THE BASIS OF ANTIMALARIAL ACTION - NON-WEAK BASE EFFECTS OF CHLOROQUINE ON ACID VESICLE PH
THE BASIS OF ANTIMALARIAL ACTION - NON-WEAK BASE EFFECTS OF CHLOROQUINE ON ACID VESICLE PH
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DOI：
10.4269/ajtmh.1987.36.213
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发表时间：
1987-03-01
影响因子：
3.3
通讯作者：
SCHLESINGER, PH
中科院分区：
文献类型：
--
作者：
KROGSTAD, DJ;SCHLESINGER, PH
生物活性浓度的氯喹在3-5分钟内增加寄生虫酸囊泡的pH值。这种pH值的增加由两种机制引起，其中一种在氯喹抗性寄生虫中显著降低。因为氯喹是弱碱，所以它在氯喹敏感和抗性寄生虫和哺乳动物细胞中通过该机制增加囊泡pH（基于它的两个pK和酸性囊泡与细胞外环境之间的Δ pH）。在对氯喹敏感的寄生虫中，而不是在对氯喹有抗性的寄生虫或哺乳动物细胞中，氯喹使酸性囊泡的pH值增加700至800倍，这是因为它是一种弱碱。纳摩尔氯喹在易感寄生虫中的非弱碱效应引起的酸囊泡pH值增加表明氯喹通过干扰寄生虫中的酸囊泡功能（例如血红蛋白的内吞作用和蛋白水解以及溶酶体酶的细胞内靶向）起作用。纳摩尔氯喹对寄生虫囊泡pH值的非弱碱效应也是其安全性的原因，因为这些氯喹浓度不会影响哺乳动物细胞。
Biologically active concentrations of chloroquine increase the pH of the parasite''s acid vesicles within 3-5 min. This increase in pH results from two mechanisms, one of which is markedly reduced in chloroquine-resistant parasites. Because chloroquine is a weak base, it increases vesicle pH by that mechanism in chloroquine-susceptible and resistant parasites and mammalian cells (based on its two pKs and the .DELTA.pH between the acid vesicle and the extracellular environment). In chloroquine-susceptible parasites, but not resistant parasites or mammalian cells, chloroquine increses the pH of acid vesicles 700- to 800-fold more than can be accounted for by its properties as a weak base. The increase in acid vesicle pH caused by thee non-weak base effects of nanomolar chloroquine in susceptible parasites suggests that chloroquine acts by interfering with acid vesicle functions in the parasite such as the endocytosis and proteolysis of hemoglobin, and the intracellular targeting of lysosomal enzymes. The non-weak base effects of nanomolar chloroquine on parasite vesicle pH are also responsible for its safety because these chloroquine concentrations do not affect mammalian cells.