New insights into carcinogenesis of the classical model arylamine 2-acetylaminofluorene

2-Acetylaminofluorene (AAF) is a complete carcinogen in rat liver. The geno toxic effects of reactive metabolites are considered necessary but not suff icient to explain tumor formation. An overview is given of an AAF-feeding e xperiment designed to demonstrate early effects, preceding the development of enzyme-altered foci to support the hypothesis that toxic effects lead to a cirrhosis-like transformation as a prerequisite for the expansion of ini tiated foci and how those effects influence the dose-time-response relation ship of tumor formation. Male Wistar rats were fed 0.005, 0.01, 0.02, 0.04 and 0.08% AAF in the diet for 2, 4, 8, and 16 weeks. GST-P-positive foci de veloped more than proportionately only at 16 weeks. As a first sign of morp hological alterations the number of apoptoses increased (2 weeks), the prol iferation rate followed with some delay and was maximal at 4 weeks. The mos t sensitive parameter for adaptive responses was the inhibition of the mito chondrial permeability transition, studied ex vivo. All parameters increase d dose-dependently at low doses. A threshold could not be detected, but eff ects developed much more gradually with the lowest, non-toxic dose. The sit uation of massive development of foci observed with the higher doses at 16 weeks was not reached. Apoptosis and proliferation rate reach a plateau bet ween 4 and 8 weeks with some of the doses indicating a period in which some balance between adaptation and stress response exists. (C) 1999 Elsevier S cience Ireland Ltd. All rights reserved.