Maternal antioxidant supplementation does not reduce the incidence of phenytoin‐induced cleft lip and related malformations in rats

Wiley - Tập 74 Số 2 - Trang 201-206 - 2005
Dominique Abela1, Andrew M. Howe1, Diana A. Oakes1, William S. Webster2
1Department of Anatomy and Histology, University of Sydney, Sydney, Australia
2Department of Anatomy and Histology, University of Sydney, Sydney NSW 2006 Australia

Tóm tắt

AbstractThere 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 Q10) 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. Birth Defects Res B 74:201–206, 2005. © 2005 Wiley‐Liss, Inc.

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Tài liệu tham khảo

Abela D, 2003, Honour Thesis, 1

10.1002/gepi.1370110404

10.1002/(SICI)1096-9926(199803)57:3<117::AID-TERA1>3.0.CO;2-Y

10.1002/tera.1026

10.1046/j.1528-1157.2002.28999.x

10.1016/S0306-4522(02)00324-X

10.1203/00006450-200106000-00007

Danielsson BR, 1997, Drug toxicity in embryonic development. II: Advances in understanding mechanisms of birth defects: mechanistic understanding of human developmental toxicants, 161, 10.1007/978-3-642-60447-8_4

10.1002/(SICI)1096-9926(199710)56:4<271::AID-TERA6>3.0.CO;2-1

10.1006/taap.1999.8858

10.2174/1381612013397744

10.1016/S0920-1211(03)00119-0

10.1161/01.RES.78.1.15

Dravet C, 1992, Epilepsy, antiepileptic drugs, and malformations in children of women with epilepsy: a French prospective cohort study, Neurology, 42, 75

10.1002/tera.1420460313

10.1002/tera.1420520404

10.1002/(SICI)1096-9926(199603)53:3<196::AID-TERA7>3.0.CO;2-2

10.1074/jbc.M010189200

10.1128/MCB.23.1.359-369.2003

Harbison RD, 1977, Proposed mechanism for dephenylhydantoin‐induced teratogenesis [Abstract], Pharmacologist, 19, 179

10.1002/ajmg.1320580309

10.1016/S0891-5849(02)00916-4

Martz F, 1977, Phenytoin teratogenesis: correlation between embryopathic effect and covalent binding of putative arene oxide metabolite in gestational tissue, J Pharmacol Exp Ther, 203, 231

10.1126/science.7221553

10.1073/pnas.78.9.5722

10.1038/sj.bjp.0700969

10.1093/jn/123.11.1939

Sanyal S, 1993, Reduction in phenytoin teratogenicity by pretreatment with the antioxidant D‐a‐tocopherol acetate (vitamin E) in CD‐1 mice [Abstract], Toxicologist, 13, 252

10.1002/ar.1091950201

10.1161/01.RES.79.1.79

10.1002/(SICI)1096-9926(199603)53:3<168::AID-TERA4>3.0.CO;2-0

10.1016/S0890-6238(98)00066-5

10.1016/0041-008X(89)90244-5

10.1016/0041-008X(89)90325-6

10.1016/S0891-5849(98)00193-2

10.1006/taap.1995.1040

10.1002/tera.1420490315

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Wiley

Tập 74 Số 2

201-206

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