Evidence for a pfcrt-Associated Chloroquine Efflux System in the Human Malarial Parasite Plasmodium falciparum
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- 作者：Cecilia P. Sanchez ; Jeremy E. McLean ; Petra Rohrbach ; David A. Fidock ; Wilfred D. Stein ; and Michael Lanzer
- 刊名：Biochemistry
- 出版年：2005
- 出版时间：July 26, 2005
- 年：2005
- 卷：44
- 期：29
- 页码：9862 - 9870
- 全文大小：391K
- 年卷期：v.44,no.29(July 26, 2005)
- ISSN：1520-4995
文摘
Resistance to the antimalarial drug chloroquine has been linked with polymorphisms within agene termed pfcrt in the human malarial parasite Plasmodium falciparum, yet the mechanism by whichthis 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 clonesdiffering only in their pfcrt allelic form with the "varying-trans" procedure. In this procedure, movementof labeled substrate across a membrane is measured when unlabeled substrate is present on the trans sideof the membrane. If a transporter is mediating the substrate flow, a stimulation of cis-to-trans movementmay be observed with increasing concentrations of trans substrate. We present evidence for an associationof those pfcrt alleles found in chloroquine-resistant P. falciparum strains with the phenomenon of stimulatedchloroquine accumulation under varying-trans conditions. Such an association is not seen withpolymorphisms within pfmdr1, which encodes a homologue of the human multidrug resistance effluxpump. Our data are interpreted in terms of a model in which pfcrt is directly or indirectly involved incarrier-mediated chloroquine efflux from resistant cells.