Susceptibility of human malaria parasites to chloroquine is pH dependent.
Susceptibility of human malaria parasites to chloroquine is pH dependent.
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人类疟疾寄生虫对氯喹的敏感性取决于 pH 值。
DOI：
10.1073/pnas.82.9.2784
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发表时间：
1985
影响因子：
11.1
通讯作者：
H. Ginsburg
中科院分区：
文献类型：
--
作者：
A. Yayon;Z. Cabantchik;H. Ginsburg
氯喹（CQ）由于其弱碱性质在红细胞内疟原虫（恶性疟原虫）的酸性食物液泡中积累。在本研究中，CQ积累的程度是由跨液泡pH梯度决定的：后者的改变——要么通过改变外部pH，要么通过添加嗜酸剂NH4Cl——导致细胞和培养基之间CQ分布的相应变化。pH梯度的变化引起寄生虫对CQ敏感性的变化：在外部pH值为8.0、7.4和6.8时，CQ的IC50值分别为0.48 × 10(-7) M、1.8 × 10(-7) M和3.3 × 10(-7) M。将细胞同时暴露于CQ和10 mM NH4Cl中，pH为7.4，可使细胞对CQ产生明显的抗性（IC50 = 9.8 X 10(-7) M）。在寄生虫的酸性室内获得的CQ的最终浓度与寄生虫生长的抑制有关。在治疗药物水平下，CQ的积累引起食物液泡pH值的微小变化，而在较高的CQ浓度下，观察到大量的碱化。CQ的抗疟活性可能是由于食物液泡中积累的高浓度药物对其重要功能的干扰而发挥的。
Chloroquine (CQ) accumulates in the acidic food vacuole of intraerythrocytic malaria parasites (Plasmodium falciparum) by virtue of its weak base properties. In the present work, the extent of CQ accumulation was determined by the transvacuolar pH gradient: modification of the latter--either by changing the external pH or by adding the acidotropic agent NH4Cl--led to a corresponding change in CQ distribution between cells and medium. Changes in pH gradient provoked a change in the susceptibility of parasites to CQ: at external pH values of 8.0, 7.4, and 6.8, the IC50 values for CQ were 0.48 X 10(-7) M, 1.8 X 10(-7) M, and 3.3 X 10(-7) M, respectively. Marked resistance to CQ (IC50 = 9.8 X 10(-7) M) was conferred upon cells by exposing them simultaneously to CQ and 10 mM NH4Cl, at pH 7.4. The final concentration of CQ attained within the acidic compartment of the parasite was correlated with inhibition of parasite growth. At therapeutic drug levels, CQ accumulation caused minor changes in the food vacuole pH, whereas at higher CQ concentrations substantial alkalinization was observed. The antimalarial activity of CQ is suggested to be exerted by the interference of the high concentrations of the accumulated drug with vital functions of the food vacuole.