Effect of cycloheximide on dimethylnitrosamine-induced polyribosome disaggregation in rat liver

The simultaneous administration of a dose of 1.5 mg/kg body wt. cycloheximide with 20 mg/kg body wt. dimethylnitrosamine to rats did not affect the metabolism of the nitrosamine as deduced by following its concentration in the blood nor affect the level of alkylation by the nitrosamine of cytoplasmic RNA in the liver. Incorporation of [¹⁴C]leucine into hepatic protein, which was maximally inhibited 60% 3 h after administration of the same dose of dimethylnitrosamine alone, was reduced by 94% within 1 h in rats treated with dimethylnitrosamine and cycloheximide.Polyribosome structure was determined by sucrose gradient centrifugation. Disaggregation of hepatic polyribosomes as a result of administration of the nitrosamine alone was most marked at 4 h, but by 8 h there was a recovery of polyribosome structure and a relative decrease in the number of monomeric ribosomes. Administration of cycloheximide alone did not affect the structure of hepatic polyribosomes. When dimethylnitrosamine and cycloheximide were given simultaneously the immediate breakdown of polyribosomes that normally followed administration of dimethylnitrosamine was prevented for at least 4 h; however after 8 h there was considerable disaggregation of the polyribosomes in the liver. The implications of these observations for the mechanism of inhibition of protein synthesis by dimethylnitrosamine are discussed.