PROMOTING ACTIVITIES OF THE C-9 OXIDIZED METABOLITES OF N-2-FLUORENYLACETAMIDE IN LIVER CARCINOGENESIS IN THE RAT

The promoting potential of the C-9 oxidized metabolites of N-2-fluorenylacetamide (2-FAA) was examined and compared to that of the promoter 2-FAA in the two-stage hepatocarcinogensis system Male Sprague Dawley rats were initiated with a single intraperitoneal injection of diethylnitrosamine at 200 mg/kg of body weight (b.wt.). One, 2 and 5 weeks thereafter rats were given by gavage 5 doses per week of 2-FAA (0.05 mmol/kg of b.wt.), 9-hydroxy- or 9-oxo-2-FAA (0.05 and 0.1 mmol/kg of b.wt.) or the vehicle polyethylene glycol 400 (2 ml/kg of b.wt.). All rats underwent partial (70%) hepatectomy on day 3 after 5 initial doses. Following treatment with 2FAA, 9-hydroxy-or 9-oxo-2-FAA, the levels of gamma-glutamyl-transpeptidase activity and placental glutathione S-transferase (GST-P) were increased in the livers proportional to the increased numbers of foci of GST-P positive hepatocytes. The activities of the C-9 oxidized compounds were dose-dependent since treatment at 0.1 mmol/kg of b.wt. resulted in -2-fold greater effects than that at 0.05 mmol/kg of b.wt. The incidences of hepatocellular carcinoma increased with time after treatment and the relative order of potency was: 2-FAA>9-oxo-2-FAA>9-hydroxy-2-FAA. These data combined with our earlier evidence for preferential oxidations of 2-FAA at C-9 by hepatic microsomes of male Sprague Dawley rats support the significance of these metabolites as a promoting stimuli in liver carcinogenesis by 2-FAA.