Park Sang-Joon, Kim Ki-Suk, Kim Eun-Joo
Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, 305-600, Korea.
J Appl Toxicol. 2008 Mar;28(2):104-11. doi: 10.1002/jat.1252.
A number of clinically used drugs block delayed rectifier K+ channels and prolong the duration of cardiac action potentials associated with long QT syndrome. This study investigated the molecular mechanisms of voltage-dependent inhibition of human ether-a-go-go-related gene (HERG) delayed rectifier K+ channels expressed in HEK-293 cells by brompheniramine, an antihistamine. Brompheniramine inhibited HERG current in a concentration-dependent manner with the half-maximal inhibitory concentration (IC50) value of 1.7 microm at 0 mV. A block of HERG current by brompheniramine was enhanced by progressive membrane depolarization and showed significantly negative shift in voltage-dependence of channel activation. Inhibition of HERG current by brompheniramine showed time-dependence. The S6 residue HERG mutant Y652A and F656C largely reduced the blocking potency of HERG current. These results indicate that brompheniramine mainly inhibited the HERG potassium channel through the residue Y652 and F656 and these residues may be an obligatory determinant in inhibition of HERG current for brompheniramine.
一些临床使用的药物会阻断延迟整流钾通道，并延长与长QT综合征相关的心脏动作电位的持续时间。本研究调查了抗组胺药溴苯那敏对人ether-a-go-go相关基因（HERG）延迟整流钾通道电压依赖性抑制的分子机制，该通道在HEK-293细胞中表达。溴苯那敏以浓度依赖性方式抑制HERG电流，在0 mV时半数最大抑制浓度（IC50）值为1.7微摩尔。膜电位逐渐去极化会增强溴苯那敏对HERG电流的阻断作用，且通道激活的电压依赖性出现明显负向偏移。溴苯那敏对HERG电流的抑制具有时间依赖性。HERG的S6残基突变体Y652A和F656C大大降低了对HERG电流的阻断效力。这些结果表明，溴苯那敏主要通过Y652和F656残基抑制HERG钾通道，这些残基可能是溴苯那敏抑制HERG电流的必要决定因素。
