PMID- 12411421
OWN - NLM
STAT- MEDLINE
DCOM- 20030408
LR  - 20220408
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 137
IP  - 6
DP  - 2002 Nov
TI  - The antihistamine fexofenadine does not affect I(Kr) currents in a case report of 
      drug-induced cardiac arrhythmia.
PG  - 892-900
AB  - 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
FAU - Scherer, Constanze R
AU  - Scherer CR
AD  - Aventis Pharma Deutschland GmbH, Cardiovascular Diseases, 65926 Frankfurt am 
      Main, Germany.
FAU - Lerche, Christian
AU  - Lerche C
FAU - Decher, Niels
AU  - Decher N
FAU - Dennis, Adrienne T
AU  - Dennis AT
FAU - Maier, Patrick
AU  - Maier P
FAU - Ficker, Eckhard
AU  - Ficker E
FAU - Busch, Andreas E
AU  - Busch AE
FAU - Wollnik, Bernd
AU  - Wollnik B
FAU - Steinmeyer, Klaus
AU  - Steinmeyer K
LA  - eng
PT  - Case Reports
PT  - Journal Article
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Cation Transport Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (ERG protein, human)
RN  - 0 (ERG1 Potassium Channel)
RN  - 0 (Ether-A-Go-Go Potassium Channels)
RN  - 0 (Histamine H1 Antagonists)
RN  - 0 (KCNH2 protein, human)
RN  - 0 (KCNH6 protein, human)
RN  - 0 (Potassium Channels)
RN  - 0 (Potassium Channels, Voltage-Gated)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcriptional Regulator ERG)
RN  - 0 (potassium channel protein I(sk))
RN  - 1F7A44V6OU (Colforsin)
RN  - 7BA5G9Y06Q (Terfenadine)
RN  - 9007-49-2 (DNA)
RN  - E6582LOH6V (fexofenadine)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
SB  - IM
MH  - Aged
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Animals
MH  - Arrhythmias, Cardiac/chemically induced/*genetics/physiopathology
MH  - Base Sequence
MH  - Blotting, Western
MH  - COS Cells
MH  - *Cation Transport Proteins
MH  - Cell Line
MH  - Colforsin/pharmacology
MH  - DNA/chemistry/genetics
MH  - DNA Mutational Analysis
MH  - *DNA-Binding Proteins
MH  - ERG1 Potassium Channel
MH  - Ether-A-Go-Go Potassium Channels
MH  - Genotype
MH  - Histamine H1 Antagonists/adverse effects/*pharmacology/therapeutic use
MH  - Humans
MH  - Immunohistochemistry
MH  - Male
MH  - Membrane Potentials/*drug effects
MH  - Molecular Sequence Data
MH  - Polymorphism, Single Nucleotide
MH  - Polymorphism, Single-Stranded Conformational
MH  - Potassium Channels/genetics/*physiology
MH  - *Potassium Channels, Voltage-Gated
MH  - Pruritus/drug therapy
MH  - Sequence Homology, Amino Acid
MH  - Terfenadine/adverse effects/*analogs & derivatives/*pharmacology/therapeutic use
MH  - Tetradecanoylphorbol Acetate/pharmacology
MH  - *Trans-Activators
MH  - Transcriptional Regulator ERG
PMC - PMC1573545
EDAT- 2002/11/02 04:00
MHDA- 2003/04/09 05:00
PMCR- 2003/11/01
CRDT- 2002/11/02 04:00
PHST- 2002/11/02 04:00 [pubmed]
PHST- 2003/04/09 05:00 [medline]
PHST- 2002/11/02 04:00 [entrez]
PHST- 2003/11/01 00:00 [pmc-release]
AID - 0704873 [pii]
AID - 10.1038/sj.bjp.0704873 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2002 Nov;137(6):892-900. doi: 10.1038/sj.bjp.0704873.