Inhibition of RNA Synthesis by Derivatives of the Carcinogen 2-Acetylaminofluorene 1

Abstract

Summary

The way in which the carcinogen N-hydroxy-N-2-acetylaminofluorene inhibits hepatic RNA synthesis was studied using the reactive ester N-acetoxy-N-2-acetylaminofluorene (N-acetoxy AAF). Preincubation of isolated nuclei with N-acetoxy AAF inhibited the ability of those nuclei to carry out RNA synthesis using endogeneous template or an exogenous template poly d(AT). Likewise, the template ability of DNA for RNA synthesis and the transcriptional capacity of RNA polymerases I and II were inhibited by preincubation of these macromolecules in vitro with N-acetoxy AAF. Inactivation of enzyme or template by N-acetoxy AAF was associated with and presumably caused by binding of AAF derivatives to these macromolecules. AAF binding required to inactivate polymerase or DNA in vitro was greater than that observed in vivo under conditions where RNA synthesis was inhibited to a comparable extent suggesting that additional mechanisms may operate in vivo to sensitize enzyme and template to inactivation by AAF binding.