Study for tumor-initiating effect of acetaminophen in two-stage liver carcinogenesis of male F344 rats.

The potential liver-tumor-initiating activity of acetaminophen (paracetamol, APAP) was investigated in male F344 rats. APAP was administered by intragastric intubation either as 10 doses of 1 g/kg body weight over 5 weeks or as a single dose of 0.5 g/kg body weight 24 h after two-thirds partial hepatectomy. These initiating treatments were followed by administration of 0.1% phenobarbital in the drinking water for 12 weeks as the promoting regimen. Quantitative examination of placental glutathione S-transferase-positive foci revealed no enhancing effect of APAP on the induction of the foci consisting of more than two positive cells with either initiating treatment. If solitary positive hepatocytes were included in the effective number of foci, 10 repeated doses of 1 g/kg APAP increased the number of foci while the validity of the single positive cells is uncertain. This dose of APAP caused centrilobular necrosis. By 32P-postlabeling, although the active metabolite of APAP formed DNA adducts when incubated with isolated DNA, no DNA adduct formation was detected in the liver of rats either fed 0.1-1.5% APAP for 1 week or given 1 g/kg by gastric intubation. These results indicate that APAP possesses no tumor-initiating activity in the rat liver.