Differences due to species, sex and pregnancy in microsomal induction by diphenylhydantoin in rabbits and rats.

Diphenylhydantoin sodium (DPH), 100 mg/kg/day for 3 days markedly induced aminopyrine, hexobarbital and aniline in vitro biotransformation, and increased P-450 level in microsomes and liver microsomal protein content in female and male rabbits. However, in pregnant rabbits, only aniline biotransformation was stimulated by DPH. In female nonpregnant rats, DPH also significantly stimulated in vitro hepatic biotransformation of aminopyrine, hexobarbital and aniline, and increased P-450 level in microsomes and liver to body weight ratio. In male rats, however, none of the pathways was stimulated significantly despite increases in P-450 level; the liver to body weight ratios were significantly increased. In day 15 pregnant rats only hexobarbital and in day 20 aminopyrine and aniline biotransformation were significantly increased by DPH-pretreatment. Responsiveness of hepatic microsomal enzymes in rats was apparently decreased on day 15 of pregnancy but was returning towards normal on day 20. Normal and DPH stimulated rates of biotransformation, and P-450 content of microsomes were higher in male than in female rats. These sex differences were not seen in rabbits. Rabbits of either sex generally responded to stimulation by DPH by substantially higher hepatic microsomal biotransformation rates than rats.