Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relative ability of arylacetamide deacetylase enzyme systems of dog liver to carry out the deacetylation of the carcinogens, 4-acetylaminobiphenyl, 2-acetylaminofluorene, and 2-acetylaminaphthalene, was examined. The arylacetamides were incubated with unfortified dog liver microsomes, and enzyme activity (nmol arylamine/mg protein/hr) was estimated by colorimetric quantitation of the resulting arylamines. The dog liver enzyme system displayed characteristics similar to those described for the rodent liver enzyme system in that enzyme activity was greatest in liver tissue, was localized in the microsomal subcellular fraction, required no cofactors, and was inhibited by heat, sodium fluoride, and thiol reagents. In five replicate assays, the relative rates of deacetylation were about 10, 6, and 1 with 4-acetylaminobiphenyl (84.8 +/- 12.4), 2-acetylaminofluorene (52.5 +/- 5.1), and 2-acetylaminonaphthalene (8.8 +/- 3.3), respectively. As a canine urinary bladder carcinogen, 4-acetylaminobiphenyl is considered more potent than 2-acetylaminofluroene, while 2-acetylaminonaphthalene is devoid of detectable carcinogenic activity, despite the fact that 2-aminoaphthalene is a well-established canine urinary bladder carcinogen. Removal of the acetyl group may be a requirement for urinary bladder carcinogenesis; accordingly, the present studies demonstrate the appearance of a direct relationship between dog liver deacetylase enzyme specificity and urinary bladder susceptibility to these carcinogenic arylacetamides.
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PMID:Enzymic deacetylation of carcinogenic arylacetamides by tissue microsomes of the dog and other species. 0 50

In studies in this and other laboratories, induction of hepatocardinoma by several different chemical carcinogens was enhanced in rats fed diets deficient in lipotropes (choline, methionine, folic acid), amino acids, and niacin, and high in fat. In some cases, specific supplementation with lipotropes blocked carcinogenesis. In studies reported here, specific supplementation of a marginally deficient diet that enhanced carcinogenesis in rats, with the amino acids or lipotropes in which it was deficient, significantly decreased induction of hepatocarcinoma by N-nitrosodiethylamine. Niacin supplementation decreased hepatocarcinoma incidence only slight; the addition of beef fat to an adequate diet did not enhance tumor induction. Rats fed the amino acid- or lipotrope-supplemented diets had an increased incidence of hepatic hemangioendothelial sarcomas, compared to deficient rats or to rats fed the adequate control diet. Methionine was contained in both the amino acid and the lipotrope supplement and probably was responsible for reducing hepatocarcinoma incidence. Methionine has been found to have an anticarcinogenic effect in other studies and also to block the depletion of hepatic folate stores that is induced by N-nitrosodiethylamine. Interactions between carcinogens, S-adenosylmethionine, and folate may be significant in hepatic or other tissue carcinogenesis. One of more hepatic microsomal oxidases were depressed in rats fed any of the high-fat diets but were not correlated with tumor incidence.
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PMID:Reduction of N-nitrosodiethylamine carcinogenesis in rats by lipotrope or amino acid supplementation of a marginally deficient diet. 6 28

Hepatic levels of S-adenosylmethionine (AdoMet), of glutathione, and of the microsomal enzymes p-nitroanisole demethylase and benzo(a)pyrene hydroxylase were measured in male and female rats fed a diet marginally deficient in choline and methionine and void of folic acid (lipotrope deficient) or an adequate diet for 0 to 14 weeks with and without added 2-acetylaminofluorene (AAF). The urinary metabolites of AAF were determined throughout the experimental period. After 2 to 4 weeks of dietary administration, the hepatic AdoMet levels were 43% lower in male rats fed the lipotrope-deficient diet than in male rats fed the lipotrope-adequate diet; no differences were found in hepatic AdoMet of females fed the lipotrope-deficient or lipotrope-adequate diets for 2 to 14 weeks. Administration of AAF to lipotrope-deficient female rats for 2 weeks led to a transient decrease in hepatic levels of AdoMet. The administration of AAF for 2 to 14 weeks did not significantly affect hepatic AdoMet in female rats fed the lipotrope-adequate diet or in male rats fed either diet. Female rats fed the lipotrope-deficient diet and treated with AAF excreted decreased proportions of N-hydroxy-2-acetylaminofluorene and increased proportions of 5-hydroxy-2-acetylaminofluorene in their urine. However, the urine of lipotrope-deficient male rats treated with AAF contained increased proportions of N-hydroxy-2-acetylaminofluorene and decreased levels of 5-hydroxy-2-acetylaminofluorene. The urinary excretion of 7-hydroxy-2-acetylaminofluorene by male and female lipotrope-deficient rats treated with AAF was generally similar to that in lipotrope-adequate rats. The lipotrope-deficient diet did not appear to alter the hepatic levels of glutathione, p-nitroanisole demethylase, or benzo(a)pyrene hydroxylase activity was lower in the livers of lipotrope-deficient male rats treated with AAF for 8 to 14 weeks than in the livers of lipotrope-deficient rats not receiving the carcinogen. The altered metabolism of AAF correlated well with the previously reported effects of a marginal lipotrope deficiency on AAF carcinogenesis.
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PMID:The effects of a marginally lipotrope-deficient diet on the hepatic levels of S-adenosylmethionine and on the urinary metabolites of 2-acetylaminofluorene in rats. 6 17

Nonimmunological defenses are very diverse in type. Some are directed against already transformed cells and belong to mechanisms of containment. Others exert a surveillance by preventing or inhibiting initial events of carcinogenesis. Chalones and oncolytic factors in sera and exudates are agents of containment. Under appropriate circumstances, the autoxidation of thiols and the formation of mixed disulfides lead to destruction of tumor cells in vitro and in vivo. Both processes involve the generation of superoxide radicals and of hydrogen peroxide which, in turn, activate the peroxide:peroxidase:halide system. Thiol:disulfide ratios and interchange codetermine the antioxidative activity of cellular membranes, thus bearing on carcinogenesis. Many aliphatic and aromatic antioxidants are endowed with anticarcinogenic properties. The fact that they are inhibitors of free radical processes corroborates the increasingly evident role of free radicals in carcinogenesis. Endogenous antioxidants and exogenous ones in foods are agents of surveillance. Antioxidant activity, linked with the ergastoplasm, points to a homeostatic mechanism that prevents self-accelerating chain reactions from leading to membrane damage or to carcinogenesis. Carcinogens can also be inactiviated by microsomal enzymes belonging to an overall mechanism of detoxification. Activity levels of these systems depend on diet and state of nutrition. They may be naturally very low, but they can be increased with various inducers.
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PMID:Nonimmunological host defenses: a review. 17 22

Biochemical data provide good evidence of a lack of acid and alkaline RNase activities in ascites tumour cells. Analyses of whole solid tumours appear of doubtful value, but fractionation studies reveal RNase deficiencies in mitochondrial fractions whereas inconsistent results are reported for microsomal fractions. Nuclei, nucleoli, and ribosomes isolated from tumours show relatively weak activities. Large variations are noted in determinations on purified lysosomes. Histochemical analyses by two different approaches demonstrate a multifocal loss of RNase activities in preneoplastic tissues, a lack of activities in cancer cells, and the presence of appreciable activities in stromal tissue and necrotic areas of tumours. These results suggest that RNase activities found in homogenates and cellular fractions of heterogeneous tumours may derive mainly from stromal cells, phagocytes, and extracellular fluids of necrotic areas. A close correlation seems to exist between activation of RNases and tumour regression. A large variety of therapeutic agents induce increases in tumour RNase activities whereas ineffective agents do not. The activation of RNases precedes obvious regression and apparently represents de novo synthesis of RNases in cancer cells. It emerges from these studies that loss of RNase activities could represent a critical event in carcinogenesis, that RNase deficiencies would persist in cancer cells, and that RNase activation would be closely associated with tumour regression. Losses of RNase activities in preneoplastic tissues are followed by changes in the properties of cytoplasmic RNA probably due to alterations in ribosomes in areas of neoplastic transformation. Deficiencies in the RNase system could be the source of abnormalities in cellular RNA or RNA-containing particles that would lead to neoplasia.
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PMID:Ribonucleases and neoplasia. 18 16

A microsomal butyrylesterase (L-I) was purified from the livers of male W rats treated with phenobarbital, and an antiserum against this purified L-I was raised in a rabbit. By the Ouchteriony double-diffusion test, a precipitin line was observed between the anti-L-I antiserum and each Triton X-100 extract of livers during development, regeneration after partial hepatectomy, and carcinogenesis and of hyperplastic nodules and hepatomas, all of which revealed L-I in their esterase isoenzyme patterns. These precipitin lines exhibited esterase activity. The fusion of the lines of these tissue extracts and that of the purified L-I indicated the presence of an antigen site common to their esterases. The extracts of adult and fetal livers and also of hepatomas resembling fetal liver in the esterase isoenzyme pattern did not produce a precipitin line with anti-L-I antiserum.
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PMID:A microsomal butyrylesterase appearing in rat livers during development, regeneration, and carcinogenesis, and after phenobarbital treatment. 28 21

Liver enlargement is frequently reported in studies on the short-term toxicity of chemicals. In many such studies no histological evidence of damage is present but biochemically there is often an increased microsomal enzyme activity (MEA) which is interpreted to represent a type of work hypertrophy. In a few instances, the MEA in the enlarged liver is either normal or less than normal. In such instances histochemical evidence of liver damage (depression of G-6-Pase and autophagy) is found. A compound which produced the latter changes is Ponceau MX. When administered for up to 21 months at a dose-level which produces biochemical and histochemical evidence of liver injury, a series of changes were observed consisting of progerssive diminution of MEA, areas of glycogen accumulation and centrilobular fatty change and these were followed first by nodular hyperplasia and then by frank carcinoma. The protective effect of increased MEA in carcinogenesis was shown by the reduction in tumour incidence on the administration of phenobarbitone simultaneously with acetylaminofluorene, 4-dimethyl aminoazo benzene and diethylnitrosamine. But no such protective effect is seen if the phenobarbitone is administered after treatment with these carcinogens. In fact the number of tumours is enhanced presumably due to preferential stimulation of the growth of malignant cells.
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PMID:Liver growth and tumorigenesis in rats. 28 28

Neither immunologic nor genetic concepts of carcinogenesis have yet been decisively confirmed, and epigenetic theories, as formulated so far, are either non-predictive or insufficiently consistent with morphologic and experimental evidence. Computing data, concerned with carcinogenic mechanisms and neoplastic changes at the level of the endoplasmic reticulum, may lead to a new coherent understanding of tumor pathogenesis. Carcinogenic agents initiate biophysical perturbations, chemical alterations and conformational transitions in the membrane lattice of the endoplasmic reticulum. Foremost among the resulting neoplastic changes is an increased, irreversible separation of polyribosomes from membranes of the ergastoplasm. The carcinogenic process, apparently, deletes a protein required for polysome attachment. Since microsomal cytochromes can be synthesized by membrane-bound polysomes only, the translation of genetic information for their biosynthesis is irreversibly restricted. A similar, self-perpetuating deficiency may be postulated for the polysome attachment protein. Activities, depending on cytochromes P-450 and b5, are hampered, e.g. those of the monoxygenase system. Cholesterogenesis is derepressed. Ratios of phospholipids/cholesterol are decreased, and lipid-protein complexes, altered both in structure and function. Another distinct effect of the membrane-polysome separation is the unmasking of thiol-disulfide exchange enzymes which, in turn, stimulate the biosyntehsis of proteins and of deoxyribonucleotides involved in cell replication.
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PMID:Microsomal aspects of carcinogenesis and neoplasia. 37 54

The effect of paraoxon, a microsomal deacetylase inhibitor, on the mutant genicity of 2-acetylaminofluorene (AAF) by liver homogenates was compared between the AAF carcinogenesis-resistant guinea pigs and the susceptible mice and rats. The mutagenicity of AAF was mostly abolished by paraoxon, not only in the 3 kinds of untreated animals but also in guinea pigs treated with a combination of phenobarbital and 5,6-benzoflavone, whereas about 50% of the mutagenicity was resistant to paraoxon in treated mice and rats. We suggest that microsomal deacetylase activity is crucially involved in the mutagenic activation of AAF by guinea pig liver homogenates, while the enzyme activity other than the deacetylase activity is also important in the activation by liver homogenates from treated mice or rats.
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PMID:Differential effect of a microsomal deacetylase inhibition on the mutagenicity in Salmonella typhimurium of 2-acetylaminofluorene by liver homogenates of guinea pigs, mice and rats. 39 79

The effect of portacaval shunt on hepatocarcinogenesis was studied in rats fed 3'-methyl-4-dimethylaminoazobenzene. Portacaval anastomosis resulted in a decrease of hepatocarcinogenesis as reflected by a delay in the early peak of alpha-fetoproteins, an absence of late appearance of alpha-fetoproteins, and a significantly lower incidence of tumors than in nonshunted rats. Reduction of hepatocarcinogenesis in shunted rats was associated with a decrease of the binding of 3'-methy-4-dimethylamioazobenzene metabolites to liver proteins. This effect seemed to be related to modifications of carcinogen-metabolic pathways. While the detoxifying azoreductase activity was not affected by portal diversion, the activating pathway leading to the binding of 4-dimethylaminoazobenzene metabolites to DNA, a major step for cell carcinogenesis that is mediated by microsomal enzymes, was decreased in shunted rats to about 50 percent of control values. The decrease of liver weight that occurred in shunted rats without loss of body weight produced a very significant reduction of the total capacity of liver to activate 4-dimethylaminoazobenzene while the total capacity of detoxification remained unchanged. This could be a direct consequence of portacaval anastomosis, as has been shown for other microsomal enzymes.
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PMID:Modifications of 3'-methyl-4-dimethylaminoazobenzene carcinogenesis of rat liver and carcinogen metabolism by portacaval anastomosis. 41 69


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