Embryonic arrhythmia by inhibition of HERG channels: a common hypoxia-related teratogenic mechanism for antiepileptic drugs?
OBJECTIVE
There is evidence that drug-induced embryonic arrhythmia initiates phenytoin (PHT) teratogenicity. The arrhythmia, which links to the potential of PHT to inhibit a specific potassium channel (Ikr), may result in episodes of embryonic ischemia and generation of reactive oxygen species (ROS) at reperfusion. This study sought to determine whether the proposed mechanism might be relevant for the teratogenic antiepileptic drug trimethadione (TMO).


METHODS
Effects on embryonic heart rhythm during various stages of organogenesis were examined in CD-1 mice after maternal administration (125-1,000 mg/kg) of dimethadione (DMO), the pharmacologically active metabolite of TMO. Palatal development was examined after administration of a teratogenic dose of DMO and after simultaneous treatment with DMO and a ROS-capturing agent (alpha-phenyl-N-tert-butyl-nitrone; PBN). The Ikr blocking potentials of TMO and DMO were investigated in HERG-transfected cells by using voltage patch-clamping tests.


RESULTS
DMO caused stage-specific (gestation days 9-13 only) and dose-dependent embryonic bradycardia and arrhythmia at clinically relevant maternal plasma concentrations (3-11 mM). Hemorrhage in the nasopharyngeal part of the embryonic palate (within 24 h) preceded cleft palate in fetuses at term. Simultaneous treatment with PBN significantly reduced the incidence of DMO-induced cleft palate, from 40 to 13%. Voltage patch-clamping studies showed that particularly DMO (70% inhibition), but also TMO, had Ikr blocking potential at clinically relevant concentrations.


CONCLUSIONS
TMO teratogenicity, in the same way as previously shown for PHT, was associated with Ikr-mediated episodes of embryonic cardiac arrhythmia and hypoxia/reoxygenation damage.
Azarbayjani
Faranak
F
Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, Uppsala, Sweden.
Danielsson
Bengt R
BR
D000014:Abnormalities, Drug-Induced / Q000196:embryology* / Q000209:etiology; D000367:Age Factors; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D004114:Dimethadione / Q000494:pharmacology / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D005315:Fetal Diseases / Q000139:chemically induced*; D005318:Fetal Heart / Q000187:drug effects / Q000196:embryology; D005311:Fetal Hypoxia / Q000150:complications* / Q000378:metabolism; D005865:Gestational Age; D006340:Heart Rate, Fetal / Q000187:drug effects* / Q000502:physiology; D008431:Maternal-Fetal Exchange; D051379:Mice; D017202:Myocardial Ischemia / Q000196:embryology / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000139:chemically induced / Q000196:embryology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010672:Phenytoin / Q000633:toxicity; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects; D024642:Potassium Channels, Voltage-Gated; D011247:Pregnancy; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015534:Trans-Activators; D014293:Trimethadione / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*
D000927:Anticonvulsants; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D010672:Phenytoin; D004114:Dimethadione; D014293:Trimethadione