Maternal antioxidant supplementation does not reduce the incidence of phenytoin-induced cleft lip and related malformations in rats
Maternal antioxidant supplementation does not reduce the incidence of phenytoin-induced cleft lip and related malformations in rats
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DOI：
10.1002/bdrb.20037
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发表时间：
2005-04-01
影响因子：
--
通讯作者：
Webster, WS
中科院分区：
文献类型：
--
作者：
Abela, D;Howe, AM;Webster, WS
有相当多的证据表明，苯妥英引起的大鼠出生缺陷是胚胎期心动过缓和缺氧的结果。实验旨在验证苯妥英诱导的出生缺陷是由缺氧后再氧化期间胚胎受到自由基损伤引起的。雌性大鼠（每组bb90）在怀孕前和怀孕期间分别饲喂对照饮食或富含抗氧化剂（维生素C、E和辅酶Q(10)）的饮食，然后在妊娠第11天给予致畸剂量的苯托英（180 mg/kg）。第20天处死大鼠，检查胎儿是否畸形。初步结果表明，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，这一结果与喂食抗氧化饮食的大鼠的食物摄入量减少和施用苯妥英时母体体重明显降低相混淆。由于苯妥英是通过腹腔注射（i.p）给药的，对照大鼠接受了更高的苯妥英绝对剂量，据推测，这导致了更高的胎儿暴露。在第二个实验中，老鼠被成对喂养，没有证明高抗氧化饮食有任何保护作用。这些结果不支持苯妥英致畸的再氧化假说。另一种解释是缺氧诱导的转录相关变化导致细胞周期阻滞和凋亡。(c) 2005 Wiley-Liss, Inc。
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. (c) 2005 Wiley-Liss, Inc.