Inhibition of Rat Liver Ribonucleic Acid Polymerase by the Carcinogen N-Hydroxy-2-fluorenylacetamide

Abstract

Abstract A single intraperitoneal injection of the carcinogenic arylhydroxamic acid N-hydroxy-2-fluorenylacetamide given to male rats inhibited the two RNA polymerase activities of isolated liver nuclei by as much as 80%. Low doses of the carcinogen inhibited the Mg2+-dependent polymerase activity preferentially; high doses inhibited the Mn2+ + (NH4)2SO4-dependent activity to a greater extent. Inhibition was detectable 15 min after injection of the compound and was maximal in 1 hour. Several related noncarcinogenic compounds and carcinogenic arylhydroxamic acids which were inactive toward the liver completely lacked the inhibitory effect shown by N-hydroxy-2-fluorenylacetamide. Female rats, which develop few liver tumors on administration of N-hydroxy-2-fluorenylacetamide, were refractory to the inhibition of liver RNA polymerase by this compound. The depression of RNA synthesis by N-hydroxy-2-fluorenylacetamide was not due to decreased permeability of the nuclear membrane to substrates, nor to increased hydrolysis of newly synthesized RNA. Similar types of RNA were made in the control and treated rats, and the template capacities of liver chromatin and DNA were not affected by the carcinogen. These data suggest that the inhibition of RNA synthesis by N-hydroxy-2-fluorenylacetamide is due to inactivation of the RNA polymerases and not to decreased availability of DNA for transcription.