Abstract
1) Phenobarbitone (PB) was administered to male C3H/He and C57B1/6 strain mice (high and low incidence of spontaneous hepatic nodule formation respectively), and to Sprague-Dawley rats at several dose levels for up to 14 days. Maximal stimulation of hepatic microsomal cytochrome P-450 content and some associated enzyme activities occurred at doses >75 mg/kg/day to mice and >125 mg/kg/day to rats. 2) A maximally stimulating dose of PB (85 mg/kg/day) was administered in the diet to C3H/He mice for up to 90 weeks, and aspects of liver growth and enzyme induction were measured. Synthesis of DNA accompanied an increase of liver size. After the initial growth period liver size remained constant until the development of large hepatic nodules, which were readily dissectable after 70 weeks of treatment. Activities of both Phase I and Phase II xenobiotic metabolising enzymes were induced by PB treatment, and remained stimulated throughout the entire period of PB administration. Enzyme activities in nodular tissue were similar to those in host tissue, and induction was reversible on cessation of treatment. PB appeared to induce similar form(s) of cytochrome P-450 in both nodules and host tissue. 3) The inductive effect of short term PB treatment to the rat and two mouse strains on aspects of glutathione metabolism was investigated. Similarly the metabolism and excretion of [14C] PB was investigated. No differences between species and strains were detected that might explain the differing susceptibilities to hepatic nodule formation. 4) The effect of prolonged dietary administration of the hepatocarcinogen o-aminoazotoluene, at a concentration of 0. 03%, on hepatic xenobiotic metabolising enzymes was investigated in the two mouse strains. During nodule formation enzyme induction was noted, although induction was not seen when a higher dose of the carcinogen was used.