azaserine and Choline-Deficiency

The sensitivity of elevated serum ornithine carbamyltransferase (OCT) as an index of hepatotoxicity in rats was assessed in different studies conducted over a number of years and originally designed to examine the toxicity or carcinogenicity of a variety of test chemicals and diets. Changes in serum OCT activities were compared with the more widely used clinical endpoints, alanine aminotranserase (ALT) and aspartate aminotransferase (AST). In the first study, rats received a single oral dose of the hepatotoxic and hepatocarcinogenic fungal toxin aflatoxin B(1) (AFB(1)). The increase in enzyme levels between control and AFB(1)-treated rats was greater for serum OCT than for ALT or AST. This response was similar to the changes in serum enzyme levels in studies where rats ingested a hepatotoxic and hepatocarcinogenic choline deficient (CD) diet. When rats were exposed to the hepatotoxic and nephrotoxic fungal toxin fumonisin B(1) (FB(1)) by intraperitoneal injection for 6 days, serum AST and ALT were significantly elevated above control levels while OCT was unaffected. The peroxisome proliferator ciprofibrate caused elevated ALT and AST but not OCT at week 52 of dietary exposure, after the development of liver nodules and tumours. Of the two liver-specific enzymes examined in all of the studies, ALT was more consistently predictive of hepatotoxicity than OCT.

Topics: Administration, Oral; Aflatoxin B1; Alanine Transaminase; Animals; Antibiotics, Antineoplastic; Aspartate Aminotransferases; Azaserine; Carboxylic Acids; Choline Deficiency; Clofibric Acid; Dose-Response Relationship, Drug; Fibric Acids; Fumonisins; Injections, Intraperitoneal; Kidney; Liver; Male; Mycotoxins; Ornithine Carbamoyltransferase; Peroxisome Proliferators; Predictive Value of Tests; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Retrospective Studies

Putatively preneoplastic, pancreatic atypical acinar cell foci (AACF) and nodules (AACN), collectively termed atypical acinar cell lesions (AACL), were induced in male Lewis rats by L-azaserine (300 mg/kg body weight [bw] in divided doses). Rats given carcinogen and then fed a lipotrope deficient (LD) diet developed a significantly greater number of larger lesions than animals fed complete diet throughout the experiment. It is suggested that lipotrope deficiency plays a promoting role in this model of pancreatocarcinogenesis. Ultrastructural morphometric studies of AACF, when compared to control tissues, revealed the following significant results: 1) a decrease in surface area of cell cytoplasm with no change in nuclear area, and hence increased nucleus/cytoplasm (N/C) ratio; 2) a reduction in size and uniformity of zymogen granules; and 3) an increase in number of granules per microns 2 of cell. The results suggest that arrested development of the AACF cells is associated with reduced cytoplasm and zymogen production per cell. AACL may be eosinophilic due to an overall increased concentration of zymogen in these hyperplastic lesions and not because individual acinar cells in the AACL contain an increased amount of zymogen or are "zymogen-rich," as has been reported.

Topics: Animals; Azaserine; beta-Lipotropin; Cell Transformation, Neoplastic; Choline Deficiency; Cytoplasmic Granules; Diet; Enzyme Precursors; Folic Acid Deficiency; Male; Methionine; Microscopy, Electron; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Inbred Lew; Vitamin B 12 Deficiency