Inhibition of RNA polymerase B activity in normal and regenerating rat liver after administration of 9-aminoacridine.

Ledakrin, 1-nitro-9-[3'-(N,N'-dimethyl)aminopropyl]aminoacridine administered intraperitoneally at a dose up to 20 mg/kg into sham operated and partially hepatectomized rats inhibited RNA polymerase B activity in the isolated liver nuclei. The average chain length of the in vitro transcript was reduced while the number of elongating RNA polymerase B molecules was not changed after Ledakrin treatment. The drug inhibited RNA polymerase B activity in 18 hour regenerating liver to a much greater extent than in control liver. However, one molecule of tritium-labelled Ledakrin was bound with the same number of base pairs of DNA both in normal and regenerating liver. About 60 to 70% of the label was found to form labile complexes with DNA and could be liberated on thermal, alkaline or acidic denaturation of DNA. The remaining label seems to be covalently bound to DNA. The drug induced "cross-links" between the two strands of rat liver DNA in vivo. DNA from the liver nuclei unable to synthesize RNA due to Ledakrin treatment, retained the template activity against E. coli RNA polymerase. The presented results point to a limited preference of Ledakrin to bind to the transcriptionally active regions of chromatin.