Molecular Basis for the Lack of HERG K⁺ Channel Block-Related Cardiotoxicity by the H₁ Receptor Blocker Cetirizine Compared with Other Second-Generation Antihistamines

Abstract

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 inXenopus 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 3 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.