Abstract

The hepatic metabolism of benzo(a)pyrene, p-chloro-N-methylaniline and chlorcyclizine, the concentration of cytochrome P-450 and the reduction of cytochrome P-450 were studied at various times during the pre-and postnatal life of the guinea pig. The oxidation of the foreign compound substrates and the rate of reduction of cytochrome P-450 increased slowly during the fetal life of the guinea pig whereas the concentration of cytochrome P-450 in the liver increased rapidly. Shortly after birth (48-72 hours) substrate oxidation and P-450 reduction were observed to occur at a rate equal to or greater than the rate observed in preparations from adult animals but the concentration of cytochrome P-450 was slightly below adult levels. The effect of phenobarbital administration to pregnant guinea pigs on fetal benzo(a)pyrene hydroxylase, p-chloro-N-methylaniline demethylase and cytochrome P-450 reductase activities and on fetal hepatic cytochrome P-450 levels was investigated at different stages of gestation. Treatment of the dam with sodium phenobarbital (100 mg/kg/day p.o.) for 3 days prior to sacrifice stimulated the hepatic benzo(a)pyrene hydroxylase activity in the fetus throughout the second half of gestation (days 33-63). In contrast, p-chloro-N-methylaniline demethylase and cytochrome P-450 reductase activities, as well as cytochrome P-450 levels, were not induced by phenobarbital treatment of the dam until just prior to parturition (day 63). The ultrastructure of the hepatocyte of the developing guinea pig was examined by electron microscopy and a direct correlation between microsomal mixed-function oxidase activity and the proliferation of the smooth endoplasmic reticulum was observed in normal and phenobarbital-treated animals.