HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine.
BACKGROUND
Administration of the antihistamine terfenadine (Seldane) to patients may result in acquired long QT syndrome and ventricular arrhythmias. One human cardiac target is Kv1.5, which expresses the ultrarapid outward K+ current (Ikur) in atrium but may play only a minor role in ventricle. Another possible target is HERG, the human ether-a-go-go-related gene that expresses a delayed rectifier current (IKr) in human ventricle and produces hereditary long QT syndrome when defective.


RESULTS
We therefore heterologously expressed Kv1.5 and HERG in Xenopus oocytes to compare the sensitivity of each to terfenadine. We found that HERG was 10 times more sensitive than Kv1.5 to terfenadine block. The apparent Kd values for HERG and Kv1.5 currents were 350 nmol/L and 2.7 mumol/L, respectively. These Kd values compare well with values reported for terfenadine block of IKr and IKur currents in human atrial myocytes. The Kd value for HERG block is relevant to the toxicity of the antihistamine, since the clinical terfenadine concentrations in human plasma may reach the 100 nmol/L range.


CONCLUSIONS
Terfenadine carboxylate, the major metabolite of terfenadine, does not block either HERG or Kv1.5, which agrees with the hypothesis that the buildup of parent terfenadine is the likely explanation for its cardiotoxicity. We propose that the blocking of HERG by terfenadine explains the acquired long QT syndrome. HERG is likely to be the primary target for the known cardiotoxic effects of other, related antihistamines.
Roy
M
M
Rammelkamp Center for Research, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44109-1998, USA.
Dumaine
R
R
Brown
A M
AM
D000818:Animals; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D006634:Histamine H1 Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008133:Long QT Syndrome / Q000139:chemically induced; D008564:Membrane Potentials / Q000187:drug effects*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D016593:Terfenadine / Q000009:adverse effects / Q000494:pharmacology*; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014981:Xenopus
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; D011994:Recombinant Proteins; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D016593:Terfenadine