Dose-dependency of 2-acetylaminofluorene binding to liver DNA and hemoglobin in mice and rats

Abstract

The carcinogenic activity of 2-acetylaminofluorene (2-AAF) in mice and rats has been accurately described so that it is a suitable archetypical chemical for investigations of parameters of cross-species variation. The binding of orally administered [9- 14C]2-AAF to liver DNA in mice and rats was dose related in a linear manner between 1 to 100 μmol/kg body wt. By Sephadex LH-20 chromatography, it was determined that the formation of 2-AAF adducts over the dose range studied was both qualitatively and quantitatively similar. Hepatic DNA binding was greater in rats compared to mice. No sex difference was observed in the DNA binding in rats so that the higher incidence of liver cancer in male compared to female rats could not be explained by a greater amount of DNA binding in males. The binding of orally administerd [9- 14C]2-AAF to hemoglobin in mice and rats was dose related in a linear manner between 0.1 to 100 μmol/kg. The results of 2-AAF binding to DNA and hemoglobin would indicate that for an oral dose of 2-AAF, the rate of formation of reactive metabolites was similar between 0.1 and 100 μmol/kg body wt. However, the sevenfold greater DNA binding and 2.5-fold greater hemoglobin binding in rats compared to mice were more than an order of magnitude less than 246-fold greater carcinogenicity of 2-AAF in rat liver. The results of the study supported a pharmacokinetic model that related the metabolism of 2-AAF to reactive metabolites to the binding of the metabolites to DNA and hemoglobin. The results did not support a relationship of macromolecular binding to carcinogenic potency.