Effects of dimethylnitrosamine on RNA synthesis and metabolism in mouse liver

Abstract

Following i.p. injection of dimethylnitrosamine into male C57BL mice, synthesis of liver nuclear heterogeneous RNA was inhibited significantly, reaching approximately 20% of control within 2 hr of a dose of 40 mg/kg. Synthesis of nucleolar RNA was also inhibited, although to a smaller extent, reaching about 70% of control after the same treatment. These effects were observed both during RNA synthesis in vivo and during in vitro transcription with isolated nuclei and nucleoli. Examination of RNA polymerases I and II, isolated and partially purified by diethylaminoethyl Sephadex column chromatography, did not indicate any change either in their activities in the transcription of exogenous DNA or in their in vivo binding to chromatin. On the other hand, the activity of purified chromatin as a template for transcription by added, partially purified RNA polymerase II was significantly reduced, suggesting that carcinogen-induced damage to chromatin was the cause of the observed inhibition of heterogeneous RNA synthesis. When purified DNA was used in place of chromatin as a template for transcription by partially purified RNA polymerase II, no inhibition was observed. Dimethylnitrosamine treatment had a pronounced effect on the kinetics of appearance of the cytoplasmic RNA species. Four hr after a 40-mg/kg dose of dimethylnitrosamine, the rate of appearance in the cytoplasm of polyadenylate-containing RNA was inhibited by 50%, while that of 4S, 18S, and 28S ribosomal RNA was inhibited by over 80%.