Webster William S, Howe Andrew M, Abela Dominique, Oakes Diana J
Department of Anatomy and Histology, University of Sydney, Sydney, NSW 2006, Australia.
Curr Pharm Des. 2006;12(12):1431-48. doi: 10.2174/138161206776389868.
Cleft lip (CL) is a common malformation that has both genetic and exogenous causes. The main pharmaceutical cause is exposure to phenytoin during early facial development in the 5th to 6th weeks of gestation. Phenytoin also causes CL if administered to pregnant rats during the period of early facial development. Evidence is presented that in the pregnant rat, a teratogenic dose of phenytoin slows the early embryonic heart and causes a prolonged period of embryonic hypoxia. It is proposed that this hypoxia, through an undefined downstream mechanism, leads to the development of CL. The involvement of hypoxia in the pathogenesis of CL is in agreement with studies in mouse strains with a spontaneous rate of CL in which exposure to hypoxia has been shown to increase the rate and hyperoxia to decrease the rate. Other exogenous risk factors during pregnancy for human CL include maternal cigarette smoking, residence at high altitude and exposure to corticosteroids. It is suggested that these exposures all involve an increased risk of embryonic hypoxia. It has been proposed that phenytoin affects the embryonic heart by inhibition of the human-ether-a-go-go (HERG) potassium channel. Phenytoin also inhibits sodium and calcium channels and these properties may also be involved in the observed effect on the embryonic heart. Phenytoin-induced bradycardia leading to embryonic hypoxia may be an important mechanism by which phenytoin causes birth defects.
唇裂（CL）是一种常见的畸形，其病因既有遗传因素也有外部因素。主要的药物性病因是在妊娠第5至6周面部早期发育期间接触苯妥英钠。在面部早期发育期间给怀孕大鼠施用苯妥英钠也会导致唇裂。有证据表明，在怀孕大鼠中，致畸剂量的苯妥英钠会使早期胚胎心脏跳动减慢，并导致胚胎缺氧期延长。有人提出，这种缺氧通过一种尚不明确的下游机制导致唇裂的发生。缺氧在唇裂发病机制中的作用与对具有自发唇裂率的小鼠品系的研究结果一致，在这些研究中，已表明暴露于缺氧环境会增加唇裂发生率，而暴露于高氧环境会降低唇裂发生率。人类唇裂在孕期的其他外部风险因素包括母亲吸烟、居住在高海拔地区以及接触皮质类固醇。有人认为，这些暴露都增加了胚胎缺氧的风险。有人提出，苯妥英钠通过抑制人醚 - 去极化相关基因（HERG）钾通道来影响胚胎心脏。苯妥英钠还抑制钠通道和钙通道，这些特性也可能与观察到的对胚胎心脏的影响有关。苯妥英钠诱导的心动过缓导致胚胎缺氧可能是苯妥英钠导致出生缺陷的一个重要机制。
