First evidence of cytochrome P-450 induction in the mouse brain by phenytoin.

Long-term administration of phenytoin (60 mg/kg) to male C57Bl/6J mice causes an average drug serum level of 16-19 micrograms/ml. Cytological changes consisting of focal axonal swellings in the deep cerebellar nuclei are characterized by an increasing accumulation of vesiculotubular membranes in the dense, but ribosome-deficient axoplasm. Microsomal fractions of brain and liver were prepared at intervals until the 80th day of treatment to determine their cytochrome P-450 activities and isoenzyme characteristics. The cerebellar tissue was shown to be distinguished by a 15-fold enhancement of cytochrome P-450 PB3a activity, that means twice the extent of that found in liver and cerebrum.