417 PHARMACOGENETIC PREDISPOSITION TO PHENYTOIN-INDUCED BIRTH DEFECTS

Abstract

The role of phenytoin(DPH) in causing birth defects is uncertain. Only a minority of fetuses exposed to DPH have malformations. Arene oxide metabolites(AOM) of DPH may be involved in fetal toxicity. We found genetic differences in detoxification of AOM in patients with adverse reactions to DPH. Therefore, we have explored the contribution of detoxification defects to DPH-induced birth defects. 29 children from 18 families exposed to DPH during gestation and their parents were studied using an in vitro assay in which lymphocyte capacity to detoxify AOM is assessed. Analyses were performed blind to the identity and clinical findings of the subjects. A positive(+) test showed a significant increase in cell death in the presence of 62.5uM DPH and a metabolite-generating system. Following completion of in vitro studies, physical findings were analyzed for all subjectis. There was an increase in major malformations in + subjects: Scoring minor and major anomalies, there was a significant increase in number and severity of malformations in + patients. For each + patient, one or both parents were +. An inherited deficiency in detoxification of AOM of DPH may modify the outcome of in utero exposure to the drug.