thioacetamide and Adenoma--Bile-Duct

A sequential, histologic analysis of the livers of male albino rats chronically fed the hepatocarcinogen thioacetamide (TAA) is performed after one, two, three, four, eight and twelve months of treatment. Liver cell alterations present after one, two and three months consist of centrolobular liver cell degeneration and oval cell proliferation. After 8 months of TAA treatment, a variety of benign tumors (cystadenomas, angiomas, cholangiomas) is observed. From the 12th month all experimental animals develop cholangiocarcinomas. Pulmonary metastases are discovered after 15 months. The role of the oval cells in relation to the later appearing cholangiocarcinoma is discussed. A review of literature is given.

Topics: Acetamides; Adenoma, Bile Duct; Animals; Cell Nucleolus; Cell Nucleus; Cytoplasm; Liver; Liver Neoplasms; Male; Rats; Rats, Inbred Lew; RNA; Thioacetamide; Time Factors

A morphological, cytophotometrical and autoradiographical study was carried out on the early liver cell lesions present after one month of thioacetamide (TAA) exposure. We wanted to determine the extent of cell damage in the hepatocytes in relation to the later occurring cholangiocarcinoma. Cytoplasmic and nuclear alterations were present in the hepatocytes. They were mainly due to the toxic influence of the metabolites of TAA. No Feulgen-DNA changes have been observed in the hepatocytes in any of the studied zones. The increased TdR H3+ uptake and mitotic activity in the periportal and midzonal areas represented regenerative activity. In addition to these hepatocytic changes, the centrolobular area was infiltrated by oval cells. These cells appeared at first singly, later on they formed clusters. The electron microscopy of these cells revealed phenotypic characteristics, which were different from the hepatocytes. When separately, these cells resembled undifferentiated cells with cytoplasmic extensions and absent basement membrane. When arranged in clusters, a definite canalicular arrangement was present with characteristics of bile canalicular cells with microvillous extensions at the apical border of the cytoplasm and the presence of a basement membrane. A transition from the first oval cell type to the second oval cell type was suggested. This transition might represent a differentiation process of cells, which are regarded as the target cell and the precursor cell in the development of the cholangiocarcinoma. This is the first study reporting oval cell proliferation in the centrolobular area in a multistep model of livercarcinogenesis in rats.

Topics: Acetamides; Adenoma, Bile Duct; Animals; Autoradiography; Coloring Agents; Cytophotometry; DNA, Neoplasm; Liver; Liver Neoplasms, Experimental; Male; Microscopy, Electron; Mitotic Index; Rats; Rats, Inbred Lew; Rosaniline Dyes; Staining and Labeling; Thioacetamide

Topics: Adenoma, Bile Duct; Animals; Bile Duct Neoplasms; Liver; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Rats; Rats, Inbred Strains; Spleen; Thioacetamide

Hepatocarcinogenesis in rats produced by prolonged feeding of thioacetamide appears as a progressive phenomenon in which morphological changes are associated with important biochemical modifications. It seems most likely that changes in the permeability of cell membrane induced by the carcinogen are responsible for increased intracellular accumulation of Ca2+, and for the ensuring of cell injury produced by Ca2+ overloading of the mitochondria. This calcification of the mitochondria may play a role in the neoplastic transformation of the cell, especially as far as it concerns metabolic behavior and the genetic specification of the permeability characteristics of the transformed cell membrane. The increased synthesis of acid glycosaminoglycans suggests their involvement in calcium-mediated control of tumor development and growth.

Topics: Acetamides; Adenoma, Bile Duct; Animals; Calcium; Diet; DNA, Neoplasm; Glycosaminoglycans; Liver; Liver Neoplasms; Magnesium; Male; Phospholipids; Potassium; Rats; RNA, Neoplasm; Sodium; Subcellular Fractions; Thioacetamide