ANTIEPILEPTIC DRUGS ALTER ENDOGENOUS RETINOID CONCENTRATIONS - A POSSIBLE MECHANISM OF TERATOGENESIS OF ANTICONVULSANT THERAPY

The major antiepileptic drugs used for the control of seizures can ind uce developmental toxicity when administered during pregnancy. Vitamin A and retinoids are thought to control many processes of embryonic de velopment including growth, differentiation and morphogenesis. We have therefore studied if the teratogenic action of antiepileptic agents c ould be mediated via alteration of the endogenous vitamin A - retinoid metabolism. Retinol and its oxidative metabolites all-trans-, 13-cis- and 13-cis-4-oxo-retinoic acid were measured in the plasma of 75 infa nts and children treated with various antiepileptic drugs for the cont rol of seizures, and in 29 untreated controls of comparable age. Retin ol levels increased with age, while the concentrations of retinoic aci d compounds did not exhibit age-dependency. Valproic acid monotherapy increased retinol levels in the young age group and a trend toward inc reased retinol concentrations was also observed in all other patient g roups. The plasma levels of the oxidative metabolites 13-cis- and 13-c is-4-oxo-retinoic acids were strongly decreased in all patient groups treated with phenytoin, phenobarbital, carbamazepine and ethosuximide, in combination with valproic acid, to levels which were below 1/3rd a nd 1/10th of corresponding control values, respectively. Little change s were observed with all-trans-retinoic acid except in one patient gro up treated with valproic acid / ethosuximide cotherapy where increased levels of this retinoid were found. Our study indicates that therapy with antiepileptic agents can have a pronounced effect on the endogeno us retinoid metabolism. Because of the importance of retinoids for the signaling of crucial biological events during embryonic development, such altered retinoid metabolism may be highly significant in regard t o antiepileptic drug teratogenesis.