Molecular Pharmacology, Vol 11, 36-43, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

Modification of Hepatic Ribonucleic Acid Polymerase Activities by N-Hydroxy-2-acetylaminofluorene and N-Acetoxy-2-acetylaminofluorene

¹ Department of Pharmacology, Emory University, Atlanta, Georgia 30322
² Department of Chemistry, Emory University, Atlanta, Georgia 30322

Treatment of partially hepatectomized rats with the hepatocarcinogen N-hydroxy-2-acetylaminofluorene (N-hydroxy-AAF) inhibited the activities of nucleolar and nucleoplasmic RNA polymerase in hepatic nuclei. DEAE-Sephadex chromatography of nuclear RNA polymerases obtained from partially hepatectomized rats treated with N-hydroxy-AAF revealed stimulation in the activity of RNA polymerase I (nucleolar) and inhibition and an altered activity profile of RNA polymerase II (nucleoplasmic). No alterations were observed in the template activity of rat liver DNA from similarly treated animals. Assessment of the template activities of hepatic DNA after reaction with N-acetoxy-2-acetylaminofluorene (N-acetoxy-AAF) at 22° indicated that RNA polymerase II activity was affected to a greater degree than that of RNA polymerase I or Escherichia coli RNA polymerase, particularly at lower concentrations of carcinogens. In contrast, hepatic DNA that had reacted with N-acetoxy-AAF at 37° resulted in a 20-30-fold reduction in the concentration of activated carcinogen necessary to effect a 50% reduction in either rat liver or E. coli RNA polymerase activities. Whereas inhibition of nucleoplasmic RNA polymerase can account for the impairment in synthesis of extranucleolar species of RNA, it appears that inhibition of the synthesis of ribosomal RNA is not a direct result of reduction in nucleolar RNA polymerase or DNA template activity.