Genetic predisposition to phenytoin-induced birth defects

Area of Science:

• Pharmacogenetics
• Toxicology
• Teratology

Background:

• Phenytoin is an anticonvulsant medication used to treat epilepsy.
• Arene oxides are reactive metabolites of phenytoin that can be toxic.
• Genetic variations in detoxification pathways may influence susceptibility to drug-induced birth defects.

Purpose of the Study:

• To investigate the role of arene oxide metabolites of phenytoin and genetic defects in detoxification pathways in phenytoin-induced birth defects.
• To determine if in-vitro testing can predict susceptibility to major congenital anomalies.

Main Methods:

• Lymphocytes from 24 children exposed to phenytoin during gestation and their families were challenged in vitro with phenytoin metabolites.
• A murine hepatic microsomal drug-metabolizing system was used to generate phenytoin metabolites.
• Cell death assays were performed in a blind protocol.

Main Results:

• 14 out of 24 children showed a positive assay result, indicating significant cell death.
• Children with positive assay results had at least one parent with a positive result.
• Positive in-vitro challenge strongly correlated with major birth defects (e.g., congenital heart disease, cleft lip/palate, microcephaly).
• No significant difference in minor birth defects was observed between positive and negative groups.

Conclusions:

• A genetic defect in arene oxide detoxification appears to increase the risk of major birth defects in infants exposed to phenytoin.
• In-vitro testing of arene oxide detoxification may serve as a predictive marker for susceptibility to phenytoin-induced teratogenicity.