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2-Acetylaminofluorene and N-hydroxy-2-acetylaminofluorene inhibition of incorporation of orotic acid-5-3H into nuclear ribosomal and heterogeneous RNA in normal and regenerating liver.

The effects of 2-acetylaminofluorene and N -hydroxy-2-acetylaminofluorene (N-OH-AAF) on the incorporation of orotic acid-5-3H into nuclear ribosomal RNA and heterogeneous RNA were evaluated in normal and regenerating liver. The N -hydroxy metabolite was approximately 8 times more potent than the parent carcinogen on the basis of dose-response studies in partially hepatectomized male rats, while 7-hydroxy-2-acetylaminofluorene was without effect on nuclear RNA. Partially hepatectomized male and female animals were more sensitive than sham-operated animals to the inhibitory effects produced by 2-acetylaminofluorene and N-OH-AAF; partially hepatectomized female animals were less responsive than male animals. No changes occurred in the specific radioactivity of uridine triphosphate in the liver at 1 to 4 hr after injection of N-OH-AAF, although a 55% elevation in the concentration of uridine triphosphate occurred at this time. Inhibition of nuclear RNA synthesis by N-OH-AAF also resulted in a concomitant reduction in ribosomal RNA and messenger RNA associated with free and membrane-bound polyribosomes. Experimental evidence is presented which suggests that the inhibitory effects of N-OH-AAF on RNA synthesis is the result of inhibition of RNA polymerase activities associated with the synthesis of nucleolar ribosomal RNA and extranucleolar heterogeneous RNA.