title: Inhibition by acetaminophen of neoplastic initiation elicited in rat liver by the DNA-reactive hepatocarcinogen N-acetyl-2-aminofluorene.
abstract: Acetaminophen, a monocyclic phenolic compound and analgesic, when fed at 8900 p.p.m. in the diet, was reported to inhibit the hepatocarcinogenicity in rats of the aromatic amine proximate carcinogen N-hydroxy-N-acetyl-2-aminofluorene. To elucidate the mechanism(s) of this anticarcinogenicity, the present study examined whether acetaminophen at lower doses has the ability to inhibit the initiating effects in the rat liver of the precursor hepatocarcinogen N-acetyl-2-aminofluorene. Male F344 rats were allocated to six groups, which were maintained under reverse light cycle conditions to assure acetaminophen ingestion at the time of N-acetyl-2-aminofluorene administration during the dark phase, which was imposed from 07.00 to 19.00 h. Group 1 served as vehicle control (0.5% carboxymethylcellulose) for N-acetyl-2-aminofluorene, which was administered intragastrically 3 days per week at 2.6 mg/kg for 8 weeks (group 4) to achieve initiation. Acetaminophen was given in the diet either alone at 2400 or 4800 p.p.m. for 9 weeks (groups 2 and 3), or with N-acetyl-2-aminofluorene (groups 5 and 6), starting 1 week before N-acetyl-2-aminofluorene administration. Acetaminophen blood levels were about 1 and 4 microg/ml at the two dietary concentrations. N-acetyl-2-aminofluorene induced hepatocellular preneoplastic lesions measured as hepatocellular altered foci expressing glutathione S-transferase-P, reflecting initiation. Induced foci were reduced with administration of both concentrations of acetaminophen. Acetaminophen by itself produced no DNA adducts nor did it alter the high formation of N-acetyl-2-aminofluorene-DNA adducts, about 200 in 10 nucleotides, measured by nucleotide postlabeling. Acetaminophen did not affect background liver cell proliferation, but significantly reduced N-acetyl-2-aminofluorene-induced increased proliferation measured by proliferating cell nuclear antigen immunostaining. Thus, acetaminophen effectively protected hepatocytes from the initiating effects of N-acetyl-2-aminofluorene, possibly through a cytoprotective effect resulting from slowing the rate of induced cell turnover.
authors: Department of Pathology, New York Medical College, Valhalla, New York, USA. Gary_Williams@NYMC.edu
authors: Gary M
authors: GM
authors: Williams
authors: Michael J
authors: MJ
authors: Iatropoulos
authors: Alan M
authors: AM
authors: Jeffrey
authors: Jian-Dong
authors: JD
authors: Duan
authors: Carmen E
authors: CE
authors: Perrone
mesh_terms: D015073:2-Acetylaminofluorene / Q000031:analogs & derivatives*; D000082:Acetaminophen / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D018736:DNA Adducts / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D000082:Acetaminophen; D015073:2-Acetylaminofluorene