Liver regeneration and hepatic microsomal enzyme induction by acetaminophen and derivatives

Liver regeneration was stimulated in male rats with two-thirds of the liver removed by feeding a basal diet supplemented with acetaminophen (0.35-1.5%; weight basis), 2-acetamidophenol (1.0%) and acetophenetidin (1.0%) over a period of 10 days po, but was in the control range with the m-isomer, 3-acetamidophenol (1.0%), N-butyryl-p-aminophenol (1.0%), o-, m- and p-aminophenols (0.50%) and 4-acetamidothiophenol. In fact, the latter inhibited at a level of 0.60%. The operated young or mature female underwent no significant increase in control response with acetaminophen (1-1.5%). However, as with the male, the wet and dry liver weight percentages were markedly increased in the intact female fed acetaminophen (1.0-1.5%) as also with 2-acetamidophenol (1.0%). Liver enlargement occurred in the intact male with acetophenetidin (1.0%) but not with the N-butyryl- and thiophenol derivatives fed at 1.0 and 0.50%, respectively. Hepatic microsomal preparations from the intact and operated series showed no remarkable changes in cytochrome P-450 nor in the enzymes, aminopyrine demethylase and benzo[a]pyrene hydroxylase, with the more polar acetaminophen and the N-butyryl compound but the enzymes were elevated in the group fed acetophenetidin. Inductive effects on microsomal enzymes were further amplified by injection of several animals per group with phenobarbital ip daily at 80 mg/kg for the last 3 days prior to sacrifice. Increases in increments or liver weight percentages ensued over the basal values and as investigated in an intact male series, the enzymes ranged higher than the uninjected controls and with the thiophenol-fed group, exceeded those of the phenobarbital-injected controls.