Abela Dominique, Howe Andrew M, Oakes Diana A, Webster William S
Department of Anatomy and Histology, University of Sydney, Sydney, Australia.
Birth Defects Res B Dev Reprod Toxicol. 2005 Apr;74(2):201-6. doi: 10.1002/bdrb.20037.
There is considerable evidence that phenytoin-induced birth defects in the rat are a consequence of a period of bradycardia and hypoxia in the embryos. Experiments were designed to test the hypothesis that phenytoin-induced birth defects result from free-radical damage to the embryos during the reoxygenation period posthypoxia. Female rats (>9 per group) were fed either a control diet or a diet high in antioxidants (vitamins C and E and coenzyme Q(10)) both before and during pregnancy and were then given a teratogenic dose of phenytoin (180 mg/kg) on GD 11. The rats were killed on GD 20 and the fetuses were examined for malformations. The initial results showed that the antioxidant diet had a significant protective effect, with far fewer antioxidant-group fetuses showing cleft lip or maxillary hypoplasia compared with the control group. However, this result was confounded by reduced food intake by the rats fed the antioxidant diet and a significantly lower maternal body weight at the time of phenytoin administration. Since the phenytoin was administered by intraperitoneal injection (i.p.) the control rats received higher absolute doses of phenytoin and it is speculated that this results in higher fetal exposure. A second experiment, in which the rats were pair-fed, failed to demonstrate any protective effect of the high antioxidant diet. These results do not support the reoxygenation hypothesis for phenytoin teratogenesis. An alternative explanation would be hypoxia-induced transcription-related changes resulting in cell cycle arrest and apoptosis.
有大量证据表明，苯妥英钠诱发大鼠出生缺陷是胚胎期心动过缓和缺氧的结果。设计实验以检验以下假设：苯妥英钠诱发的出生缺陷是由于缺氧后复氧期胚胎受到自由基损伤所致。将雌性大鼠（每组>9只）在怀孕前及怀孕期间分别喂食对照饮食或富含抗氧化剂（维生素C、维生素E和辅酶Q10）的饮食，然后在妊娠第11天给予致畸剂量的苯妥英钠（180 mg/kg）。在妊娠第20天处死大鼠，并检查胎儿是否有畸形。初步结果显示，抗氧化剂饮食具有显著的保护作用，与对照组相比，抗氧化剂组出现唇裂或上颌发育不全的胎儿要少得多。然而，这一结果因喂食抗氧化剂饮食的大鼠食物摄入量减少以及给予苯妥英钠时母体体重显著降低而受到混淆。由于苯妥英钠是通过腹腔注射给药，对照组大鼠接受的苯妥英钠绝对剂量更高，据推测这会导致胎儿接触量更高。在第二项实验中，对大鼠进行配对喂食，结果未能证明高抗氧化剂饮食有任何保护作用。这些结果不支持苯妥英钠致畸作用的复氧假说。另一种解释可能是缺氧诱导的与转录相关的变化导致细胞周期停滞和细胞凋亡。
