Maternal antioxidant supplementation does not reduce the incidence of phenytoin-induced cleft lip and related malformations in rats.
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.
Abela
Dominique
D
Department of Anatomy and Histology, University of Sydney, Sydney, Australia.
Howe
Andrew M
AM
Oakes
Diana A
DA
Webster
William S
WS
D000014:Abnormalities, Drug-Induced / Q000517:prevention & control*; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D000975:Antioxidants / Q000008:administration & dosage*; D001205:Ascorbic Acid / Q000008:administration & dosage; D001835:Body Weight / Q000187:drug effects; D002971:Cleft Lip / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D003067:Coenzymes; D004032:Diet; D004435:Eating / Q000187:drug effects; D005260:Female; D008297:Male; D008437:Maxilla / Q000002:abnormalities* / Q000187:drug effects; D010672:Phenytoin / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000633:toxicity*; D014451:Ubiquinone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014810:Vitamin E / Q000008:administration & dosage
D000927:Anticonvulsants; D000975:Antioxidants; D003067:Coenzymes; D013723:Teratogens; D014451:Ubiquinone; D014810:Vitamin E; D010672:Phenytoin; C024989:coenzyme Q10; D001205:Ascorbic Acid