Dimethylnitrosamine - Induced Neoplasms in F344 Male Rats With Various Manipulations of the Mixed-Function-Oxidase System: Macroscopic, Microscopic, Ultrastructural, and Immunocytochemical Evaluation.
Date of Award
Doctor of Philosophy (PhD)
Aminopyrine and nitrite were administered to male F344 rats at concentrations of 1 mg each per ml drinking water as precursors of dimethylnitrosamine (DMN). Rats were divided into groups based on manipulations of the mixed-function-oxidase (MFO) system including: partial hepatectomy, subcutaneous injections of aminoacetonitrile (AAN), phenobarbital (plus 1.75% ethanol) and 1.75% ethanol. Rats were killed at 4 weeks, 12 weeks, 24 weeks, and 36 weeks following initiation of the carcinogenic regimen. DMN-induced neoplasms occurred in the liver, kidneys, and lungs. The number and types of tumors, as well as the target organ affected depended on the particular MFO system manipulation. The most striking effect was the hepatoprotective action of both phenobarbital and ethanol. By macroscopic, microscopic, and ultrastructural evaluation, DMN-induced tumors included those derived from both hepatocytic and bile duct epithelium in the liver, endothelial cells within the liver, from proximal convoluted tubular epithelium and the interstitial cortical fibrocyte in the kidney, and from the type II pneumocyte within the lung. A metabolic study on the specific activity of hepatic O-demethylase, a P-450 dependent microsomal enzyme, from frozen liver samples of sacrificed animals over the course of the experiment, revealed that this enzyme was generally induced by phenobarbital and ethanol. Immunocytochemical analysis of DMN-induced neoplasms was attempted using several commercial products and the avidin-biotin immunoperoxidase method. Selected tumors were examined for cytokeratin, vimentin, desmin, and Factor VIII-related-antigen immunoreactivity. Malignant hepatic tumors of endothelial origin showed strong immunoreactivity for vimentin and Factor VIII-RA, corroborating their endothelial origin. Renal mesenchymal tumors exhibited a staining pattern which suggested a primarily vasoformative tendency, although this varied among tumors. Positive cytokeratin immunoreactivity varied with the primary antibody product used, but was noted in focal cell groups in pulmonary carcinomas usually associated with squamous metaplasia, in the benign tumors derived from biliary ductular epithelium, and in sequestered and compressed renal tubules present in renal mesenchymal tumors and renal adenocarcinomas, respectively. Antibodies against cytokeratins were generally unsuccessful in labelling neoplasms derived from hepatocytes and proximal convoluted tubular epithelial cells.
Gliatto, John Michael, "Dimethylnitrosamine - Induced Neoplasms in F344 Male Rats With Various Manipulations of the Mixed-Function-Oxidase System: Macroscopic, Microscopic, Ultrastructural, and Immunocytochemical Evaluation." (1987). LSU Historical Dissertations and Theses. 4356.