CHLOROQUINE RESISTANCE NOT LINKED TO MDR-LIKE GENES IN A PLASMODIUM-FALCIPARUM CROSS
CHLOROQUINE RESISTANCE NOT LINKED TO MDR-LIKE GENES IN A PLASMODIUM-FALCIPARUM CROSS
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DOI：
10.1038/345253a0
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发表时间：
1990-05-17
期刊：
影响因子：
64.8
通讯作者：
KROGSTAD, DJ
中科院分区：
文献类型：
--
作者：
WELLEMS, TE;PANTON, LJ;KROGSTAD, DJ
氯喹被认为通过在寄生虫的酸性囊泡中积累并干扰其功能来对抗恶性疟疾1 -4。对氯喹有抗药性的寄生虫会以不变的形式迅速排出药物，从而降低囊泡中的蓄积水平5。维拉帕米在体外部分逆转氯喹耐药的发现导致了这样的建议，即外排可能涉及ATP驱动的P-糖蛋白泵，类似于哺乳动物多药耐药（mdr）肿瘤细胞系。事实上，恶性疟原虫含有至少两个omdr样基因7，8，其中一个已被建议赋予氯喹耐药（CQR）表型7，9，10。为了确定这些基因是否与氯喹抗性相关，我们在CQR和氯喹敏感（CQS）克隆的P。恶性疟原虫。16个独立的重组后代的检查表明，快速外排表型是由一个单一的基因或一组紧密连锁的基因控制。但是，在快速外排、CQR表型和dr-like P之间没有联系。恶性疟原虫基因或这些基因的扩增。这些数据表明，控制氯喹外排和抗性的遗传位点是独立的knownmdr-like基因。
CHLOROQUINE is thought to act against falciparum malaria by accumulating in the acid vesicles of the parasite and interfering with their function1–4. Parasites resistant to chloroquine expel the drug rapidly in an unaltered form, thereby reducing levels of accumulation in the vesicles5. The discovery that verapamil partially reverses chloroquine resistancein vitro6led to the proposal that efflux may involve an ATP-driven P-glycoprotein pump similar to that in mammalian multidrug-resistant (mdr) tumor cell lines. Indeed,Plasmodium falciparumcontains at least twomdr-like genes7,8, one of which has been suggested to confer the chloroquine resistant (CQR) phenotype7,9,10. To determine if either of these genes is linked to chloroquine resistance, we performed a genetic cross between CQR and chloroquine-susceptible (CQS) clones ofP. falciparum. Examination of 16 independent recombinant progeny indicated that the rapid efflux phenotype is controlled by a single gene or a closely linked group of genes. But, there was no linkage between the rapid efflux, CQR phenotype and either of themdr-likeP. falciparumgenes or amplification of those genes. These data indicate that the genetic locus governing chloroquine efflux and resistance is independent of the knownmdr-like genes.