Danielsson Bengt R, Danielsson Christian, Nilsson Mats F
Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, S-751 24 Uppsala, Sweden.
Reprod Toxicol. 2007 Jul;24(1):42-56. doi: 10.1016/j.reprotox.2007.04.005. Epub 2007 Apr 27.
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.
在成年生物体中，缺氧后再灌注可能是致命的，并会导致活性氧（ROS）的产生以及随后的组织损伤，这一点已得到充分证实。也有大量证据表明，胚胎的氧气供应暂时减少或再灌注期间ROS的产生会导致胚胎组织的损伤。短暂的胚胎缺氧可导致各种各样不同的畸形，这取决于缺氧事件的持续时间、程度和时机。本文的论点是，阻断钾通道IKr的药物，无论是作为预期的药理作用还是作为不良副作用，都可能通过一种常见的与ROS相关的机制而具有致畸性。阻断IKr通道的药物，如阿吗卡兰、多非利特、苯妥英、西沙必利和阿司咪唑，都会产生类似的与缺氧相关的畸形模式。机制研究表明，这些畸形之前会出现胚胎心律失常以及胚胎组织中的缺氧/再氧合期。用具有捕获ROS能力的自由基清除剂进行预处理或同时处理，可显著降低不同IKr阻断药物的致畸性。本综述的第二个目的是证明，传统的致畸学研究设计对于检测由IKr阻断药物引起的畸形并非最佳。重复高剂量会因胚胎心律失常导致胚胎死亡的高发生率，从而掩盖它们的致畸潜力。相反，在特定日期单次给药被认为是表征IKr阻断药物致畸潜力的更好方法。
