The influence of phenytoin on the ontogenesis of hepatic monooxygenases in the perinatal guinea pig

Phenytoin (diphenylhydantoin, DPH) was administered orally (25 mg/kg body wt) for 3 consecutive days to pregnant or lactating guinea pigs at different pre- and postnatal stages. The dams, fetuses, and pups were killed 24 hr after the third dose. Hepatic p-nitroanisole O-demethylase (OD) aniline hydroxylase (AH) and NADPH-cytochrome c reductase (NADPH-CcR) activities in calcium-aggregated, isolated microsomes were measured. The developing guinea pig liver was examined by electron microscopy. Tissue (blood serum and liver) residues of DPH were quantitated by gas-liquid chromatography. While the transplacentally acquired DPH had little visible effect on hepatic morphology at 58–66 days of gestation, statistically significant increases in enzymatic activity were observed in the treated fetuses. The DPH residues acquired by neonatal guinea pigs from the breast milk caused twofold increases in drug-metabolizing enzyme activities concomitant with marked increases in the hepatic smooth endoplasmic reticulum (S) as early as 4 days after birth and up to 14 days of age. Subsequently, in 21- and 28-day-old pups, tissue DPH residues were negligible and no induction of S-related enzymes was detected as a consequence of their being weaned by this age. High tissue levels of DPH in pregnant dams may reflect a lowered rate of biotransformation whereas, in the lactating animal, the low residue levels may reflect an increased elimination via the milk.