Phenobarbital induction does not potentiate hepatotoxicity but accelerates liver cell necrosis from acetaminophen overdose in the rat

Abstract

Rats were pretreated with phenobarbital to induce hepatic cytochrome P-450. Compared to noninduced rats, a similar relation between the dose of acetaminophen and mortality, and between dose and changes in liver function (prothrombin index) and identical time courses, was found. The urinary excretion of acetaminophen mercapturate and acetaminophen cysteine was identical in induced and noninduced rats. The metabolism of acetaminophen in terms of blood levels and excreted metabolites was not influenced by phenobarbital induction. At the same dose level, hepatic necrosis was accelerated (maximum 24 h) compared to noninduced animals (maximum 72 h), but no difference in the maximum extent was found. These data cannot support the concept that induction of cytochrome P-450 leads to greater formation of the hypothetical toxic metabolite of acetaminophen, or that induction enhances its hepatotoxicity, in the rat. Several factors may contribute to accelerate the necrotic changes which make it possible to histologically identify cell damage and death. In that case, functional studies are more relevant than morphological evaluation in quantitative assessment of liver damage.