Embryotoxicity of phenytoin in adrenalectomized CD-1 mice.
It has been proposed that the anticonvulsant drug phenytoin (PHT) and glucocorticoids induce orofacial clefting by the same mechanism. Previous work had demonstrated that PHT treatment significantly increased endogenous maternal corticosterone concentrations for approximately 48 hr after dosing in A/J mice. The purpose of the present investigation was to determine whether PHT is embryotoxic in the absence of endogenous maternal glucocorticoids. Maternal adrenal glands were removed on Day 7 of gestation, and the incidence of clefting after PHT treatment was determined. There was a high level of maternal toxicity following adrenalectomy (ADX) and PHT treatment at either 60 or 75 mg/kg. This increased toxicity did not appear to be due to altered maternal drug levels in ADX mice. There was a significant increase in the clefting incidence among offspring of ADX dams treated with PHT at 60 mg/kg. This dose of PHT did not elevate maternal corticosterone levels in ADX dams. These data suggest that PHT is capable of producing clefts in the absence of endogenous maternal corticosterone.
Hansen
D K
DK
Division of Reproductive and Developmental Toxicology, Food and Drug Administration, Jefferson, Arkansas 72079-9502.
Branham
W S
WS
Sheehan
D M
DM
Holson
R R
RR
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000315:Adrenalectomy; D000818:Animals; D002972:Cleft Palate / Q000139:chemically induced*; D003345:Corticosterone / Q000097:blood; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced; D051379:Mice; D010672:Phenytoin / Q000097:blood / Q000633:toxicity*; D011247:Pregnancy
D010672:Phenytoin; D003345:Corticosterone