Polymorphisms within PfMDR1 alter the substrate specificity for anti-malarial drugs in Plasmodium falciparum.
Resistance to several anti-malarial drugs has been associated with polymorphisms within the P-glycoprotein homologue (Pgh-1, PfMDR1) of the human malaria parasite Plasmodium falciparum. Pgh-1, coded for by the gene pfmdr1, is predominately located at the membrane of the parasite's digestive vacuole. How polymorphisms within this transporter mediate alter anti-malarial drug responsiveness has remained obscure. Here we have functionally expressed pfmdr1 in Xenopus laevis oocytes. Our data demonstrate that Pgh-1 transports vinblastine, an established substrate of mammalian MDR1, and the anti-malarial drugs halofantrine, quinine and chloroquine. Importantly, polymorphisms within Pgh-1 alter the substrate specificity for the anti-malarial drugs. Wild-type Pgh-1 transports quinine and chloroquine, but not halofantrine, whereas polymorphic Pgh-1 variants, associated with altered drug responsivenesses, transport halofantrine but not quinine and chloroquine. Our data further suggest that quinine acts as an inhibitor of Pgh-1. Our data are discussed in terms of the model that Pgh-1-mediates, in a variant-specific manner, import of certain drugs into the P. falciparum digestive vacuole, and that this contributes to accumulation of, and susceptibility to, the drug in question.
Sanchez
Cecilia P
CP
Hygiene Institut, Abteilung Parasitologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
Rotmann
Alexander
A
Stein
Wilfred D
WD
Lanzer
Michael
M
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics*; D017125:Genes, Protozoan; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials; D009865:Oocytes / Q000378:metabolism / Q000502:physiology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D016053:RNA, Protozoan / Q000235:genetics; D013379:Substrate Specificity; D014982:Xenopus laevis / Q000235:genetics / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D015800:Protozoan Proteins; D016053:RNA, Protozoan; C059987:mdr gene protein, Plasmodium