Modification of dimethylnitrosamine-induced changes in renal metabolism and subsequent effect on carcinogenic activity of actinomycin D and cycloheximide

Abstract

This paper concerns further investigation of nucleic acid and protein metabolism in the kidney of protein-depleted rats during the week following a single injection of dimethylnitrosamine that would cause a high incidence of renal tumours. The maximum doses of actinomycin D and cycloheximide that could be tolerated when administered to rats simultaneously with or shortly after 40 mg/kg of body weight dimethylnitrosamine were determined. When administered to dimethylnitrosamine-treated rats the inhibitors did not affect the rate of metabolism of the nitrosamine or the level of alkylation of liver and kidney nucleic acids. These doses of actinomycin D and cycloheximide were shown to be sufficient to inhibit renal RNA, protein and DNA synthesis in otherwise untreated rats, and were found to have a similar effect on RNA and protein synthesis in dimethylnitrosamine-treated rats. Stimulation of renal DNA synthesis by dimethylnitrosamine 2–3 days after administration was prevented by injection of actinomycin D and cycloheximide. Renal DNA synthesis at other times was also affected by these compounds but to a lesser extent. Relationships between periods of DNA, RNA and protein synthesis in the kidney of the nitrosamine-treated rat are considered. The inhibitors did not modify the incidence of dimethylnitrosamine-induced renal tumours but actinomycin D did affect the survival time of rats bearing the tumours. The relationship that biochemical responses to the administration of dimethylnitrosamine bear to its carcinogenic activity is discussed.