Embryonic cardiac arrhythmia and generation of reactive oxygen species: common teratogenic mechanism for IKr blocking drugs.
In the adult organism, it is well established that hypoxia followed by reperfusion may be fatal and result in generation of reactive oxygen species (ROS) and subsequent tissue damage. There is also considerable evidence that temporary decrease or interruption in oxygen supply to the embryo and ROS generation during reperfusion result in tissue damage in embryonic tissues. A wide spectrum of different malformations by transient embryonic hypoxia could be produced, depending on the duration, extent, and timing of the hypoxic event. It is the contention of this paper that drugs that block the potassium channel IKr, either as an intended pharmacologic effect or as an unwanted side-effect, are potentially teratogenic by a common ROS related mechanism. Drugs blocking the IKr channel, such as almokalant, dofetilide, phenytoin, cisapride and astemizole, do all produce a similar pattern of hypoxia-related malformations. Mechanistic studies show that the malformations are preceded by embryonic cardiac arrhythmia and periods of hypoxia/reoxygenation in embryonic tissues. Pretreatment or simultaneous treatment with radical scavengers with capacity to capture ROS, markedly decrease the teratogenicity of different IKr blocking drugs. A second aim of this review is to demonstrate that the conventional design of teratology studies is not optimal to detect malformations caused by IKr blocking drugs. Repeated high doses result in high incidences of embryonic death due embryonic cardiac arrhythmia, thus masking their teratogenic potential. Instead, single dosing on specific days is proposed to be a better way to characterize the teratogenic potential of Ikr blocking drugs.
Danielsson
Bengt R
BR
Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, S-751 24 Uppsala, Sweden. bengt.danielsson@mpa.se
Danielsson
Christian
C
Nilsson
Mats F
MF
D000014:Abnormalities, Drug-Induced / Q000196:embryology / Q000378:metabolism* / Q000517:prevention & control; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000633:toxicity*; D000927:Anticonvulsants / Q000633:toxicity; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000196:embryology / Q000378:metabolism / Q000517:prevention & control; D016589:Astemizole / Q000633:toxicity; D020117:Cisapride / Q000633:toxicity; D004114:Dimethadione / Q000633:toxicity; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D005765:Gastrointestinal Agents / Q000633:toxicity; D006321:Heart / Q000187:drug effects / Q000196:embryology; D006633:Histamine Antagonists / Q000633:toxicity; D006801:Humans; D000860:Hypoxia / Q000139:chemically induced* / Q000196:embryology / Q000378:metabolism / Q000517:prevention & control; D010672:Phenytoin / Q000633:toxicity; D026902:Potassium Channel Blockers / Q000633:toxicity*; D011247:Pregnancy; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018600:Teratology / Q000379:methods*; D018675:Toxicity Tests
D000889:Anti-Arrhythmia Agents; D000927:Anticonvulsants; D051638:Ether-A-Go-Go Potassium Channels; D016166:Free Radical Scavengers; D005765:Gastrointestinal Agents; D006633:Histamine Antagonists; D026902:Potassium Channel Blockers; D017382:Reactive Oxygen Species; D010672:Phenytoin; D016589:Astemizole; D004114:Dimethadione; D020117:Cisapride