Potentiation of the teratogenic effects and altered disposition of diphenylhydantoin in mice fed a purified diet

The effect of a standardized purified diet (AIN-76) on the teratogenic response to diphenylhydantoin (DPH) was studied in mice. Mice were fed either the purified diet or Purina Rodent Laboratory Chow for 2-4 weeks prior to mating, and were treated with either saline or 50 mg/kg of DPH on Days 12, 13, and 14 of gestation (copulatory plug = Day 0). The teratogenic response to DPH was found to be markedly potentiated in mice fed the purified diet (75% cleft palate) as compared to mice fed rodent chow (21% cleft palate). The potentiated teratogenic response to DPH correlated with markedly higher plasma DPH levels in pregnant mice fed the purified diet, indicating that the disposition of DPH was impaired. These effects were attributed to a decreased basal level of drug-metabolizing enzymes in mice fed the purified diet, as indicated by markedly prolonged hexobarbital sleeping times. Modifications of the purified diet, which included the replacement of soluble carbohydrate (50% sucrose) in the purified diet with either cornstarch or casein, did not alter the high incidence of cleft palate. A reduction in the incidence of cleft palate was observed, however, when corn oil in the purified diet was replaced with linseed oil. The replacement of corn oil with linseed oil in the purified diet also restored the hexobarbital sleeping times to those observed in mice fed rodent chow. It is concluded that mice fed purified diets have decreased basal levels of drug-metabolizing activity that alter the disposition of DPH and, as a consequence, potentiate its teratogenic effects.