Evidence for a pfcrt-associated chloroquine efflux system in the human malarial parasite Plasmodium falciparum.
Resistance to the antimalarial drug chloroquine has been linked with polymorphisms within a gene termed pfcrt in the human malarial parasite Plasmodium falciparum, yet the mechanism by which this gene confers the reduced drug accumulation phenotype associated with resistance is largely unknown. To investigate the role of pfcrt in mediating chloroquine resistance, we challenged P. falciparum clones differing only in their pfcrt allelic form with the "varying-trans" procedure. In this procedure, movement of labeled substrate across a membrane is measured when unlabeled substrate is present on the trans side of the membrane. If a transporter is mediating the substrate flow, a stimulation of cis-to-trans movement may be observed with increasing concentrations of trans substrate. We present evidence for an association of those pfcrt alleles found in chloroquine-resistant P. falciparum strains with the phenomenon of stimulated chloroquine accumulation under varying-trans conditions. Such an association is not seen with polymorphisms within pfmdr1, which encodes a homologue of the human multidrug resistance efflux pump. Our data are interpreted in terms of a model in which pfcrt is directly or indirectly involved in carrier-mediated chloroquine efflux from resistant cells.
Sanchez
Cecilia P
CP
Hygiene Institut, Abteilung Parasitologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
McLean
Jeremy E
JE
Rohrbach
Petra
P
Fidock
David A
DA
Stein
Wilfred D
WD
Lanzer
Michael
M
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002738:Chloroquine / Q000737:chemistry / Q000378:metabolism*; D004351:Drug Resistance / Q000235:genetics*; D004910:Erythrocyte Membrane / Q000235:genetics / Q000378:metabolism / Q000469:parasitology; D005502:Food; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010080:Oxazoles / Q000737:chemistry; D010963:Plasmodium falciparum / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D013050:Spectrometry, Fluorescence; D014617:Vacuoles / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
C120434:2-(4-pyridyl)-5-((4-(2-dimethylaminoethylaminocarbamoyl)methoxy)phenyl)oxazole; D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D010080:Oxazoles; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; D002738:Chloroquine