Chloroquine uptake, altered partitioning and the basis of drug resistance: evidence for chloride-dependent ionic regulation.
Chloroquine uptake, altered partitioning and the basis of drug resistance: evidence for chloride-dependent ionic regulation.
复制标题
氯喹的吸收、分配的改变和耐药性的基础：氯依赖性离子调节的证据。
DOI：
10.1002/9780470515730.ch18
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发表时间：
1999
影响因子：
--
通讯作者：
Roepe,P
中科院分区：
文献类型：
--
作者：
Martiney,JA;Ferrer,AS;Cerami,A;Dzekunov,S;Roepe,P
The biochemical mechanism of chloroquine resistance inPlasmodium falciparumremains unknown. We postulated that chloroquine‐resistant strains could alter ion fluxes that then indirectly control drug accumulation within the parasite by affecting pH and/or membrane potential (‘altered partitioning mechanism’). Two principal intracellular pH‐ regulating systems in many cell types are the amiloride‐sensitive Na+/H+exchanger (NHE), and the sodium‐independent, stilbene‐sensitive CI−/HCO−3antiporter (AE). We report that under physiological conditions (balanced CO2and HCO−3) chloroquine uptake and susceptibility are not altered by amiloride analogues. We also do not detect a significant difference in NHE activity between chloroquine‐sensitive and chloroquine‐ resistant strains via single cell photometry methods. AE activity is dependent on the intracellular and extracellular concentrations of Cl−and HCO−3ions. Chloroquine‐ resistant strains differentially respond to experimental modifications in chloride‐ dependent homeostasis, including growth, cytoplasmic pH and pH regulation. Chloroquine susceptibility is altered by stilbene DIDS only on chloroquine‐resistant strains. Our results suggest that a Cl−‐dependent system (perhaps AE) has a significant effect on the uptake of chloroquine by the infected erythrocyte, and that alterations of this biophysical parameter may be part of the mechanism of chloroquine resistance in P.falciparum.
