Sanchez CP, Rotmann A, Stein WD, Lanzer M
Polymorphisms within PfMDR1 alter the substrate specificity for antimalarial drugs in Plasmodium falciparum. [JOURNAL ARTICLE]
Mol Microbiol 2008 Aug 18.
Resistance to several antimalarial 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 antimalarial 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 antimalarial drugs halofantrine, quinine, and chloroquine. Importantly, polymorphisms within Pgh-1 alter the substrate specificity for the antimalarial drugs. Wildtype 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.
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