Effects of diphenylhydantoin and phenobarbital on protein metabolism in the rat cerebral cortex

The effects of the anticonvulsant drugs diphenylhydantoin and phenobarbital on the in vivo incorporation of L-[4,5-3H] leucine into trichloroacetic acid-precipitable rat cerebral cortical protein were investigated. Protein specific activities were corrected for differences in precursor leucine specific activities. Incorporation was substantially depressed following the establishment of plasma concentrations of either drug which approximate therapeutic levels in humans. Plasma diphenylhydantoin levels of about 10 /µ/ml were associated with a 41% depression when radioisotope incorporation was conducted for 5 min; phenobarbital concentrations of approximately 28 µg/ml resulted in a 42% depression following incorporation for the same period, A threefold increase in the diphenylhydantoin plasma levels and a six-fold increase in the phenobarbital levels were found to invoke little, if any, additional effect. The induction period for the diphenylhydantoin effect was short (less than Ih), whereas a relative latency was associated with the phenobarbital effect. Simultaneous alterations in cortex and plasma concentrations of several amino acids were detected, but there appeared to be no correlation between these changes and the extent of depression of leucine incorporation. Dose-related increases in cortex leucine, isoleucine and valine levels occurred following treatment with either drug. Cortex glycine concentrations were elevated only in response to the largest doses administered. Whereas plasma leucine, isoleucine and valine levels were also elevated, no change in plasma glycine concentrations were noted following any dose of either drug. The results indicate that diphenylhydantoin and phenobarbital inhibit the in vivo incorporation of radioactive leucine in the rat cortex when plasma drug levels have been attained that are therapeutically rational in the human; and substantial inhibitions would probably occur following much lower doses in the rat. The relationship of the altered amino acid levels to the effects on protein metabolism remains uncertain.