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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 Liver¹

Departments of Pharmacology [R. I. G., R. C. N.] and Chemistry, [L. E. G., F. M. M.], Emory University, Atlanta, Georgia 30322

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.

¹ Publication 1198 of the Division of Basic Health Sciences of Emory University. This study was supported by Grant CA-14162 and Training Grant GM-179 from the NIH and a grant from the National Science Foundation.

Received 2/ 6/74. Accepted 5/31/74.