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Study for tumor-initiating effect of acetaminophen in two-stage liver carcinogenesis of male F344 rats
Authors:Hasegawa, Ryohei   Furukawa, Fumio   Toyoda, Kazuhiro   Jang, Ja June   Yamashita, Katsumi   Sato, Sigeaki   Takahashi, Michihito   Hayashi, Yuzo
Affiliation:1Division of Pathology, National Institute of Hygienic Sciences Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158, Japan
2Department of Pathology, Korea Cancer Center Hospital 215-4 Gong Neung-Dong, Do Bong-ku, Seoul 130-02, Korea
3Biochemistry Division, National Cancer Center Research Institute Tsukiji 5-1-1, Chuo-ku, Tokyo 104, Japan
Abstract:The potential liver-tumor-initiating activity of acetaminophen(paracetamol, APAP) was investigated in male F344 rats. APAPwas administered by intragastric intubation either as 10 dosesof 1 g/kg body weight over 5 weeks or as a single dose of 0.5g/kg body weight 24 h after two-thirds partial hepatectomy.These initiating treatments were followed by administrationof 0.1% phenobarbital in the drinking water for 12 weeks asthe promoting regimen. Quantitative examination of placentalglutathione S-transferase-positive foci revealed no enhancingeffect of APAP on the induction of the foci consisting of morethan two positive cells with either initiating treatment. Ifsolitary positive hepatocytes were included in the effectivenumber of foci, 10 repeated doses of 1 g/kg APAP increased thenumber of foci while the validity of the single positive cellsis uncertain. This dose of APAP caused centrilobular necrosis.By 32P-postlabeling, although the active metabolite of APAPformed DNA adducts when incubated with isolated DNA, no DNAadduct formation was detected in the liver of rats either fed0.1–1.5% APAP for 1 week or given 1 g/kg by gastric intubation.These results indicate that APAP possesses no tumor-initiatingactivity in the rat liver.
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