Chronic phenytoin administration and the hepatic mixed function oxidase system in female rats.

The long term effects of phenytoin administration on mixed function oxidase activities and serum estradiol in female rats were examined. No induction of hepatic mixed function oxidases was seen until 8 days after the administration of 100 mg phenytoin/kg/day either orally or intraperitoneally. Maximum increase in aniline hydroxylase, aryl hydrocarbon hydroxylase (AHH) and ethylmorphine-N-deethylase activities occurred between days 8 and 16 of treatment and decreased thereafter. No induction of lung or intestinal AHH activity was observed. Serum levels of estradiol were significantly decreased after 16 days of phenytoin treatment. Maximal increases in hepatic cytochrome P-450 and cytochrome c reductase occurred after 8-16 days of treatment. Furthermore, pentobarbital sleeping times were shortest after 16 days of phenytoin administration. The activities of all enzymes after 32 days of phenytoin treatment were less than at the peak activities at 8-16 days.