The mechanism of carcinogenic action of 1,2‐dimethylhydrazine (sdmh) in rats

Abstract

The radioactivity level in blood, bile, urine and contents of parts of the gastro‐intestinal tract in rats was studied after subcutaneous administration of ³H‐1,2‐dimethylhydrazine (³H‐SDMH) which induces colonic tumours. The alkylation of DNA, RNA and protein in the intestinal mucosa, liver and kidneys was estimated 1 h to 28 days after ³H‐SDMH treatment from the ³H‐incorporation into these macro‐molecules. Administration of ³H‐1,2‐diethylhydrazine (³H‐SDEH) which does not induce intestinal tumours was made as a control. Fifteen to 30 min after ³H‐SDMH treatment, marked radioactivity was found in blood, bile, urine and in contents of all regions of gastro‐intestinal tract. After ³H‐SDMH administration no label occurred in the contents of localized segments of gastro‐intestinal tract although it was present in blood, bile and urine. ³H‐SDMH methylated DNA, RNA and proteins of intestinal mucosa, liver and kidney to a high degree. One hour after ³H‐SDMH treatment the incorporation of label into protein of intestinal mucosa was higher than into liver and kidneys. ³H‐SDEH did not alkylate macromolecules in these organs but did so in thymus, spleen and brain, which are target organs for this carcinogen. After total hepatectomy. ³H‐SDMH did not methylate macromolecules of the intestinal mucosa. The following mechanism for the carcinogenic effect of SDMH is suggested. A carcinogenic metabolite of SDMH forms, in the liver, a conjugate with glucuronic acid. This glucuronide enters the gut both with bile and directly via the circulation. Microbial β‐glucuronidase releases the active metabolite which, in turn, alkylates tissue macro‐molecules.