Polymorphisms within PfMDR1 alter the substrate specificity for anti-malarial drugs in Plasmodium falciparum

Mol Microbiol. 2008 Nov;70(4):786-98. doi: 10.1111/j.1365-2958.2008.06413.x. Epub 2008 Aug 18.


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.

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Antimalarials / pharmacology*
  • Drug Resistance / genetics*
  • Genes, Protozoan
  • Hydrogen-Ion Concentration
  • Membrane Potentials
  • Oocytes / metabolism
  • Oocytes / physiology
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / genetics*
  • Plasmodium falciparum / metabolism
  • Polymorphism, Genetic
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism*
  • RNA, Protozoan / genetics
  • Substrate Specificity
  • Xenopus laevis / genetics
  • Xenopus laevis / metabolism


  • ATP-Binding Cassette Transporters
  • Antimalarials
  • Protozoan Proteins
  • RNA, Protozoan
  • mdr gene protein, Plasmodium