Contribution of the pfmdr1 gene to antimalarial drug-resistance
Contribution of the pfmdr1 gene to antimalarial drug-resistance
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DOI：
10.1016/j.actatropica.2005.04.008
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发表时间：
2005-06-01
期刊：
影响因子：
2.7
通讯作者：
Cowman, AF
中科院分区：
文献类型：
--
作者：
Duraisingh, MT;Cowman, AF
抗药性的出现是控制疟疾的主要障碍。鉴定了哺乳动物细胞中主要多药转运蛋白的同源物，恶性疟原虫多药耐药蛋白-1，pfmdr1，也称为P-糖蛋白同源物1，Pgh-1。几项研究已经证明，在实验室和现场分离株中，对广泛使用的抗疟药氯喹的耐药性与pfmdr1基因突变之间存在强烈的关联，尽管不完全。遗传学研究已经证实了pfmdr1基因突变和氯喹耐药性之间的联系。尽管pfmdr1对氯喹抗性不是必需的，但它在调节抗性水平中起作用。与此同时，它似乎是对结构上相关的药物奎宁的耐药性的重要组成部分。在田间分离株中，已观察到野生型pfmdr1的拥有、pfmdr1的扩增和对疏水性药物如芳氨基醇甲氟喹和内过氧化物青蒿素衍生物的耐药性之间存在强关联。这得到了遗传学研究的支持。芳基氨基醇和内过氧化物药物是结构上不相关的药物，这种耐药性类似于真正的多药耐药性。在pfmdr1和基因扩增的多态性已被观察到在世界各地和他们的有用性在预测耐药水平的影响，每个人口的药物选择的历史。(c)2005 Elsevier B.V.保留所有权利。
The emergence of drug-resistance poses a major obstacle to the control of malaria. A homolog of the major multidrug-transporter in mammalian cells was identified, Plasmodium falciparum multidrug resistance protein-1, pfmdr1, also known as the P-glycoprotein homolog 1, Pgh-1. Several studies have demonstrated strong, although incomplete, associations between resistance to the widely used antimalarial drug chloroquine and mutation of the pfmdr1 gene in both laboratory and field isolates. Genetic studies have confirmed a link between mutation of the pfmdr1 gene and chloroquine-resistance. Although not essential for chloroquine-resistance, pfmdr1 plays a role in modulating levels of resistance. At the same time it appears to be a significant component in resistance to the structurally related drug quinine. A strong association has been observed between possession of the wildtype form of pfmdr1, amplification of pfmdr1 and resistance to hydrophobic drugs such as the arylaminoalcohol mefloquine and the endoperoxide artemisinin derivatives in field isolates. This is supported by genetic studies. The arylaminoalcohol and endoperoxide drugs are structurally unrelated drugs and this resistance resembles true multidrug resistance. Polymorphism in pfmdr1 and gene amplification has been observed throughout the world and their usefulness in predicting resistance levels is influenced by the history of drug selection of each population. (c) 2005 Elsevier B.V. All rights reserved.