Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Br J Pharmacol
2002 Nov 01;1376:892-900. doi: 10.1038/sj.bjp.0704873.
Show Gene links
Show Anatomy links
The antihistamine fexofenadine does not affect I(Kr) currents in a case report of drug-induced cardiac arrhythmia.
Scherer CR
,
Lerche C
,
Decher N
,
Dennis AT
,
Maier P
,
Ficker E
,
Busch AE
,
Wollnik B
,
Steinmeyer K
.
???displayArticle.abstract???
1. The human HERG gene encodes the cardiac repolarizing K(+) current I(Kr) and is genetically inactivated in inherited long QT syndrome 2 (LQTS2). The antihistamine terfenadine blocks HERG channels, and can cause QT prolongation and torsades de pointes, whereas its carboxylate fexofenadine lacks HERG blocking activity. 2. In the present study the ability of fexofenadine to block the K897T HERG channel variant was investigated. The underlying single nucleotide polymorphism (SNP) A2960C was identified in a patient reported to develop fexofenadine-associated LQTS. 3. K897T HERG channels produced wild-type-like currents in Xenopus oocytes. Even at a concentration of 100 micro M, fexofenadine did not inhibit wild-type or K897T HERG channels. Coexpression of wild-type and K897T HERG with the ss-subunit MiRP1, slightly changed current kinetics but did not change sensitivity to terfenadine and fexofenadine. 4. Western blot analysis and immunostaining of transiently transfected COS-7 cells demonstrated that overall expression level, glycosylation pattern and subcellular localization of K897T HERG is indistinguishable from wild-type HERG protein, and not altered in the presence of 1 micro M fexofenadine. 5. We provide the first functional characterization of the K897T HERG variant. We demonstrated that K897T HERG is similar to wild-type HERG, and is insensitive to fexofenadine. Although the polymorphism changes PKA and PKC phosphorylation sites, regulation of K897T HERG by these kinases is not altered. 6. Our results strongly indicate that QT lengthening and cardiac arrhythmia in the reported case of drug-induced LQT are not due to the K897T exchange or to an inhibitory effect of fexofenadine on cardiac I(Kr) currents. British Journal of
Abbott,
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.
1999, Pubmed,
Xenbase
Abbott,
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.
1999,
Pubmed
,
Xenbase
Craig-McFeely,
Evaluation of the safety of fexofenadine from experience gained in general practice use in England in 1997.
2001,
Pubmed
Delauche-Cavallier,
QT interval monitoring during clinical studies with mizolastine, a new H1 antihistamine.
1999,
Pubmed
Dhar,
Fexofenadine-induced QT prolongation: a myth or fact?
2000,
Pubmed
Dhein,
[Drug-induced long QT syndrome and torsade de pointes arrhythmias].
2000,
Pubmed
Escande,
Pharmacogenetics of cardiac K(+) channels.
2000,
Pubmed
Ficker,
Novel characteristics of a misprocessed mutant HERG channel linked to hereditary long QT syndrome.
2000,
Pubmed
,
Xenbase
Giraud,
QT lengthening and arrhythmias associated with fexofenadine.
1999,
Pubmed
Honig,
Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin.
1992,
Pubmed
Honig,
Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences.
,
Pubmed
Iwasa,
Twenty single nucleotide polymorphisms (SNPs) and their allelic frequencies in four genes that are responsible for familial long QT syndrome in the Japanese population.
2000,
Pubmed
January,
Long QT syndrome: cellular basis and arrhythmia mechanism in LQT2.
2000,
Pubmed
Kiehn,
HERG potassium channel activation is shifted by phorbol esters via protein kinase A-dependent pathways.
1998,
Pubmed
,
Xenbase
Kupershmidt,
A K+ channel splice variant common in human heart lacks a C-terminal domain required for expression of rapidly activating delayed rectifier current.
1998,
Pubmed
Lai,
Polymorphism of the gene encoding a human minimal potassium ion channel (minK).
1994,
Pubmed
Laitinen,
Survey of the coding region of the HERG gene in long QT syndrome reveals six novel mutations and an amino acid polymorphism with possible phenotypic effects.
2000,
Pubmed
Larsen,
High-throughput single-strand conformation polymorphism analysis by automated capillary electrophoresis: robust multiplex analysis and pattern-based identification of allelic variants.
1999,
Pubmed
Lees-Miller,
Molecular determinant of high-affinity dofetilide binding to HERG1 expressed in Xenopus oocytes: involvement of S6 sites.
2000,
Pubmed
,
Xenbase
Lerche,
Molecular cloning and functional expression of KCNQ5, a potassium channel subunit that may contribute to neuronal M-current diversity.
2000,
Pubmed
,
Xenbase
Mitcheson,
A structural basis for drug-induced long QT syndrome.
2000,
Pubmed
,
Xenbase
Pinto,
QT lengthening and life-threatening arrhythmias associated with fexofenadine.
1999,
Pubmed
Pratt,
Cardiovascular safety of fexofenadine HCl.
1999,
Pubmed
Roy,
HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine.
1996,
Pubmed
,
Xenbase
Salata,
Cardiac electrophysiological actions of the histamine H1-receptor antagonists astemizole and terfenadine compared with chlorpheniramine and pyrilamine.
1995,
Pubmed
Sesti,
A common polymorphism associated with antibiotic-induced cardiac arrhythmia.
2000,
Pubmed
Smith,
The inward rectification mechanism of the HERG cardiac potassium channel.
1996,
Pubmed
Splawski,
Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1.
1998,
Pubmed
Suessbrich,
Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole.
1996,
Pubmed
,
Xenbase
Taglialatela,
Inhibition of HERG1 K(+) channels by the novel second-generation antihistamine mizolastine.
2000,
Pubmed
,
Xenbase
Taglialatela,
Cardiac ion channels and antihistamines: possible mechanisms of cardiotoxicity.
1999,
Pubmed
Thomas,
Deletion of protein kinase A phosphorylation sites in the HERG potassium channel inhibits activation shift by protein kinase A.
1999,
Pubmed
,
Xenbase
Tristani-Firouzi,
Molecular biology of K(+) channels and their role in cardiac arrhythmias.
2001,
Pubmed
Villmann,
Kainate binding proteins possess functional ion channel domains.
1997,
Pubmed
,
Xenbase
Vincent,
The molecular genetics of the long QT syndrome: genes causing fainting and sudden death.
1998,
Pubmed
