N‐Nitroso‐2‐acetylaminofluorene: A Direct‐acting Carcinogen Inducing Hepatocellular Carcinoma in Sprague‐Dawley Rats

To compare the hepatotoxicity and hepatocarcinogenicity of N‐nitroso‐2‐acetylaminofluorene (NO‐AAF) and its parent compound, 2‐acetylaminofluorene (AAF), male Sprague‐Dawley rats were given intraperitoneal (i.p.) or subcutaneous (s.c.) injections of AAF or NO‐AAF (60 mg/kg body weight/week) for ten months. In the AAF group, morphological changes were produced which involved gross distortions of the liver with multiple nodule formations. The rat livers in the NO‐AAF group appeared to be smooth with a blunt‐thick superior segment of the lateral lobe. The serum γ‐glutamyl transpeptidase activity in both the AAF group and the NO‐AAF group was significantly elevated (P< 0.0005). The present study shows that i.p. and s.c. injections of NO‐AAF resulted in a high incidence of well‐differentiated hepatocellular carcinomas (HCC) (7/9 and 4/6, respectively), while poorly differentiated HCCs were induced by i.p. or s.c. administration of AAF (6/9 or 2/6, respectively). Subcutaneous lesions consisting of an inflammatory reaction and fibroadenoma formation were observed in the NO‐AAF‐treated rats, whereas no such skin lesions were detected in the AAF‐treated animals. These results suggest that NO‐AAF is a new direct‐acting carcinogen which may be useful for investigating hepatocarcinogenesis.