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首页> 外文期刊>Biochemistry >Evidence for a pfcrt-associated chloroquine efflux system in the human malarial parasite Plasmodium falciparum
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Evidence for a pfcrt-associated chloroquine efflux system in the human malarial parasite Plasmodium falciparum

机译：人类疟疾寄生虫恶性疟原虫中与pfcrt相关的氯喹外排系统的证据

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摘要

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.
机译：抗疟疾药物氯喹的抗药性已与人类疟疾寄生虫恶性疟原虫pfcrt基因内的多态性相关联，但该基因赋予与抗药性相关的减少的药物蓄积表型的机制尚不清楚。为了研究pfcrt在介导氯喹抗性中的作用，我们用“可变反式”方法对恶性疟原虫克隆仅以pfcrt等位基因形式有所不同。在该程序中，当未标记的底物存在于膜的反面时，将测量标记的底物在膜上的运动。如果转运蛋白介导底物流，则随着反式底物浓度的增加，可以观察到顺式至反式运动的刺激。我们提供的证据表明，那些在抗氯喹的恶性疟原虫菌株中发现的那些pfcrt等位基因与在不同反式条件下刺激的氯喹蓄积现象相关。 pfmdr1内的多态性未发现这种关联，该基因编码人类多药耐药性外排泵的同源物。我们的数据是根据pfcrt直接或间接参与抗性细胞的载体介导的氯喹流出的模型解释的。

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