DOSE-RESPONSE EFFECTS OF 2-ACETYLAMINOFLUORENE ON DNA-DAMAGE, CYTOTOXICITY, CELL-PROLIFERATION AND NEOPLASTIC CONVERSION IN RAT-LIVER

This study measured the effect of precise doses of 2-acetylaminofluore ne (AAF) in inducing DNA damage, functional changes and neoplastic con version in rat liver. Groups of male F344 rats at 9 weeks of age were exposed to cumulative doses of 0.5 or 2.0 mmol AAF per kg body weight given by gavage daily 5 days per week over an 8-week period and mainta ined with no further exposure for up to 8 weeks. Administration of AAF resulted in the formation of N-deoxyguanosin-(8-yl)-2-aminofluorene i n liver DNA in relationship to dose. In centrilobular hepatocytes the zone of glutamine synthetase-expressing cells was reduced by exposure. By 8 weeks, but not at 4 weeks, the higher of the two doses of AAF pr ovoked an increase in cell proliferation measured by immunohistochemic al incorporation of bromode-oxyuridine. Altered hepatocellular foci ex pressing the placental form of glutathione transferase were induced by the high dose of AAF at 4 weeks, but not at the low dose. At 8 weeks the incidence of foci at the high dose was 79 times that induced by th e low dose. These foci were highly proliferative. In animals exposed t o AAF for 8 weeks and maintained for 4 weeks with no exposure, DNA add ucts decreased by 80% and cell proliferation subsided by 80%, although the glutamine synthetase zone remained diminished. After discontinuat ion of AAF, the number of foci diminished by 50% and their proliferati on subsided by 80% at 4 weeks, indicating a phenotypic reversion of ma ny foci. With this protocol of administration of precise doses of AAF, we have established non-linearity of effects and a lack of correlatio n between DNA adduct formation and induction of cellular lesions. We s uggest that doses in the range of those reported can be used to study the contribution of epigenetic and genotoxic effects in carcinogenesis and to study threshold events.