Selective induction of microsomal 2-acetylaminofluorene N-hydroxylation by dietary 2-acetylaminofluorene in rats.

Inbred male ACI/N rats were treated with an intermittent carcinogenic regimen of 2-acetylaminofluorene (2-AAF) until the development of hepatomas (40 weeks), and the activation of 2-AAF by liver S-9 and the oxidation of 2-AAF; and 2 other drugs by microsomal functions were periodically examined. The S-9 activity increased at the end of 1 feeding cycle (3 weeks 2-AAF diet and 1 week normal diet), reaching a maximum of 400% of controls after 2 or 3 feedings cycles. It then declined, but the elevated S-9 activity (300 to 250% of controls) was sustained until the development of hyperplastic nodules in the livers. The microsomal oxidation of 2-AAF to N-hydroxy-2-AAF was activated by dietary 2-AAF, but the activity of cytosol (S-105) to produce mutagen from N-hydroxy-2-AAF was not affected. Cytochrome P-450 content and microsomal oxidation of aminopyrine and aniline were gradually decreased below the normal levels by 2-AAF feeding, although microsomal p-hydroxylation of aniline was temporarily elevated to about 130% of control at the first or the second feeding cycle. These results indicate that dietary 2-AAF selectively induces microsomal 2-AAF N-hydroxylase which mediates the oxidation of 2-AAF to N-hydroxy-2-AAF, a proximate carcinogenic or mutagenic metabolite.