Ritchie G Y, Mungthin M, Green J E, Bray P G, Hawley S R, Ward S A
Department of Pharmacology and Therapeutics, University of Liverpool, UK.
Mol Biochem Parasitol. 1996 Dec 2;83(1):35-46. doi: 10.1016/s0166-6851(96)02746-6.
Recent investigations into quinoline and phenanthrene methanol resistance in Plasmodium falciparum have described a linkage between amplification of the mdr homologue pfmdr1 and decreased susceptibility to mefloquine (MQ) and halofantrine (HF). We have examined the current theories on cross-resistance patterns and pfmdr1 gene expression by comparing the chloroquine (CQ) resistant isolate K1 with K1Hf, developed from the K1 isolate by intermittent exposure to halofantrine. Reduced halofantrine susceptibility in K1Hf was accompanied by reduced sensitivity to mefloquine and increased sensitivity to chloroquine. These sensitivity changes were reflected by changes in parasite drug accumulation. The loss of high level chloroquine resistance in K1Hf was associated with an inability of verapamil to enhance chloroquine sensitivity or accumulation. In contrast verapamil retained the chemosensitising potential against quinine in this isolate. The changes in phenotype were achieved without any amplification or increased expression of pfmdr1 or reversion of the Tyr86 mutation in the gene. Our data indicates that acquisition of halofantrine and mefloquine resistance and the loss of high level chloroquine resistance can be achieved without enhanced expression of the pfmdr1 gene product.
近期对恶性疟原虫喹啉和菲甲醇耐药性的研究描述了mdr同源物pfmdr1的扩增与对甲氟喹（MQ）和卤泛群（HF）敏感性降低之间的联系。我们通过比较氯喹（CQ）耐药株K1和通过间歇性接触卤泛群从K1株衍生而来的K1Hf，研究了关于交叉耐药模式和pfmdr1基因表达的现有理论。K1Hf对卤泛群的敏感性降低伴随着对甲氟喹的敏感性降低和对氯喹的敏感性增加。这些敏感性变化通过寄生虫药物蓄积的变化得以体现。K1Hf中高水平氯喹耐药性的丧失与维拉帕米无法增强氯喹敏感性或蓄积有关。相比之下，维拉帕米在该分离株中保留了对奎宁的化学增敏潜力。表型变化在没有pfmdr1的任何扩增或表达增加或该基因中Tyr86突变逆转的情况下实现。我们的数据表明，获得卤泛群和甲氟喹耐药性以及高水平氯喹耐药性的丧失可以在不增强pfmdr1基因产物表达的情况下实现。
