Common biochemical pathway of dysmorphogenesis in murine embryos: use of the glucocorticoid pathway by phenytoin.
Phenytoin (5,5-diphenylhydantoin), a common anticonvulsant drug, is known to produce anomalies in the craniofacial region of animals and humans. Furthermore, recent evidence suggests that phenytoin disrupts craniofacial and neural tube morphogenesis by inhibiting the arachidonic acid cascade, a pathogenesis already implicated for glucocorticoids and hyperglycemia in the palate. This study tested the hypothesis that phenytoin interferes with the arachidonic acid cascade via the same biochemical pathway demonstrated for glucocorticoids. The proposed pathway was tested at two levels. First, indomethacin, an inhibitor of the enzyme cyclooxygenase, was used in culture to block the correction of phenytoin-induced defects by arachidonic acid. Second, cortexolone, an anti-glucocorticoid that binds at the glucocorticoid receptor binding site, was tested for its ability to prevent phenytoin-induced teratogenicity. Eighty-four percent of the embryos cultured in phenytoin and 93% of those cultured in phenytoin plus arachidonic acid and indomethacin had neural tube and/or craniofacial deformities. In contrast, only 14% of the embryos cultured in phenytoin plus cortexolone were affected. Indomethacin itself produced anomalies in 83% of the exposed embryos. These data are consistent with the hypothesis that the teratogenic action of phenytoin in murine embryo cultures occurs via the glucocorticoid anti-inflammatory pathway. Thus, the glucocorticoid receptor appears to be responsible for mediating phenytoin-induced teratogenicity.
Kay
E D
ED
Department of Pediatrics, College of Medicine, University of Illinois, Chicago 60612.
Goldman
A S
AS
Daniel
J C
JC
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D003350:Cortodoxone / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors; D004622:Embryo, Mammalian / Q000502:physiology; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005147:Facial Bones / Q000002:abnormalities*; D005260:Female; D005333:Fetus; D005938:Glucocorticoids / Q000378:metabolism / Q000633:toxicity; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D009024:Morphogenesis / Q000187:drug effects*; D010672:Phenytoin / Q000378:metabolism / Q000633:toxicity*; D011247:Pregnancy; D012886:Skull / Q000002:abnormalities*
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D005938:Glucocorticoids; D016718:Arachidonic Acid; D010672:Phenytoin; D003350:Cortodoxone; D007213:Indomethacin