Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
Molecules. 2019 Mar 29;24(7):1233. doi: 10.3390/molecules24071233.
Artemisinins are widely used to treat infections due to their high clinical efficacy; however, the antimalarial mechanism of artemisinin remains unresolved. Mutations in ATPase6 (PfATP6), a sarcoplasmic endoplasmic reticulum Ca-transporting ATPase, are associated with increased tolerance to artemisinin. We utilized as a model to examine the involvement of Pmr1p, a functional homolog of PfATP6, on the toxicity of artemisinin. Our analysis demonstrated that cells lacking Pmr1p are less susceptible to growth inhibition from artemisinin and its derivatives. No association between sensitivity to artemisinin and altered trafficking of the drug efflux pump Pdr5p, calcium homeostasis, or protein glycosylation was found in ∆ yeast. Basal ROS levels are elevated in ∆ yeast and artemisinin exposure does not enhance ROS accumulation. This is in contrast to WT cells that exhibit a significant increase in ROS production following treatment with artemisinin. Yeast deleted for are known to accumulate excess manganese ions that can function as ROS-scavenging molecules, but no correlation between manganese content and artemisinin resistance was observed. We propose that loss of function mutations in Pmr1p in yeast cells and PfATP6 in are protective against artemisinin toxicity due to reduced intracellular oxidative damage.
青蒿素类药物因临床疗效高而被广泛用于治疗 感染；然而，青蒿素的抗疟机制仍未解决。肌浆内质网 Ca 转运 ATP 酶（PfATP6）的 ATPase6 突变与对青蒿素的耐受性增加有关。我们利用 作为模型，研究了 PfATP6 的功能同源物 Pmr1p 在青蒿素毒性中的作用。我们的分析表明，缺乏 Pmr1p 的细胞对青蒿素及其衍生物的生长抑制作用的敏感性降低。在 ∆酵母中，未发现对青蒿素敏感性与药物外排泵 Pdr5p 的转运改变、钙稳态或蛋白质糖基化之间存在关联。 ∆酵母中的基础 ROS 水平升高，而青蒿素暴露不会增强 ROS 积累。这与 WT 细胞形成对比，WT 细胞在用青蒿素处理后会产生大量的 ROS 。已知酵母中缺失 会积累过量的锰离子，这些锰离子可以作为 ROS 清除分子，但未观察到锰含量与青蒿素耐药性之间存在相关性。我们提出，酵母细胞中 Pmr1p 功能丧失突变和疟原虫 PfATP6 的缺失可能会降低细胞内氧化损伤，从而对青蒿素毒性起到保护作用。
