Rohrbach Petra, Sanchez Cecilia P, Hayton Karen, Friedrich Oliver, Patel Jigar, Sidhu Amar Bir Singh, Ferdig Michael T, Fidock David A, Lanzer Michael
Hygiene Institut, Abteilung Parasitologie, Universitätsklinikum Heidelberg, Heidelberg, Germany.
EMBO J. 2006 Jul 12;25(13):3000-11. doi: 10.1038/sj.emboj.7601203. Epub 2006 Jun 22.
The P-glycoprotein homolog of the human malaria parasite Plasmodium falciparum (Pgh-1) has been implicated in decreased susceptibility to several antimalarial drugs, including quinine, mefloquine and artemisinin. Pgh-1 mainly resides within the parasite's food vacuolar membrane. Here, we describe a surrogate assay for Pgh-1 function based on the subcellular distribution of Fluo-4 acetoxymethylester and its free fluorochrome. We identified two distinct Fluo-4 staining phenotypes: preferential staining of the food vacuole versus a more diffuse staining of the entire parasite. Genetic, positional cloning and pharmacological data causatively link the food vacuolar Fluo-4 phenotype to those Pgh-1 variants that are associated with altered drug responses. On the basis of our data, we propose that Pgh-1 imports solutes, including certain antimalarial drugs, into the parasite's food vacuole. The implications of our findings for drug resistance mechanisms and testing are discussed.
人类疟原虫恶性疟原虫（Pgh-1）的P-糖蛋白同系物与对包括奎宁、甲氟喹和青蒿素在内的几种抗疟药物的敏感性降低有关。Pgh-1主要位于寄生虫的食物泡膜内。在此，我们描述了一种基于Fluo-4乙酰氧基甲酯及其游离荧光染料的亚细胞分布的Pgh-1功能替代检测方法。我们鉴定出两种不同的Fluo-4染色表型：食物泡的优先染色与整个寄生虫更弥散的染色。遗传、定位克隆和药理学数据将食物泡Fluo-4表型与那些与药物反应改变相关的Pgh-1变体因果联系起来。基于我们的数据，我们提出Pgh-1将溶质，包括某些抗疟药物，导入寄生虫的食物泡中。讨论了我们的发现对耐药机制和检测的影响。
