigated. The results of trans-stimulation kinetics suggest that high accumulation of quinine is brought about by a carrier-mediated import system. This import system seems to be weakened in parasites with reduced quinine susceptibility. Other data show that polymorphisms within PfCRT are causatively linked with an increased verapamil-sensitive quinine efflux that, depending on the genetic background, resulted in reduced quinine accumulation. The polymorphisms within PfMDR1 investigated did not affect quinine accumulation. Our data are consistent with the model that several factors, including acidotropic trapping, binding to intracellular sites and carrier-mediated import and export transport systems, contribute to steady-state intracellular quinine accumulation.
Sanchez
Cecilia P
CP
Hygiene Institut, Abteilung Parasitologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
Stein
Wilfred D
WD
Lanzer
Michael
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000378:metabolism*; D016054:DNA, Protozoan / Q000235:genetics; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism*; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D011803:Quinine / Q000378:metabolism*; D053058:Trophozoites / Q000254:growth & development; D014700:Verapamil / Q000494:pharmacology
D000255:Adenosine Triphosphate; D000962:Antimalarials; D016054:DNA, Protozoan; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; D011803:Quinine; D014700:Verapamil; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum