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 gamma-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.