Formation of DNA adducts in vivo in rat liver and intestinal epithelium after administration of the carcinogen 3,2'-dimethyl-4-aminobiphenyl and its hydroxamic acid.

Abstract

Administration of the 3H-labeled colon carcinogen, 3,2'-dimethyl-4-aminobiphenyl (DMABP) and its hydroxamic acid derivative, N-hydroxy-N-acetyl-DMABP, to male F344 rats resulted in high levels of covalent binding to hepatic and intestinal DNA, RNA and protein. For both compounds, binding to hepatic macromolecules was 2-4 times higher than in the intestine. High pressure liquid chromatographic analysis of the enzymatically hydrolyzed DNA from liver and intestinal epithelium indicated the presence of two carcinogen-DNA adducts: 5-(deoxyguanosin-N2-yl)-DMABP (15%), N-(deoxyguanosin-8-yl)-DMABP (50%), and a decomposition product of the latter (15%). N-acetylated adducts were not detected. When measured after 7 days, all adducts in the intestinal DNA had decreased by 70%, while only a 29% decrease had occurred in the hepatic DNA. To determine if the loss of DMABP products was a consequence of cell turnover or repair, rats were treated with [3H]thymidine and DMABP, and the specific activity of hepatic liver and intestinal DNA was measured. Between 1 and 7 days only a slight decrease in [3H]thymidine content occurred in hepatic DNA as compared with a 95% reduction in intestinal DNA. Thus, the higher rate of DNA synthesis in the intestine versus that in the liver may serve to promote fixation of the initiating lesion and account for the preferential induction of intestinal cancer by DMABP. Furthermore, comparison of these data with metabolic activation pathways reported earlier strongly suggest that N-hydroxy-DMABP is the proximate carcinogenic metabolite of both DMABP and N-hydroxy-N-acetyl-DMABP.