Dey S, Papadopoulou B, Haimeur A, Roy G, Grondin K, Dou D, Rosen B P, Ouellette M
Department of Biochemistry, Wayne State University School of Medicine, Detroit, MI 48201.
Mol Biochem Parasitol. 1994 Sep;67(1):49-57. doi: 10.1016/0166-6851(94)90095-7.
Leishmania tarentolae cells selected for resistance to the oxyanions pentavalent or trivalent antimonials or to trivalent arsenicals exhibited cross-resistance to the other oxyanions. The basis for resistance in these mutants was studied by transport experiments using radioactive arsenite. All mutants exhibiting high level resistance to arsenite showed a marked decrease in the steady-state accumulation of arsenite. Decreased accumulation was also observed in antimonials-resistant mutants cross-resistant to various concentrations of arsenite. Cells depleted of endogenous energy reserves with metabolic inhibitors were loaded with radioactive arsenite; following addition of glucose, rapid efflux of arsenite was observed from arsenite mutant cells. Mutants resistant to high levels of arsenicals exhibited amplification of the P-glycoprotein related gene ltpgpA or of a linear amplicon of unknown function. However, the efflux-mediated arsenite resistance did not correlate with the amplification of the ltpgpA gene or with the presence of the linear amplicon. The calcium channel blocker verapamil and arsenite act in synergy in cells exhibiting the efflux system. Overall the oxyanion efflux system in Leishmania shares several properties with other resistance efflux systems mediated by transporters.
选择对五价或三价锑的含氧阴离子或三价砷具有抗性的大利什曼原虫细胞，对其他含氧阴离子表现出交叉抗性。通过使用放射性亚砷酸盐的转运实验研究了这些突变体的抗性基础。所有对亚砷酸盐表现出高水平抗性的突变体，其亚砷酸盐的稳态积累均显著下降。在对不同浓度亚砷酸盐具有交叉抗性的抗锑突变体中也观察到积累减少。用代谢抑制剂耗尽内源性能量储备的细胞加载放射性亚砷酸盐；添加葡萄糖后，观察到亚砷酸盐从亚砷酸盐突变体细胞中快速流出。对高浓度砷具有抗性的突变体表现出P-糖蛋白相关基因ltpgpA或功能未知的线性扩增子的扩增。然而，外排介导的亚砷酸盐抗性与ltpgpA基因的扩增或线性扩增子的存在无关。钙通道阻滞剂维拉帕米和亚砷酸盐在表现出外排系统的细胞中协同作用。总体而言，利什曼原虫中的含氧阴离子外排系统与其他由转运蛋白介导的抗性外排系统具有若干共同特性。
