Lack of hepatocarcinogenic potential of acetaminophen in rats with liver damage associated with a choline-devoid diet.
The potential carcinogenic activity of acetaminophen (paracetamol, APAP) was studied in male F344 rats with pre-existing liver damage induced by a choline-devoid (CD) diet. In a short-term experiment, APAP was administered by intragastric intubation as single doses of 0.5-1.5 g/kg body wt after 4 weeks feeding of CD diet had produced fatty livers in rats. Two-thirds partial hepatectomy was performed 4 h subsequent to the initiating treatment step. After a 2 week recovery period, all rats were subjected to the selection procedure of Cayama et al. and killed at week 9 of the experiment. Quantitative analysis of placental form glutathione S-transferase (GST-P)-positive liver lesion development did not reveal any enhancement by APAP, whereas administration of a non-necrogenic dose of diethylnitrosamine (20 mg/kg body wt) in the same protocol demonstrated significant promotion, confirming the utility of the model for detection of weak carcinogenicity of chemicals. In the second long-term experiment, APAP was fed at doses of 0.45 and 0.9% for 25 weeks following 27 weeks administration of CD diet which produced liver cirrhosis in the rats. Despite a slight enhancement of focal liver lesions positive for gamma-glutamyltranspeptidase (GGT), no significant promotion of GST-P-positive altered foci or nodules was observed. In contrast, continuous feeding of CD diet or 0.5% phenobarbital treatment after generation of cirrhosis with CD diet clearly enhanced the induction of both GST-P and GGT-positive liver lesions. Thus, these results indicate that APAP does not possess significant carcinogenic activity in damaged rat liver.
Maruyama
H
H
Department of Oncological Pathology, Nara Medical College, Japan.
Takashima
Y
Y
Murata
Y
Y
Nakae
D
D
Eimoto
H
H
Tsutsumi
M
M
Denda
A
A
Konishi
Y
Y
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens; D002796:Choline Deficiency / Q000473:pathology*; D004052:Diethylnitrosamine; D005260:Female; D005982:Glutathione Transferase / Q000032:analysis; D006498:Hepatectomy; D007527:Isoenzymes / Q000032:analysis; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000473:pathology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D012016:Reference Values
D002273:Carcinogens; D007527:Isoenzymes; D000082:Acetaminophen; D004052:Diethylnitrosamine; D005982:Glutathione Transferase