Molecular basis for the lack of HERG K+ channel block-related cardiotoxicity by the H1 receptor blocker cetirizine compared with other second-generation antihistamines

Maurizio Taglialatela, Anna Pannaccione, Pasqualina Castaldo, Giovanna Giorgio, Zhengfeng Zhou, Craig T. January, Arturo Genovese, Gianni Marone, Lucio Annunziato

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125 Scopus citations


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 μM. 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 ~300-fold less potent (IC50 ≃ 100 μM). 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 (I(HERG)), as well as in human embryonic kidney 293 cells stably transfected with HERG cDNA, extracellular perfusion with μM cetirizine did not exert any inhibitory action on I(HERG). Astemizole (3 μM), on the other hand, was highly effective. Terfenadine (3 μM) caused a marked (≃-80%)inhibition of I(HERG) in SH-SY5Y cells, whereas loratadine, at the same concentration, caused a 40% blockade. Furthermore, the application of cetirizine (3 μM) on the intracellular side of the membrane of HERG-transfected human embryonic kidney 293 cells did' not affect I(HERG), 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.

Original languageEnglish (US)
Pages (from-to)113-121
Number of pages9
JournalMolecular pharmacology
Issue number1
StatePublished - Jul 1998
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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