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 animals fed 4-dimethylaminoazobenzene there are modifications in the distribution of extra- and intracellular cations in liver. The correlation between the cell ionic permeability changes and the induction of cholangiocarcinoma or hepatoma is analyzed at the light of the histological and biochemical findings. A new concept of chemical carcinogenesis is stated in which the increase of passive Ca2+-influx produces mitochondria damage associated with permanent modifications of the structural and functional characteristics of the cell membranes as well as of the genetic mechanisms controlling cell division.
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PMID:Liver tumors induced by 4-dimethylaminoazobenzene: experimental basis for a chemical carcinogenesis concept. 19 Sep 73

We have studied glucagon induction of enzymes, adenosine 3', 5'-monophosphate concentrations, and glucose repression in Morris 9618A hepatoma and in the liver of rats fed, for periods of up to 5 weeks, a solid diet containing 2-acetylaminofluorene or 3'-methyl-4-dimethylaminoazobenzene. While the basal levels of the enzymes serine dehydratase and tyrosine aminotransferase were the same as those found in control rats, their response to glucagon was reduced in experimental animals with or without tumors. However, the basal or glucagon-stimulated levels of adenosine 3', 5'-monophosphate in the liver of rats given the carcinogens were not changed. In Morris 9618A hepatoma, these parameters were, likewise, comparable to those in control animals. When glucose was administered to carcinogen-treated or tumor-bearing rats that had received a single dose of glucagon, there was no suppression of the increase in activity of serine dehydratase and tyrosine aminotransferase observed after glucagon treatment alone. The loss of glucose repression was seen already at 2 to 3 weeks following initiation of the carcinogenic diets. As previous studies had established for normal liver, the hormone-induced high levels of adenosine 3',5'-monophosphate remained unchanged also in Morris 9618A hepatoma and in rats given carcinogen. These results indicate that alterations in enzyme induction during chemical carcinogenesis are not the consequence of changes in adenosine 3',5'-monophosphate levels caused by carcinogens. The early disappearance of the glucose effect, which persists in slow-growing hepatomas, may be an expression of interference by carcinogens with the translation apparatus of the hepatic cell.
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PMID:Induction of enzymes by glucagon, glucose repression, adenosine 3',5'-monophosphate concentration during carcinogenesis and in Morris 6918A hepatoma. 23 92

Biosynthesis of cholesteryl 14-methylhexadecanoate, cholesteryl palmitate and cholesteryl stearate was studied in the liver of rats bearing the Walker 256 carcinoma. Zajdela hepatoma and during chemical carcinogenesis following the administration of benzo[a]-pyrene. An up to 9-fold enhanced production of all these esters was found in liver homogenate during the 10--16th day after Walker tumor transplantation. Only the enzyme system esterifying cholesterol in the cytosol at pH 6.5 was stimulated while the activity of similar enzymes in mitochondria, microsomes and cytosol at an acid pH were not affected. Activity of the cytosol enzyme esterifying cholesterol at pH 6.5 was also enhanced during the active growth of Zajdela hepatoma and during the period of chemical carcinogenesis characterized by the appearance of first palpable subcutaneous tumors. Enhanced activity of cholesterol esterifying enzymes in the liver exactly coincided with periods of elevated levels of cholesteryl 14-methylhexadecanoate in the liver and blood plasma as described earlier. An increased demand of the tumor-bearing host for this cholesteryl ester utilized as a co-factor for enhanced protein synthesis is obviously met by its stimulated production in the liver tissue.
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PMID:Biosynthesis of cholesteryl 14-methylhexadecanoate in the liver of rats bearing transplantable tumors and during chemical carcinogenesis. 43 54

Dimethyl fumarate and dimethyl maleate are potent inducers of cytosolic NAD(P)H:(quinone acceptor) oxidoreductase (here designated quinone reductase) activity in Hepa 1c1c7 murine hepatoma cells in culture, whereas fumaric and maleic acids are much less potent, in agreement with the much greater reactivity of the esters as Michael reaction acceptors (P. Talalay, M. J. De Long, and H. J. Prochaska, Proc. Natl. Acad. Sci. USA, 85:8261-8265, 1988). Dimethyl fumarate also induced quinone reductase in mutants of the Hepa 1c1c7 cell line that were either defective in the Ah receptor or in cytochrome P1-450 activity, thereby establishing that this compound is a monofunctional inducer (H. J. Prochaska and P. Talalay, Cancer Res., 48: 4776-4782, 1988). Addition of dimethyl fumarate to the diet of female CD-1 mice and female Sprague-Dawley rats at 0.2-0.5% concentrations elevated cytosolic glutathione transferases and quinone reductase activities in a variety of organs, whereas much higher concentrations of fumaric acid were only marginally active. The widespread induction of such detoxication enzymes by dimethyl fumarate suggests the potential value of this compound as a protective agent against chemical carcinogenesis and other forms of electrophile toxicity. This proposal is supported by the finding that the concentrations of dimethyl fumarate required to obtain substantial enzyme inductions were well tolerated by rodents. Furthermore, the parent fumaric acid has low chronic toxicity and is a naturally occurring metabolic intermediate that is already in the food chain as an additive, and fumarate salts and esters are used for therapeutic purposes in man.
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PMID:Induction of glutathione transferases and NAD(P)H:quinone reductase by fumaric acid derivatives in rodent cells and tissues. 212 43

Monoclonal antibodies (moabs) to neoplastic and preneoplastic liver cells in rats have been selected to follow cellular changes in the livers during chemical carcinogenesis. The moabs were induced by immunizations of BALB/c mice with four partially purified liver cell preparations: 1) oval cells induced in male Fischer rats fed 0.05% N-2-acetylaminofluorene in a choline deficient diet: 2) preneoplastic gamma-glutamyltranspeptidase positive hepatocytes induced by i.p. injection of diethylnitrosamine into male Fischer rats followed by 0.02% N-2-acetylaminofluorene and partial hepatectomy (Solt-Farber model): 3) sharply dissected neoplastic nodules induced in male Fischer rats by five 2-week cycles of 0.05% N-2-acetylaminofluorene diet: and 4) Morris hepatomas 7777 and 5123 passaged in male Buffalo rats. The hybridomas were screened by enzyme linked immunosorbent assay or by indirect immunofluorescence on composite cryostat sections of fetal and adult rat liver, liver containing neoplastic nodules, and Morris hepatoma 7777. Positive clones were limit diluted and partially characterized by indirect immunofluorescence on cryostat sections of other preneoplastic and neoplastic rat livers as well as normal rat tissues. Two moabs to oval cells, two moabs to hepatocytes, and one moab to hepatomas have been selected for further study.
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PMID:Production of monoclonal antibodies to preneoplastic liver cell populations induced by chemical carcinogens in rats and to transplantable Morris hepatomas. 247 76

Different lineages of hepatocellular carcinoma (HCC) were identified by the application of selected monoclonal antibodies to the study of the sequential histopathological changes which occurred during two regimens of chemical carcinogenesis in the rat. One regimen, that of Solt-Farber, caused prominent oval cell proliferation and large multiple neoplastic nodules, and the other regimen, continuous administration of diethylnitrosamine, produced minimal oval cell proliferation and a few small nodules. However, both regimens produce HCC in most exposed rats. Three monoclonal antibodies to liver cells, OV-6, H-4, and T-6, were selected on the basis of different tissue staining. OV-6 stains the cytoskeleton of bile duct cells, oval cells, and HCC but not that of hepatocytes. H-4 stains the cytoplasm of hepatocytes but of not hepatomas. T-6 stains the cytoskeleton of HCC only. In the Solt-Farber model, the monoclonal antibodies identified groups of hepatocytes within the persistent neoplastic nodules which had acquired the OV-6 epitope and had lost the H-4 epitope. HCC derived from this regimen had the same staining pattern, suggesting that the OV-6 positive H-4 negative hepatocytes were the precursors of the HCC. The presence within the nodules of oval cells, atypical duct structures, cells intermediate between duct cells and hepatocytes, and nodular hepatocytes all containing the OV-6 epitope raises the possibility that any of these cell types could serve as the precursor of the OV-6 positive hepatocytes that arose within the nodule. In the continuous diethylnitrosamine regimen a different staining pattern was seen. T-6 positive hepatocytes first appeared in periportal areas by the 5th week. These cells increased in numbers during the later weeks and with rare exceptions neither acquired the OV-6 epitope nor completely lost the H-4 epitope. Most HCC derived by the continuous diethylnitrosamine regimen were T-6 positive and OV-6 negative, suggesting a direct lineage from the periportal T-6 positive hepatocytes. These findings indicate that the lineage and phenotype of chemically induced HCC may vary with the carcinogenic regimen used and that HCC which arise in nodules may originate from cell types other than typical nodular cells.
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PMID:Different lineages of chemically induced hepatocellular carcinoma in rats defined by monoclonal antibodies. 247 77

A persuasive body of evidence indicates that substantial protection against chemical carcinogenesis can be achieved by induction of enzymes concerned with the metabolism of carcinogens. There are two classes of anticarcinogenic enzyme inducers: (a) monofunctional inducers (e.g., phenolic antioxidants, isothiocyanates, coumarins, thiocarbamates, cinnamates, 1,2-dithiol-3-thiones) that elevate Phase II enzymes (such as glutathione S-transferases, NAD(P)H:quinone reductase, UDP-glucuronosyl-transferases) in various tissues without significantly raising the Phase I enzyme, aryl hydrocarbon hydroxylase (cytochrome P1-450); and (b) bifunctional inducers (e.g., polycyclic aromatic hydrocarbons, flavonoids, and azo dyes) that induce both Phase I and Phase II enzymes of xenobiotic metabolism. Induction of Phase II enzymes appears to be a sufficient condition for achieving chemoprotection, and since certain Phase I enzymes are responsible for activating carcinogens to their ultimate reactive forms, selective Phase II enzyme inducers offer intrinsically safer prospects for achieving chemoprotection. Whereas induction of both Phase I and II enzymes by bifunctional inducers depends on the Ah receptor, induction of Phase II enzymes by monofunctional inducers is independent of a functional Ah receptor. Studies on the structural requirements for induction of quinone reductase [NAD(P)H:(quinone acceptor) oxidoreductase; EC 1.6.99.2] by monofunctional inducers in Hepa 1c1c7 murine hepatoma cells have revealed that such inducers contain a distinctive chemical feature (or acquire this feature by metabolism) that regulates the synthesis of this protective enzyme. The inducers are all Michael reaction acceptors characterized by olefinic (or acetylenic) linkages that are rendered electrophilic by conjugation with electron-withdrawing groups. Typical examples are alpha, beta-unsaturated aldehydes, ketones (including quinones), thioketones, sulfones, esters, nitriles and nitro groups. The potency of these inducers parallels their reactivity as Michael acceptors. These generalizations have provided mechanistic insight into the vexing question of how so many seemingly unrelated anticarcinogens induce chemoprotective enzymes. They have also led to the prediction of entirely new and unsuspected structures of inducers, with potential for chemoprotective activity.
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PMID:Mechanisms of induction of enzymes that protect against chemical carcinogenesis. 269 44

Almost all experimental studies on hepatocarcinogenesis have been performed on models induced by chemicals. The human hepatocellular carcinoma (HCC), a highly malignant tumor, particularly frequent in the Far East and in Africa, is overwhelmingly associated with hepatitis B virus (HBV) infections and only very rarely is it caused by chemicals. This raises the question as to what degree observations on the preferentially studied chemical carcinogenesis apply to human HCC. This question is timely, since a woodchuck model has been developed in which laboratory infection with a hepadna virus, biologically and genomically similar to HBV, regularly produces HCC in prolonged surface antigen carrier woodchucks. Permanent surface antigen carriage by itself may also be a risk factor. A comparison, based on available observations of chemical and hepadna viral carcinogenesis, was attempted on four aspects: (1) histologic features, (2) growth patterns, (3) growth factors, and (4) molecular biological observations. At this time, only few conclusions can be drawn, mainly on a morphological and molecular biological basis. In the initial stage, chemicals cause mutations of very few bases, while in hepadna viral infections long sequences are inserted into both strands of chromosomal DNA. Additional studies appear to be indicated, to the greatest degree with existing methods and primarily on hepadna viral carcinogenesis. A key question is whether the active necroinflammation, preceding or observed at the time the HCC is recognized, in woodchuck and also in human chronic HBV infections is a promoting event or a secondary reaction. Additional therapeutic strategies, specific for hepadna viral carcinogenesis, can be considered, particularly elimination of hepatocytes carrying integrated viral sequences and prevention or suppression of the promoting necroinflammation. Success in HCC may be applicable to cancers related to papilloma virus in other organs, for instance, the female genital tract.
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PMID:Viral versus chemical hepatocarcinogenesis. 284 91

The liver is, under normal conditions, mitotically inactive and relatively resistant to chemical carcinogenesis. When rat or mouse hepatocytes are stimulated to divide, however, the liver becomes exquisitely sensitive to carcinogenesis. The heightened sensitivity of dividing liver cells to carcinogens is one of the most dramatic phenomena in the field of experimental chemical carcinogenesis and is reproducible with a wide variety of chemical agents and experimental conditions. This same phenomenon seems to apply to humans, as circumstances that produce a sustained hepatocellular proliferation in man are associated with an increased risk of hepatocellular carcinoma (HCC). These include inborn errors of metabolism (e.g., haemochromatosis, Wilson's disease, hereditary tyrosinaemia) as well as alcoholism. A recent editorial in this Journal suggested that any condition resulting in cirrhosis is also associated with an increased risk of HCC, and this may in turn be due to regenerative hyperplasia always present in cirrhotic liver (Johnson PJ, Williams R. J Hepatol 1987; 4: 140-147). In the case of HCC associated with hepatitis B virus (HBV) infection, the possibility must be entertained that chronic HBV infection serves to produce a sustained hepatonecrosis with concurrent (regenerative) hyperplasia. This proliferative state would in theory serve to increase the liver's susceptibility to environmental dietary carcinogens and may tend to increase the risk of HCC by this indirect mechanism. Until a molecular mechanisms is demonstrated whereby HBV produces a defined cellular lesion that endows hepatocytes with a malignant phenotype, it should not be assumed that HBV is a direct cause of HCC.
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PMID:Cell proliferation and the aetiology of hepatocellular carcinoma. 285 89

On the occasion of a hitherto unique observation of three hepatocellular carcinomas in workers of the same industrial plant within 7 years following long-term exposure to vinylchloride, the characteristics are discussed of a chemical carcinogenesis leading to two different malignant tumours: haemangiosarcoma and hepatocellular carcinoma. This carcinogenic sequence has been predicted by animal studies. It is not known why the transformation of hepatocytes into carcinoma is far rarer than of sinusoidal cells into sarcoma. Whereas the hepatocellular carcinoma predominantly develops in association with cirrhosis, vinyl chloride is able to cause cancer directly without other known co-carcinogenic agents. This hepatic carcinogenicity is dose-dependent. After the introduction of industrial prevention measures, a new initiation of the tumour is improbable. Nevertheless, because of its long latency period, estimated between 5 and 20 years, clinical manifestations are still possible. An early diagnosis by sonography and computertomography, possibly combined with puncture, in exposed persons or those formerly at high risk is conceivable, while laboratory data, even tumour markers are unreliable. Its fulminant course does not differ from that of other hepatocellular carcinomas and has until now hindered successful treatment.
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PMID:[Vinyl chloride induced hepatocellular carcinoma]. 298 2


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