The effect of high and low doses of cycloheximide on nucleolar ribonucleic acid synthesis

In resting rat liver a dose of cycloheximide (1 mg. per kg.) inhibits leucine incorporation by 80 per cent whereas doses above 15 mg. per kg. inhibit it more than 90 per cent, when tested at 90 minutes following intraperitoneal injection. Initial stimulation of incorporation of orotate into total cellular, nuclear, and nucleolar fractions was seen at all doses tested. After 3 hours, however, marked suppression of incorporation particularly into nucleolar RNA was seen at 5 mg. per kg. and above while 1 mg. per kg. continued to stimulate. At 5 hours there was continued marked inhibition of RNA synthesis by 30 mg. per kg. and slight depression of RNA synthesis even by 1 mg. per kg. Preliminary ultrastructural studies failed to show objective nucleolar alterations even after 5 hours of cycloheximide treatment at a dose of 30 mg. per kg. No direct effect of several concentrations of cycloheximide on RNA synthesis was seen in an in vitro nucleolar system.