SEVERAL ALLELES OF THE MULTIDRUG-RESISTANCE GENE ARE CLOSELY LINKED TO CHLOROQUINE RESISTANCE IN PLASMODIUM-FALCIPARUM
SEVERAL ALLELES OF THE MULTIDRUG-RESISTANCE GENE ARE CLOSELY LINKED TO CHLOROQUINE RESISTANCE IN PLASMODIUM-FALCIPARUM
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DOI：
10.1038/345255a0
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发表时间：
1990-05-17
期刊：
影响因子：
64.8
通讯作者：
COWMAN, AF
中科院分区：
文献类型：
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作者：
FOOTE, SJ;KYLE, DE;COWMAN, AF
由恶性疟原虫引起的人类疟疾的致死性形式在许多地区几乎是无法控制的，因为抗药性的发展，特别是氯喹抗药性(CQR)。CQR在生物学上类似于哺乳动物肿瘤细胞的多药耐药表型(MDR)，因为两者都涉及药物从细胞中排出，并且都可以被钙通道拮抗剂1逆转。哺乳动物多药耐药基因的一个同源基因(Pfmdr1)被认为与CQR有关，因为它在一些CQR分离株OFP中扩增。恶性疟原虫2，3as是多药耐药肿瘤细胞的耐药基因。我们在这里表明，来自2个CQ敏感(CQS)恶性疟原虫分离株的pfmdr1基因全序列是相同的。在5株CQR分离株中，1-4个关键核苷酸差异导致氨基酸替换。在这些替换的基础上，我们已经正确地预测了36株分离物中另外34株的CQS/CQR状态。这是一个悖论，因为如果单点突变就足够了，CQR发生的频率比预测的要低得多。我们得出结论，突变的pfmdr1基因是CQR所需的至少两个突变基因之一。
THE lethal form of human malaria caused byPlasmodium falciparumis virtually uncontrollable in many areas because of the development of drug resistance, in particular chloroquine resistance (CQR). CQR is biologically similar to the multiple drug resistance phenotype (MDR) of mammalian tumour cells, as both involve expulsion of drug from the cell and both can be reversed by calcium channel antagonists1. A homologue (pfmdr1) of the mammalian multidrug resistance gene has been implicated in CQR because it is amplified in some CQR isolates ofP. falciparum2,3as is anmdrgene in MDR tumour cells4. We show here that the complete sequences ofpfmdr1genes from 2 CQ sensitive (CQS)P. falciparumisolates are identical. In 5 CQR isolates, 1–4 key nucleotide differences resulted in amino acid substitutions. On the basis of these substitutions, we have correctly predicted the CQS/CQR status of a further 34 out of 36 isolates. This is a paradox as CQR arises much less frequently than would be predicted if single point mutations were sufficient. We conclude that a mutatedpfmdr1gene is one of at least two mutated genes required for CQR.