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Molecular basis for the lack of HERG K+ channel block-related cardiotoxicity by the H1 receptor blocker cetirizine compared with other second-generation antihistamines.
Mol Pharmacol. 1998 Jul; 54(1):113-21.MP

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+Show Affiliations

Section of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, 80131 Naples, Italy. mtaglial@unina.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9658196

Citation

Taglialatela, M, et al. "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 Pharmacology, vol. 54, no. 1, 1998, pp. 113-21.
Taglialatela M, Pannaccione A, Castaldo P, et al. Molecular basis for the lack of HERG K+ channel block-related cardiotoxicity by the H1 receptor blocker cetirizine compared with other second-generation antihistamines. Mol Pharmacol. 1998;54(1):113-21.
Taglialatela, M., Pannaccione, A., Castaldo, P., Giorgio, G., Zhou, Z., January, C. T., Genovese, A., Marone, G., & Annunziato, L. (1998). 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 Pharmacology, 54(1), 113-21.
Taglialatela M, et al. Molecular Basis for the Lack of HERG K+ Channel Block-related Cardiotoxicity By the H1 Receptor Blocker Cetirizine Compared With Other Second-generation Antihistamines. Mol Pharmacol. 1998;54(1):113-21. PubMed PMID: 9658196.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular basis for the lack of HERG K+ channel block-related cardiotoxicity by the H1 receptor blocker cetirizine compared with other second-generation antihistamines. AU - Taglialatela,M, AU - Pannaccione,A, AU - Castaldo,P, AU - Giorgio,G, AU - Zhou,Z, AU - January,C T, AU - Genovese,A, AU - Marone,G, AU - Annunziato,L, PY - 1998/7/11/pubmed PY - 1998/7/11/medline PY - 1998/7/11/entrez SP - 113 EP - 21 JF - Molecular pharmacology JO - Mol Pharmacol VL - 54 IS - 1 N2 - 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. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/9658196/Molecular_basis_for_the_lack_of_HERG_K+_channel_block_related_cardiotoxicity_by_the_H1_receptor_blocker_cetirizine_compared_with_other_second_generation_antihistamines_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9658196 DB - PRIME DP - Unbound Medicine ER -