The dual role of 2-acetylaminofluorene in hepatocarcinogenesis: Specific targets for initiation and promotion

2-Acetylaminofluorene (AAF) is one of the most widely studied model carcinogens. It produces liver tumors in rats. Comparison with other arylamides shows that promutagenic DNA lesions are necessary but not sufficient to explain this tissue-specific effect. Mutagenicity of AAF was studied in AS52 cells and compared with that of 2-acetylaminophenanthrene and trans-4-acetylaminostilbene which are incomplete carcinogens in rat liver. The major mutations were G to T transversions in all cases. All three acetamides acted as initiators in an initiation-promotion experiment with phenobarbital as a promoter. Chronic toxic effects of AAF were attributed to specific effects of AAF metabolites on mitochondrial respiration. Electron drainage by 2-nitrosofluorene causes an uncoupling effect on oxidative phosphorylation in vitro. Corresponding compensatory effects were observed in vivo. Initiating as well as promoting properties of AAF are therefore considered responsible for the generation of rat liver tumors. The results support the hypothesis that genotoxic effects generate initiated cells which begin to proliferate only when microcirculation is disturbed due to cirrhotic alterations. These are triggered by non-genotoxic interference with mitochondrial respiration and oxidative phosphorylation.