Arachidonic acid reversal of phenytoin-induced neural tube and craniofacial defects in vitro in mice.

Diphenylhydantoin (DPH), a common anticonvulsant drug, is known to produce anomalies in the craniofacial region of animals and humans. We hypothesize that phenytoin disrupts craniofacial morphogenesis by inhibiting the arachidonic acid cascade; a pathogenesis already demonstrated for glucocorticoids and hyperglycemia. This hypothesis was tested in vitro by administering DPH, with and without the addition of exogenous arachidonic acid (AA), to murine embryos. Forty-five 8.7-day-old embryos were randomly assigned to one of three groups: control, DPH, or DPH plus AA. After 48 hours in culture, all specimens were examined at 6x magnification for defects in the facial arches, head fold, and neural tube fusion. The DPH-treated specimens had a significantly greater (P less than or equal to .05) number of anomalies in each of the three anatomical areas than did the controls. Specimens cultured in DPH plus AA had significantly fewer defects in each of the three features than those treated with DPH alone. These data support the hypothesis that phenytoin disrupts normal embryonic development through interruption of the arachidonic acid cascade. Furthermore, removal of the visceral yolk sac from 50% of the specimens in control and treatment groups provided evidence that the drug had a direct effect on the embryos rather than secondary to yolk sac involvement as has been suggested in the literature.