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对20种挥发油类化合物中的对羟基苯甲酸丁酯(butyl-p-hydroxybenzoate,Bpb)的CFTR氯离子通道激活作用进行系统的分子药理学研究。利用稳定共表达人CFTR和对卤族元素碘离子高度敏感的荧光绿蛋白突变体(EYFP)的Fischer大鼠甲状腺(FRT)上皮细胞为筛选模型,测定Bpb对CFTR介导的I-内流速度的影响。发现了Bpb对野生型CFTR的Cl-通道具有显著的激活作用;Bpb不能纠正△F508-CFTR蛋白胞内转运的障碍,但却具有纠正其通道开放障碍的功能;Bpb对G551D突变型CFTRCl-通道无激活作用。激活作用具有可逆和剂量依赖的特点,初步机制分析结果表明,它可能是通过与CFTR直接结合而发挥作用的。首次发现了Bpb对CFTRCl-通道有激活作用,为深入研究Bpb的药理学作用提供了新方向,使其有可能成为治疗CFTR有关疾病的先导药物。
A systematic molecular pharmacological study of the CFTR chloride channel activation of butyl-p-hydroxybenzoate (Bpb) in 20 volatile oil compounds was performed. Fischer rat thyroid (FRT) epithelial cells stably co-expressing human CFTR and fluorescent green protein mutant (EYFP) highly sensitive to halogen elemental iodide were used as a screening model to determine the effect of Bpb on CFTR-mediated I- Impact. Found that Bpb had a significant activation on the Cl-channel of wild-type CFTR; Bpb could not correct the intracellular transport of △ F508-CFTR protein but had the function of correcting the open-circuit barrier; Bpb had no effect on G551D mutant CFTRCl- No activation. The activation was reversible and dose-dependent. The results of the preliminary mechanism analysis indicated that it may play a direct role by binding to CFTR. We found for the first time that Bpb has an activation effect on CFTRCl-channel, providing a new direction for further studying the pharmacological effects of Bpb, making it potentially as a leading drug for the treatment of CFTR-related diseases.