Molecular basis for the lack of HERG K+ channel block-related cardiotoxicity by the H1 receptor blocker cetirizine compared with other second-generation antihistamines.
Molecular basis for the lack of HERG K+ channel block-related cardiotoxicity by the H1 receptor blocker cetirizine compared with other second-generation antihistamines.
复制标题
DOI：
10.1124/mol.54.1.113
复制
发表时间：
1998-07
影响因子：
3.6
通讯作者：
Maurizio Taglialatela;A. Pannaccione;P. Castaldo;Giovanna Giorgio;Zhengfeng Zhou;Craig T. January;Arturo Genovese;G. Marone;L. Annunziato
中科院分区：
文献类型：
--
作者：
Maurizio Taglialatela;A. Pannaccione;P. Castaldo;Giovanna Giorgio;Zhengfeng Zhou;Craig T. January;Arturo Genovese;G. Marone;L. Annunziato
在目前的研究中，研究了哌嗪H1受体拮抗剂西替利嗪对人乙醚-a-go-go相关基因（HERG）编码的K+通道的潜在阻断能力，并与其他第二代抗组胺药（阿司咪唑、特非那定和氯雷他定）进行了比较。西替利嗪对非洲爪蟾卵母细胞中异源表达的HERG K+通道完全没有抑制作用。另一方面，特非那定和阿司咪唑有效阻断HERG K+通道，具有纳米摩尔亲和力（估计IC50值分别为330和480 nM），而氯雷他定的效力约为300倍（IC50约为100微米）。此外，与特非那定相比，西替利嗪没有表现出使用依赖性阻断。在SH-SY5Y细胞(一种组成性表达HERG通道携带的K+电流的人神经母细胞瘤克隆细胞（IHERG）中，以及在稳定转染HERG cDNA的人胚胎肾293细胞中，细胞外灌注3微米西替利嗪对IHERG没有任何抑制作用。另一方面，阿司咪唑（3微米）是非常有效的。特非那定（3微米）对SH-SY5Y细胞的IHERG有明显的（约80%）抑制作用，而相同浓度的氯雷他定则有40%的抑制作用。此外，在转染heg的人胚胎肾293细胞膜的胞内侧应用西替利嗪（3微米）对IHERG没有影响，而相同浓度的阿司咪唑可完全阻断IHERG。目前的研究结果表明，第二代抗组胺药在阻断HERG K+通道的能力上表现出明显的差异。特别是西替利嗪，与其他抗组胺药相比，它具有更多的极性和更小的取代基，与叔胺相连，缺乏heg阻断特性，可能解释了其治疗用途中没有点扭转性室性心律失常的原因。
In the current study, the potential blocking ability of K+ channels encoded by the human ether-a-go-go related gene (HERG) by the piperazine H1 receptor antagonist cetirizine has been examined and compared with that of other second-generation antihistamines (astemizole, terfenadine, and loratadine). Cetirizine was completely devoid of any inhibitory action on HERG K+ channels heterologously expressed in Xenopus laevis oocytes in concentrations up to 30 microM. On the other hand, terfenadine and astemizole effectively blocked HERG K+ channels with nanomolar affinities (the estimated IC50 values were 330 and 480 nM, respectively), whereas loratadine was approximately 300-fold less potent (IC50 approximately 100 microM). In addition, in contrast to terfenadine, cetirizine did not show use-dependent blockade. In SH-SY5Y cells, a human neuroblastoma clone that constitutively expresses K+ currents carried by HERG channels (IHERG), as well as in human embryonic kidney 293 cells stably transfected with HERG cDNA, extracellular perfusion with 3 microM cetirizine did not exert any inhibitory action on IHERG. Astemizole (3 microM), on the other hand, was highly effective. Terfenadine (3 microM) caused a marked (approximately 80%) inhibition of IHERG in SH-SY5Y cells, whereas loratadine, at the same concentration, caused a 40% blockade. Furthermore, the application of cetirizine (3 microM) on the intracellular side of the membrane of HERG-transfected human embryonic kidney 293 cells did not affect IHERG, whereas the same intracellular concentration of astemizole caused a complete block. The results of the current study suggest that second-generation antihistamines display marked differences in their ability to block HERG K+ channels. Cetirizine in particular, which possesses more polar and smaller substituent groups attached to the tertiary amine compared with other antihistamines, lacks HERG-blocking properties, possibly explaining the absence of torsade de pointes ventricular arrhythmias associated with its therapeutical use.