title: 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 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.
authors.affiliation: Section of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, 80131 Naples, Italy. mtaglial@unina.it
authors.forename: M
authors.initials: M
authors.lastname: Taglialatela
authors.forename: A
authors.initials: A
authors.lastname: Pannaccione
authors.forename: P
authors.initials: P
authors.lastname: Castaldo
authors.forename: G
authors.initials: G
authors.lastname: Giorgio
authors.forename: Z
authors.initials: Z
authors.lastname: Zhou
authors.forename: C T
authors.initials: CT
authors.lastname: January
authors.forename: A
authors.initials: A
authors.lastname: Genovese
authors.forename: G
authors.initials: G
authors.lastname: Marone
authors.forename: L
authors.initials: L
authors.lastname: Annunziato
mesh_terms: D000818:Animals; D016589:Astemizole / Q000494:pharmacology; D027682:Cation Transport Proteins; D017332:Cetirizine / Q000494:pharmacology*; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D017336:Loratadine / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D011969:Receptors, Histamine H1 / Q000187:drug effects* / Q000378:metabolism; D016593:Terfenadine / Q000494:pharmacology; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014982:Xenopus laevis
chemical_list: D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006634:Histamine H1 Antagonists; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011969:Receptors, Histamine H1; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D017336:Loratadine; D016593:Terfenadine; D016589:Astemizole; D017332:Cetirizine