Subject(s)
Amino Acid Chloromethyl Ketones/pharmacology , Carcinoma, Hepatocellular/metabolism , Colonic Neoplasms/metabolism , DNA Replication/drug effects , Liver Neoplasms/metabolism , Protein Biosynthesis/drug effects , Tosylphenylalanyl Chloromethyl Ketone/pharmacology , Animals , Colonic Neoplasms/chemically induced , Dimethylhydrazines/analogs & derivatives , Female , Kinetics , Liver/drug effects , Liver/metabolism , Liver Regeneration/drug effects , Neoplasms, Experimental/metabolism , RatsABSTRACT
A 0.05% solution of trimethylhydrazine hydrochloride (TMH) administered for a lifetime in drinking water to outbred Swiss albino mice, beginning at 6 weeks of age, induced tumors of blood vessels, lungs, and kidneys. The tumor incidences in these tissues in untreated controls were 5,22 and 0%, whereas in the treated groups the corresponding tumor incidences increased to 85, 44, and 6%, respectively. Histopathologically, tumors were classified as angiosarcomas of blood vessels and adenomas of the lungs and kidneys. The study thus demonstrated the tumorigenicity of TMH. Contrary to expectation, the chemical structure modification apparently failed to alter qualitatively the tumorigenic response.
Subject(s)
Adenoma/chemically induced , Hemangiosarcoma/chemically induced , Hydrazines/toxicity , Kidney Neoplasms/chemically induced , Lung Neoplasms/chemically induced , Animals , Chemical Phenomena , Chemistry , Dimethylhydrazines/analogs & derivatives , Female , Male , Methylhydrazines , Mice , Neoplasms, Experimental/chemically induced , Structure-Activity RelationshipABSTRACT
The radioactivity level in blood, bile, urine and contents of parts of the gastro-intestinal tract in rats was studied after subcutaneous administration of 3-H-1,2-dimethylhydrazine (3-H-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 3-H-SDMH treatment from the 3-H-incorporation into these macromolecules. Administration of 3-H-1,2-diethylhydrazine (3-H-SDEH) which does not induce intestinal tumours was made as a control. Fifteen to 30 min after 3-H-SDMH treatment, marked radioactivity was found in blood, bile, urine and in contents of all regions of gastro-intestinal tract. After 3-H-SDMH administration no label occurred in the contents of localized segments of gastro-intestinal tract although it was present in blood, bile and urine. 3-H-SDMH methylated DNA, RNA and proteins of intestinal mucosa, liver and kidney to a high degree. One hour after 3-H-SDMH treatment the incorporation of label into protein of intestinal mucosa was higher than into liver and kidneys. 3-H-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, 3-H-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 beta-glucuronidase releases the active metabolite which, in turn, alkylates tissue macromolecules.
