Enhancement of murine phenytoin teratogenicity by the gamma‐glutamylcysteine synthetase inhibitor L‐buthionine‐(S, R)‐sulfoximine and by the glutathione depletor diethyl maleate

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Abstract
The teratogenicity of phenytoin may result from its enzymatic bioactivation to a reactive intermediate, which, if not detoxified, can interact with embryonic tissues and alter development. Glutathione (GSH) is an important cofactor/substrate for many physiological processes and for the detoxification of xenobiotic reactive intermediates. This study examined the effects of the GSH depletor diethyl maleate (DEM) and the GSH synthesis inhibitor L-buthionine-(S,R)-sulfoximine (BSO) on phenytoin embryopathy. Phenytoin, 55 mg/kg, was administered intraperitoneally (ip) to pregnant CD-1 mice at 0900 hr on gestational days 12 and 13. Pretreatment with DEM, 150 or 300 mg/kg ip, enhanced the incidence of phenytoin-induced cleft palates by 3.3-fold and 2.3-fold, respectively (P < 0.05), without affecting the incidence of resorptions, postpartum death, or mean fetal weight. BSO, 1,800 mg/kg ip, given 0.5 hr prior to phenytoin, resulted in a 2.4-fold increase in postpartum lethality and a 5-fold increase in fetal weight loss (P < 0.05), without altering the incidence of resorptions or cleft palates. In two subsequent studies, BSO, 680–1,018 mg/kg/day, was given in the drinking water on gestational days 9 to 13 in the first study and on days 10 to 14 in the second study. Phenytoin, 55 mg/kg ip, was given on days 11 and 12 and on days 11 to 13 in the respective studies. In the first drinking water study, BSO enhanced the incidence of phenytion-induced fetal resorptions 3.8-fold and cleft palates 3.3-fold (P < 0.05) but did not affect postpartum death. In the second study, BSO enhanced the incidence of resorptions, cleft palates, and postpartum death by 2-fold, 2.6-fold, and 1.7-fold, respectively (P < 0.05). In both of the latter two studies, phenytoin-induced fetal weight loss was altered by BSO treatment (P < 0.05). BSO alone had no embryopathic effects. These results suggest that GSH may be involved in the detoxification of a reactive intermediate of phenytion and/or in fetal cytoprotection.
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