thioacetamide and Hyperplasia

The oral administration of thioacetamide to rats induces cholangiofibrosis characterized by hyperplasia of ductules surrounded by fibrous tissue. In the present study, we examined the expression of markers of cholangiocyte and hepatocyte phenotypes in these hyperplastic ductule cells and their proliferative activity immunohistochemically. The oral administration of thioacetamide to 21-day-old male Fisher 344 rats for 12 weeks induced multiple areas of various sizes with hyperplastic ductules. The ductules consisted of two types of ductules; ductules composed of cholangiocyte-like cuboidal cells with transparent nuclei and cytoplasm, and of intestinal epithelium-like (IE-like) cells of basophilic nuclei and cytoplasm, and the transition of these two types of cells in the same ductule was sometimes observed. The cholangiocyte-like cells expressed cytokeratin (CK)-7, CK-19 and OV-6 (cholangiocyte phenotype markers) but not Hep Par-1 antigen or HNF4α (hepatocyte phenotype markers). In contrast, the IE-like cells expressed Hep Par-1 antigen and HNF4α but not CK-7, CK-19 or OV-6. The examination of Ki-67 expression showed a much higher proliferative activity for the IE-like cells compared to the cholangiocyte-like cells. The present results show that the hyperplastic ductules induced by thioacetamide are composed of IE-like cells with a high proliferative activity expressing the hepatocyte phenotype markers and of cholangiocyte-like cells with a low proliferative activity expressing the cholangiocyte phenotype markers.

Topics: Animals; Bile Ducts; Biomarkers; Cell Proliferation; Fibrosis; Hepatocytes; Hyperplasia; Immunohistochemistry; Liver Cirrhosis; Male; Phenotype; Rats; Rats, Inbred F344; Thioacetamide

The proliferative response of hepatocytes in vivo can be induced by two mechanisms: severe damage to hepatic tissue results in regenerative growth and so-called primary hepatocyte mitogens can initiate liver cell proliferation without preceding loss of parenchyma. The regulation of the two responses is quite different. The decreased regenerative response of cirrhotic/fibrotic liver is well known, and is a severe obstacle to surgery of the diseased liver. In the present experiments we investigated the efficiency of a primary hepatocyte mitogen 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOB) on two different liver cirrhosis/fibrosis models in mice induced by chronic administration of CCl(4) and thioacetamide respectively. BrdU incorporation and cyclin A expression established clearly that there is a reduced but still powerful mitogenic response of the fibrotic livers. Therefore, primary hepatocyte mitogens appear to be suitable to be used to rescue the regenerative response of cirrhotic livers.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Biomarkers; Bromodeoxyuridine; Carbon Tetrachloride; Cell Proliferation; Cyclin A; Cytochrome P450 Family 2; Disease Models, Animal; Gene Expression; Hepatocytes; Hyperplasia; Liver; Liver Cirrhosis; Liver Regeneration; Male; Mice; Mice, Inbred C57BL; Pyridines; Steroid Hydroxylases; Thioacetamide; Transforming Growth Factor beta

To analyze the difference in signal intensity on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) among various hepatocellular nodules during hepatocarcinogenesis as correlated with the expressions of the transporters of Gd-EOB-DTPA.. We received institutional animal review board approval prior to the commencement of all studies. Forty rats were divided into three groups. The rats in the tumor groups received N-nitrosomorpholine solution (n = 16), and rats in the cirrhosis group (thioacetamide [TAA] group) received thioacetamide solution (n = 12). As a control, the remaining 12 rats were fed normal water. Each group was divided into two sub-groups: Group 1 for Gd-EOB-DTPA-enhanced MRI (0.025 mmol Gd/kg, n =7) and Group 2 for reverse transcription-polymerase chain reaction to compare transporter (oatp1 and mrp2) expressions (n = 5 for control and TAA groups, n = 9 for tumor groups).. Signal enhancement of tumors decreased according to the progress of hepatocarcinogenesis. Although the relative enhancement of each tumor group was significantly lower than that of the control group (P < 0.01), and there was no significant difference between TAA, hyperplastic nodules (HPN), and HCC(well) groups. The relative enhancement of the HCC(mod) group was significantly lower than the other groups (P < 0.01). The oatp1 expression of HPN tended to be higher than those of HCC(well) and HCC(mod). The mrp2 expression of TAA was significantly higher than those of HCC(well), HCC(mod), HPN and control (P < 0.01). The mrp2 expression of HPN tended to be higher than those of HCC(well ) and HCC(mod).. It was suggested that the signal enhancement on Gd-EOB-DTPA-enhanced MRI would correlate with the transporter expression in various hepatocellular nodules during hepatocarcinogenesis.

Topics: Analysis of Variance; Animals; ATP-Binding Cassette Transporters; Contrast Media; Disease Progression; Gadolinium DTPA; Hyperplasia; Lasers; Liver; Liver Cirrhosis, Experimental; Liver Neoplasms, Experimental; Magnetic Resonance Imaging; Male; Microdissection; Nitrosamines; Organic Anion Transporters, Sodium-Independent; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Thioacetamide; Time Factors

Pancreatic trophism and pancreatic enzyme composition, and plasma levels of cholecystokinin, insulin, glucagon, and glucose in liver cirrhosis induced by chronic thioacetamide administration (0.02% in the drinking water for 12 mo) were studied in rats. Advanced liver cirrhosis was evident in all thioacetamide-treated rats. The weight of the pancreas and its contents of DNA, protein, trypsinogen, chymotrypsinogen, proelastase, secretory trypsin inhibitor, and amylase were significantly increased as compared to the controls. The pancreatic secretory enzyme content changes showed a nonparallelism, characteristic of a cholecystokinin effect. Light and electron microscopy revealed a normal pancreatic architecture. Bioassayed plasma cholecystokinin levels in both fed and 24-h-fasted cirrhotic rats were significantly higher than in the corresponding controls. The plasma glucose, insulin, and glucagon levels demonstrated hypoglycemic tendencies with a glucagon predominance. These findings indicate that advanced liver cirrhosis in the rat is accompanied by pancreatic hypertrophy and hyperplasia, which might be attributed, at least in part, to elevated circulating cholecystokinin levels.

Topics: Animals; Blood Glucose; Cholecystokinin; DNA; Female; Hyperplasia; Liver; Liver Cirrhosis, Experimental; Pancreas; Proteins; Rats; Thioacetamide

An in vivo model of liver hyperplastic noduligenesis was induced in rats by long-term administration of thioacetamide (TAM) (50 mg/kg/day i.p.). Three doses of 50 mg/kg of an antitumoral Rh(III) complex were administered at 14, 9 and 5 days before the end of TAM treatment. Plasma and urine were obtained from either TAM or Rh(III) complex or TAM plus Rh(III) complex treated rats to determine the interactions of both substances with the biochemical parameters related to liver function. The rise in alkaline phosphatase (ALP), leucine aminopeptidase (LAP), gamma-glutamyl transferase (GGT) and the unchanged activities in the aspartate and alanine aminotransferases (AST, ALT) in plasma of TAM-treated rats indicated that the disease induced by this substance can be considered as a chronic obstructive biliary disease with indices of cell proliferation and tumors. The increased concentration of bilirubin both in the plasma and urine of TAM-treated rats suggested liver cholestasis and hepatobiliary obstruction. The very low values of creatinine clearance indicated that there was some degree of kidney failure due to the effect of TAM. The increased concentration of ammonia both in plasma and urine were probably a consequence of the decreased flux in the urea cycle in the liver. The Rh(III) complex alone did not produce significant changes in the plasma enzyme activities. The only significant changes were found in the concentrations of uric acid and ammonia in the urine. When the Rh(III) complex was administered to TAM-treated rats, significant restoration of the following parameters were observed: plasma enzymatic activities, blood bilirubin and ammonia, uric acid and creatinine in the urine and the creatinine clearance. These results suggest that the altered liver function induced by TAM can be restored by Rh(III) complex. The mechanisms by which this complex acts to counteract the TAM-induced changes are not yet established.

Topics: Acetamides; Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Creatine; gamma-Glutamyltransferase; Hyperplasia; Leucyl Aminopeptidase; Liver; Liver Neoplasms, Experimental; Male; Rats; Rhodium; Thioacetamide

1 Hyperplastic liver nodules were induced in F-344 rats by concurrent administration of lasiocarpine (50 ppm in diet) and thioacetamide (50 mg/kg body weight twice weekly) for 15 weeks. 2 The effect of carbohydrate calorie and total calorie restriction on the fate of hyperplastic liver nodules was examined. 3 The incidence of hepatocellular carcinoma was the same in all groups of rats irrespective of the magnitude of carbohydrate calorie restriction and 50% total calorie restriction. 4 These studies demonstrate that carbohydrate or total calorie restriction has no effect on the progression of hyperplastic nodules to hepatocellular carcinoma.

Topics: Acetamides; Animals; Body Weight; Carcinogens; Diet; Dietary Carbohydrates; Energy Intake; Hyperplasia; Liver; Liver Neoplasms; Male; Pyrrolizidine Alkaloids; Rats; Rats, Inbred F344; Thioacetamide

The cell composition of the biliary proliferations induced by thioacetamide administration was investigated. At the end of the intoxication period the main cell types identified among the neoformed bile duct cells were as follows: i) poorly differentiated cells (oval cells) usually arranged in clusters or tiny cords, provided with a great amount of free ribosomes; ii) cells arranged in bile ducts of normal appearance; iii) cells arranged in bile ducts and showing intestinal metaplasia. After withdrawal of TAA most of the biliary proliferations disappeared; in the remaining ones, where the incorporation of 3H-thymidine was still appreciable, significant changes in the bile duct cell composition were evident; in fact whereas the oval cells were no longer identifiable, those suggesting an intestinal metaplasia underwent a relative increment as well as those displaying butyrocholinesterase activity; cells devoid of junctional apparatus and filled with free ribosomes were also seen. Some of the reported finding could support the hypothesis that the biological meaning of the different cell types arisen during intoxication is different; some of them could be due to a reactive hyperplasia, while other could be considered as representing a preneoplastic step.

Topics: Acetamides; Animals; Bile Ducts; Cell Division; Cell Membrane; Cytoplasm; Cytoplasmic Granules; Female; Histocytochemistry; Hyperplasia; Rats; Thioacetamide

Pyrrolizidine alkaloids have long been considered to be hepatotoxic in man as well as in grazing animals. To investigate the effect of liver cell division induced by thioacetamide on the hepatic changes induced by these alkaloids, rats were treated concurrently with thioacetamide and the pyrrolizidine alkaloid lasiocarpine. Thioacetamide was given intraperitoneally in a dose of 50 mg/kg b. wt twice weekly and lasiocarpine was administered in the diet at a concentration of 50 ppm. At 15 weeks, the combination of thioacetamide and lasiocarpine produced numerous grossly visible grey nodules in livers of 26 of 30 rats. Microscopically, these livers revealed a severe degree of postnecrotic cirrhosis and numerous hyperplastic nodules. The cells in most nodules were arranged in solid sheets or in a trabecular pattern and shown atypia, mitosis and hyperchromasia. In contrast, there was no evidence of cirrhosis or nodule formation in livers of animals treated with either lasiocarpine or thioacetamide alone. The rapid development of liver lesions in rats treated simultaneously with low doses of lasiocarpine and thioacetamide suggests that cell proliferation accentuates the development of neoplasia.ł

Topics: Acetamides; Animals; Carcinogens; Cell Division; Chemical and Drug Induced Liver Injury; Drug Combinations; Hyperplasia; Liver; Liver Cirrhosis, Experimental; Liver Neoplasms; Male; Neoplasms, Experimental; Pyrrolizidine Alkaloids; Rats; Thioacetamide

Topics: Animals; Carcinoma, Hepatocellular; Chemical and Drug Induced Liver Injury; Endoplasmic Reticulum; Glycogen; Hyperplasia; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Microscopy, Electron; Rats; Ribosomes; Thioacetamide; Time Factors; Water