The nervous system appears to be the major target of acute and chronic phenytoin toxicity in experimental animals. In addition, repeated administration of phenytoin induces increased liver and kidney weights, centrilobular hepatic hypertrophy and diverse immunosuppressive effects. Phenytoin may reduce thyroxine concentrations and increase bone thickness in rodents, but gingival hyperplasia has been observed only in cats and monkeys and not in rodents. Phenytoin is an inducer of certain hepatic cytochrome P450 activities in humans and mice. There is evidence for the teratogenicity of phenytoin in humans ingesting 100-800mg per day during the first trimester of gestation.
Phenytoin is teratogenic in mice and rats.
Animal and a few human studies suggest that neurobehavioural deficits occur at doses which produce no dysmorphic effect. Phenytoin induced mutations in Salmonella typhimurium in the presence of a metabolic activation system in one study. No mutagenic effect was observed in Drosophila or in mammalian cells in vitro in the absence of an exogenous metabolic system. Aneuploidy was induced in one study in primary mouse embryonic fibroblasts in vitro. Cell transformation was induced in Syrian hamster embryo.