Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In isolated rat liver cells in which lipid peroxidation is stimulated by CCl4, a strong inhibition of S-adenosylmethionine decarboxylase (SAMD) activity occurs. Some purified aldehydes, which are produced during lipid peroxidation, are able to inhibit SAMD activity in Yoshida hepatoma cells. The most active aldehyde is hydroxypentenal (HPE). It inhibits by 50% SAMD activity at 0.5 mM concentration in entire hepatoma cells, or in hepatoma cell sap, and at 0.1 mM concentration in partially purified hepatoma cell sap fractions.
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PMID:Effect of aldehydes on polyamine metabolism. III. Inhibition of S-adenosyl methionine decarboxylase (SAMD) by CCl4 and by aldehydes produced during lipid peroxidation. 645 40

Effects of carbon tetrachloride (CCl4) and azathioprine (AZP) on the evolution of hyperplastic liver nodules and foci and hepatocellular carcinoma (HCC) were tested in short- and long-term in vivo experiments. In diethylnitrosamine (DEN)-treated rats, which were fed a N-2-fluorenylacetamide (FAA)-containing diet and additionally treated with repeated CCl4 injections, gamma-glutamyl transpeptidase (gamma-GTP)-positive hyperplastic nodules were markedly developed in the 8th week of the experiment. However, their number and area in liver sections were remarkably small in DEN-treated rats fed a diet containing both FAA and AZP. Increased area of gamma-GTP-positive foci was also observed in the 12th week in DEN-injected rats fed a choline-devoid died alone or treated with repeated doses of CCl4 alone. Hepatocellular carcinoma in DEN-injected rats treated with both FAA and CCl4 was first detected in the 21st week, and the incidence up to the 36th week was very high. However, no hepatocellular carcinoma developed in DEN-injected rats treated with both FAA and AZP. The increased activity of liver aniline hydroxylase observed 12 h after the administration of FAA, AZP or DEN alone was not observed when AZP was administered simultaneously with FAA to DEN-injected rats. The mechanisms of the effects of CCl4 and AZP on hepatocarcinogenesis are discussed with special reference to drug interaction.
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PMID:Effects of carbon tetrachloride and azathioprine on diethylnitrosamine and N-2-fluorenylacetamide-induced hyperplastic liver nodule and hepatocellular carcinoma. 652 46

Our earlier experiments revealed that orotic acid, a precursor for pyrimidine nucleotides, selectively stimulated the growth of carcinogen-modified liver cells to grow into enzyme-altered hepatocytes (Cancer Lett., 16: 191-196, 1982). The present study was designed to determine whether prolonged feeding of orotic acid will result in hepatocellular carcinoma in initiated rats. Accordingly, groups of rats were given i.p. either 1,2-dimethylhydrazine dihydrochloride (100 mg/kg) or an equivalent volume of 0.9% sodium chloride solution 18 hr after two-thirds partial hepatectomy. After 1 week of recovery, they were continued on either the basal diet or the basal diet containing 1% orotic acid for 10 to 13 months. Some groups of rats, in addition, received a single necrogenic dose of CCl4 8 weeks following exposure to orotic acid diet. The results obtained indicated that 87.5% of initiated rats exposed to orotic acid developed hepatocellular carcinomas in 10 months and 100% in 13 months. Initiated rats exposed to orotic acid diet coupled with a single administration of CCl4 developed 100% hepatocellular carcinoma by 10 months. In contrast, the incidence of hepatocellular carcinoma in initiated rats fed basal diet alone for 13 months was 37.5%, while, in those that received CCl4 in addition, the incidence was 25% in 10 months. Interestingly, a significant number of liver cancers (29 to 36%) in the orotic acid-fed group metastasized to lungs, whereas none of the liver cancers in rats exposed to basal diet metastasized.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Promotion by orotic acid of liver carcinogenesis in rats initiated by 1,2-dimethylhydrazine. 671 5

Weanling male mice with or without prior treatment with CCl4 (0.5 ml/kg) were exposed to either single (20.5, 25.6, 32 and 40 mg/kg) or multiple (4 mg/kg for 10 days or 8 mg/kg for 5 days) doses of aflatoxin B1. Evidence of its acute toxic and carcinogenic effects was found only in CCl4 pre-treated mice. Single dose LD 50 value under these conditions was calculated to be 26.8 mg/kg. Histological changes which predominantly occurred in the liver were characterized by acute necrosis and degeneration of the parenchymal cells. Hepatomas were observed as early as 9 months of age in CCl4 pre-treated animals given 4 mg/kg aflatoxin daily for 10 days. It is thus suggested that the repeated use of CCl4 as an anthelmintic in animals which are apparently resistant to the lethal and hepatocarcinogenic action of aflatoxin might increase their sensitivity to this mycotoxin.
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PMID:Enhanced susceptibility to aflatoxin B1 toxicity in weanling mice pretreated with carbon tetrachloride. 679 36

Lipoperoxidation by rat liver homogenates increases after in vivo administration of CCl4, colchicine and CHM. In vitro a strong lipoperoxidative action was found for ADP/Fe3+, ethionine and glucosamine. No lipoperoxidation was elicited by hepatomatous liver or by hepatoma cells.
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PMID:Effects of various metabolic inhibitors on lipoperoxidation by homogenates of normal, regenerating and hepatomatous rat liver and by hepatoma cells. 733 Apr 58

Hepatomas arising as a result of prolonged injection of CCl4 consist of cells in which the processes of dystrophy and intracellular regeneration are pronounced to a different degree. In the late stages of development, hepatomas tend to malignancy, exhibiting cells that bear ultrastructural resemblance to the cells of malignant hepatomas. Histological examination revealed high aerobic glycolysis and decreased activity of oxidizing enzymes. Discontinuance of CCl4 injection did not entail normalization of the liver structure. The sinusoidal cells are likely to play an essential role in the development of intralobular liver fibrosis.
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PMID:[Electron microscopic and histochemical characteristics of hepatomas arising during long-term administration of carbon tetrachloride]. 739 69

Hepatic tumors were generated in mice by repeated administration of carbon tetrachloride (CCl4). Eight transgenic (Tg) mice carrying a human c-H-ras proto-oncogene (rasH2 line) and 9 non-Tg mice were killed at 20 weeks. Tg mice developed more tumors than did non-Tg littermates. Most tumors were neoplastic nodules, but 1 hepatocellular carcinoma (HCC) was found in a Tg mouse at 20 weeks. Three Tg and 2 non-Tg mice were kept without further administration of CCl4. Two Tg mice died at 30 weeks of HCC with intra-abdominal bleeding, and 1 Tg mouse developed HCC with a mesenteric metastasis at 32 weeks. No HCC was found in 2 non-Tg mice at 32 weeks. Although mutations at codon 12, 13, and 61 of the H-ras gene are often found in murine hepatocarcinogenesis, neither the tumors, including one HCC, nor the normal cells revealed any such mutations. These results showed that the unmutated human c-H-ras gene facilitates malignant transformation of hepatocytes when continuous liver-cell death and regeneration is caused by repeated administration of CCl4.
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PMID:Hepatic tumors induced by carbon tetrachloride in transgenic mice carrying a human c-H-ras proto-oncogene without mutations. 796 Feb 26

Extrathymic T cells exist in the liver and are often seen in close contact with Kupffer cells in the hepatic sinusoids. Since selective depletion of Kupffer cells has become possible by using liposome-encapsulated clodronate, it was investigated whether elimination of Kupffer cells influences the level of extrathymic T cells in the liver. Extrathymic T cells were identified as interleukin-2 receptor beta-chain (IL-2R beta) intermediate TCR (TCRint) cells by two-color staining for CD3 or T cell receptor (TCR) and IL-2R beta. The elimination of Kupffer cells did not significantly affect levels of TCRint cells up to 7 days after treatment. We then examined monocyte colony stimulating factor (M-CSF)-deficient op/op mice (low levels of Kupffer cells). Extrathymic T cells both in the liver and spleen of these mice were detected at a level comparable to that of control mice. Since extrathymic T cells in the liver are sometimes located in the parenchymal space, the relationship between extrathymic T cells and hepatocytes was then examined. Electron microscopy revealed that some hepatic T cells adhered directly to hepatocytes. When hepatocytes were damaged by a single injection of CCl4, hepatocyte death and subsequent hepatic fibrosis were induced. Beginning 3 days after injection, CD3int cells, but not other type of cells, decreased prominently. Purified CD3int cells, as well as whole lymphocytes in the liver, were cytotoxic against syngeneic hepatoma. In parallel with the above-mentioned hepatic damage, the cytotoxic activity of lymphocytes against such targets was impaired in the liver. These results suggest that extra-thymic generation of TCRint cells and their acquisition of cytotoxic function are relatively independent of Kupffer cells, but are dependent on hepatocytes.
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PMID:Supportive cellular elements for hepatic T cell differentiation: T cells expressing intermediate levels of the T cell receptor are cytotoxic against syngeneic hepatoma, and are lost after hepatocyte damage. 856 37

Mammalian S-adenosylmethionine (AdoMet) synthetase exists as two isozymes, liver-type and nonhepatic-type enzymes, which are the products of two different genes. It is known that the liver-type isozyme is only expressed in adult liver. Whereas, the nonhepatic-type isozyme is widely distributed in various tissues. In addition to the liver-type isozyme, a minor amount of the nonhepatic-type isozyme is also detected in adult liver. To investigate the distribution of these two isozymes in the liver in detail, the localization of these two isozymes was examined in each cell type of liver using a combination of cell fractionation technique and Western blot analysis. In the parenchymal cells, the liver-type isozyme protein was predominantly expressed, and a small amount of the nonhepatic-type isozyme protein was also detected. On the other hand, in the stellate cells the nonhepatic-type isozyme protein was exclusively or only expressed. Interestingly, a large amount of both isozymes were present in endothelial and Kupffer cell fraction. Using both antibodies to anti-rat nonhepatic-type and liver-type isozymes, respectively, immunohistochemical analysis clearly confirmed these results. In addition, in cultured hepatocellular carcinoma cells (FAA-HTC1), the nonhepatic-type isozyme protein only was detected, and the liver-type isozyme protein completely disappeared. This result indicates that the changes in the isozyme expression is regulated within the parenchymal cells. Administration of hepatotoxic drug carbon tetrachloride (CCl4) to rats resulted in about 40% to 50% reduction of enzyme activity in parenchymal cells and stellate cells compared with those of control rats. However, enzyme activity in endothelial and Kupffer cell fraction was not changed.
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PMID:Differential expression of S-adenosylmethionine synthetase isozymes in different cell types of rat liver. 925 54

Aflatoxin B1 (AFB1), a fungal toxin produced by Aspergillus flavus, is known to be a possible hepatocarcinogen. But the molecular biologic changes which may occur following exposure to AFB1 are not known and thus the carcinogenesis is not yet understood. This study was performed to examine the expressions of c-myc, c-fos and TGF-alpha genes and to investigate the possible role of those molecular biologic changes in hepatic regeneration and in the development of hepatocellular carcinoma (HCC). Sprague-Dawley rats were divided into 3 groups: Carbon tetrachloride (CCl4) only was administered to group I, AFB1 only was administered to group II and a combination of AFB1 and CCl4 was administered to group III. The animals were sacrificed at 0.5, 1, 2, 6, 12, 24, 48, and 72 hours after treatment. In addition to the examination of the hematoxylin-eosin stained sections, hepatic regeneration and apoptosis were analyzed quantitatively by bromodeoxyuridine (BrdU)-anti-BrdU immunohistochemistry and TUNEL assay utilizing apoptosis kit, respectively. The hepatic expressions of c-myc, c-fos and transforming growth factor-alpha (TGF-alpha) were examined by immunohistochemistry and studied by Western blot. The number of BrdU labelled cells and the degree of necrosis/apoptosis were comparable among the different groups. Livers of the group II rats showed nearly normal histology without regeneration and necrosis/apoptosis. In groups I and III, the number of BrdU- labelled cells showed an increase at 48 hours after treatment, and the increment was significantly higher in group I than in group III. Most BrdU-labelled cells were mature hepatocytes in group I, whereas in group III they appeared to be less mature. In group I, apoptosis showed an increase at around 24 hours, but appeared in group III as early as 12 hours after treatment and persisted through 48 hours. The expression of c-myc and c-fos were also different between the experimental groups. The expression intensity of c-myc in group I was highest at 1 hour and decreased thereafter. In groups II and III, the expressions were much more intense than in group I, except at 1 hour, and the increased intensity persisted throughout the experiment. Group II in particular showed a peak intensity at 30 minutes and at 6 hours after treatment. In group I, c-fos was strongly expressed only at 24 hours, but in group III, there was progressively increased expression with peak intensity at 24 hours. TGF-alpha was expressed in similar intensities in all groups throughout the experiment. These results suggest that AFB1 may evoke an intense and protracted expression of c-myc, provocating the CCl4-induced necrosis of hepatocytes, and a prolonged expression of c-fos, including persistent signals for regeneration which in turn may activate the replication of immature cells. These findings will aid further investigation of molecular biologic and histologic characteristics of the hepatotoxic and hepatocarcinogenic mechanism of AFB1 in rats. And these results in rats, together with clinico-epidemiologic and molecular biologic investigations in humans and other animals, suggest that AFB1 may supply hepatocarcinogenic background in early exposure time in AFB1-contaminated areas of China and Korea.
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PMID:The effect of aflatoxin B1 on the expression of early response genes and transforming growth factor-alpha in CCl4 induced rat liver injury. 925 17


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