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)

Fischer 344 male rats fed a choline-methionine deficient diet for from 13 to 24 months developed a 100% incidence of putative preneoplastic hepatocyte nodules and a 51% incidence of hepatocellular carcinoma. The addition of 0.8% choline chloride completely prevented the development of both the nodules and the cancer. The diet contained no added known carcinogen. Analysis of the deficient and supplemented diets revealed no detectable volatile nitrosamines or nitrosamides, nitrite, nitrate or malonaldehyde, less than 0.9 p.p.b. aflatoxin B1 and barely detectable levels of Ames positive material with one strain of Salmonella typhimurium. These findings indicate that a dietary deficiency of choline and methionine can be a major rate limiting factor in the development of liver cancer.
Carcinogenesis 1984 Oct
PMID:The induction of liver cancer by dietary deficiency of choline and methionine without added carcinogens. 648 58

Ethionine, the hepatocarcinogenic antimetabolite of methionine, was fed to rats in carcinogenic doses for 1-10 weeks. Levels of 5-methyldeoxycytidine (5-MC) in nuclear DNA and total cellular levels of S-adenosylmethionine (AdoMet) and S-adenosylethionine (AdoEt) were determined at 1, 5 and 10 weeks in livers of control and ethionine-treated animals. The percentage of deoxycytidine residues modified to 5-MC in hepatic DNA of ethionine-fed animals was the same as that in the control animals at 1 week but was 3.6% and 7.6% lower than that observed in control animals at 5 and 10 weeks, respectively. Significant levels of AdoEt, a DNA methylase inhibitor, as well as decreases in the levels of AdoMet were also observed in the livers of ethionine-fed animals. In a second study, the levels of 5-MC, AdoMet and AdoEt were determined in the pancreas, kidneys, testes and thymus of control rats and rats fed ethionine for 10 weeks. Only the testes, an organ known to be susceptible to the toxic effects of ethionine, showed a significant (p less than 0.02) decrease in 5-MC in response to ethionine feeding. AdoEt was present in all tissues studied, except thymus, but at lower levels than those observed in the liver. These results demonstrate that ethionine administration alone under conditions which cause tumors is sufficient for the production of hypomethylated DNA in the target organ and one extrahepatic tissue studied. Hypomethylation of hepatic DNA would appear to result from the accumulation of AdoEt coupled with the decreased levels of AdoMet.
Carcinogenesis 1984 Aug
PMID:Hypomethylation of DNA in ethionine-fed rats. 674 18

The possible role of alterations of histone methylation by ethionine in the mechanism of ethionine carcinogenesis was studied. In regenerating rat liver, histone synthesis was inhibited by only 20 to 30% with large doses of ethionine (0.75 to 1.0 mg/g body weight). The effect of ethionine on the in vivo methylation of histones was studied by giving 0.5 mg ethionine and [methyl-3H]methionine per g body weight. In vivo methylation of lysine was inhibited by 50%, whereas the arginine methylation was inhibited by 89%. The cellular localization of the methyltransferases and S-adenosyl-L-ethionine may be related to this differential effect. Utilizing an in vitro assay for protein-lysine and protein-arginine methyltransferases, we have demonstrated that the methyl-deficient histones are transported to the nucleus and with time lose their ability to accept methyl groups in vitro.
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PMID:Alteration of methylation patterns in rat liver histones following administration of ethionine, a liver carcinogen. 678 93

Treatment of human HL-60 promyelocytic leukemia cells with phorbol-12-myristate-13-acetate (PMA), a tumor promoter and inducer of differentiation, stimulated the incorporation of label from L-[methyl-3H]methionine into the cellular phospholipids. Such a stimulation of phospholipid methylation was not observed in an HL-60 cell variant that is resistant to phorbol ester-induced differentiation. Enhanced methylation of phospholipids was detected 6 h after treatment and reached a maximum level of about twice the control level at 24-48 h. The degree of phospholipid methylation was dependent on the phorbol ester dose. The stimulation in phospholipid methylation by PMA was confirmed by measuring the activity of phosphatidylethanolamine methyltransferase in cellular lysates. After 24 or 48 h of exposure, the enzyme activity was elevated in the HL-60 cell lysates but not in the resistant cells. Phospholipid methylation was also stimulated after treatment of the HL-60 cells with the phorbol diester phorbol-12,13-dibutyrate or teleocidin, which is not a phorbol ester compound. These two chemicals and PMA are tumor promoters and inducers of cell differentiation in the HL-60 cells. Phorbol-12,13-diacetate and 4-O-methyl PMA, which are not tumor promoters or inducers of cell differentiation in the HL-60 cells, did not stimulate phospholipid methylation. The possible role of enhanced phospholipid methylation in cell differentiation of the HL-60 by these chemicals is discussed.
Carcinogenesis 1982
PMID:The control of phospholipid methylation by phorbol diesters in differentiating human myeloid HL-60 leukemia cells. 681 75

Rat liver epithelial cells were grown in the presence of the hepatocarcinogen, DL-ethionine, for 12 weeks. The cells were then cultured for an additional 32 weeks in carcinogen-free medium. At approximately monthly intervals, the cells were tested for transformation by assaying their ability to grow in soft agar and to produce tumors when injected s.c. into irradiated syngeneic rats. After a total of 34 weeks in culture, cells treated with 7.5 mM DL-ethionine were transformed according to both criteria. The experiment was repeated using medium in which methionine was replaced by its metabolic precursor, homocysteine. The cells were treated for 12 weeks with L-ethionine and its metabolite, S-adenosyl-L-ethionine (L-AdoEt), then cultured in their absence in methionine-containing medium for an additional 24 weeks. After a total of 20 weeks in culture, cells treated with 0.375 mM L-ethionine and cells treated with 0.2 mM L-AdoEt produced tumors following their injection into animals. Positive growth in soft agar was observed 5 and 11 weeks later, respectively. A total of 31 weeks in culture was required before cells treated with 0.2 mM L-ethionine became tumorigenic. Furthermore, tumors resulting from the injection into animals of cells treated with 0.2 mM L-ethionine arose 8-10 weeks later than did the corresponding tumors arising from the cells treated with 0.2 mM L-AdoEt. Thus, the results indicate that AdoEt may be a proximal carcinogenic metabolite of ethionine.
Carcinogenesis 1983
PMID:Neoplastic conversion of rat liver epithelial cells in culture by ethionine and S-adenosylethionine. 682 6

The levels of S-adenosylmethionine (AdoMet) and of S-adenosylhomocysteine (AdoHcy) as well as the ratio of AdoMet/AdoHcy were determined in the liver, lungs, testes and kidneys of weanling male rats fed a commercial chow diet or 5 different amino acid-defined diets for 1-5 weeks. The amino acid-defined diets used were as follows: diet 1, supplemented with methionine, choline, folic acid and vitamin B12; diet 2, deficient in methionine and choline; diet 3, deficient in methionine alone; diet 4, deficient in choline alone; diet 5, deficient in methionine, choline, folic acid and vitamin B12. All methionine-deficient diets were supplemented with an equimolar dose of its metabolic precursor, homocystine. The animals were sacrificed after 1, 3 and 5 weeks of treatment. In animals fed either the chow diet or diet 1, liver was the organ found to contain the highest levels of AdoMet and AdoHcy. Similarly, in animals fed diet 1 or chow, the testes and lungs contained the lowest level of AdoMet, while the lungs contained the lowest levels of AdoHcy. In general, the tissue levels of AdoHcy and AdoMet in rats fed diet 1 were very similar to the corresponding values found in chow-fed rats. Diet 1 feeding, however, led to higher hepatic levels of AdoMet than did the administration of the chow diet. The administration of the methyl-deficient diets generally led to decreased hepatic AdoMet contents at 3 and 5 weeks; the methyl-deficient diets also led to increased AdoHcy contents and decreased AdoMet:AdoHcy ratios when compared with diet 1. Linear regression analysis showed a significant direct correlation between the observed hepatic AdoMet levels and the methyl content of the diet as well as an inverse correlation between hepatic AdoHcy levels and dietary methyl contents. Unlike liver, the lung and testes did not show any decrease in AdoMet content following feeding of the methyl-deficient diets. These tissues did show, however, early significant increases in AdoHcy contents and corresponding decreases in the ratios of AdoMet:AdoHcy. These changes were found to be proportional to the dietary methyl content. The renal contents of AdoMet, AdoHcy and the ratio of AdoMet/AdoHcy were unaffected by any of the diets administered except for diet 5. The administration of diet 5 to rats for 5 weeks led to a significant increase in renal AdoHcy. These results provide evidence indicating that dietary methyl insufficiency may exert its role in carcinogenesis through a decreased availability of AdoMet in vivo.
Carcinogenesis 1983 Aug
PMID:Tissue levels of S-adenosylmethionine and S-adenosylhomocysteine in rats fed methyl-deficient, amino acid-defined diets for one to five weeks. 687 50

The treatment of rats with hepatotoxic doses of hydrazine (NH2-NH2) induces the rapid formation of 7-methylguanine and O6-methylguanine in liver DNA. The methyl moiety in these reactions might be derived from the cellular S-adenosylmethionine pool because radioactivity administered to these rats as methionine rapidly appears in the DNA as methylated guanine. An increased incorporation of radioactivity into 5-methylcytosine was previously reported followed by subsequent suppression. This increased radiolabeling of 5-methylcytosine coincided with time of maximal DNA guanine methylation. To determine the nature of S-adenosylmethionine metabolism during the period of DNA methylation induced by hydrazine treatment, and to determine if the increased radiolabeling of 5-methylcytosine at this time reflected an actual increase in 5-methylcytosine synthesis, liver DNA synthesis and S-adenosylmethionine levels and turnover were assayed. Liver S-adenosylmethionine concentrations varied slightly between control rats and hydrazinetreated rats during the first five hours after hydrazine administration, and no difference was detectable in the incorporation of administered [3H]methionine into S-adenosylmethionine. Because S-adenosylmethionine specific radioactivity in hydrazine-treated rats was not different from control rats, the previously observed increased radiolabeling of 5-methylcytosine appeared to represent an actual increase in synthesis. This conclusion was supported by finding that incorporation of radioactive thymidine into DNA was also accelerated immediately following hydrazine administration, again followed by a decrease. 5-Methylcytosine sythesis, therefore, appears to follow DNA synthesis during hydrazine toxicity, and formation of 7-methylguanine and O6-methylguanine in liver DNA of hydrazine-treated rats occurs during a short period of increased DNA sythesis and 5-methylcytosine formation very early in hydrazine toxicity.
Carcinogenesis 1983 Aug
PMID:S-adenosylmethionine metabolism and DNA methylation in hydrazine-treated rats. 687 53

Tumor promoters are compounds which dramatically enhance the appearance of tumors when chronically applied after an initiating dose of a carcinogen. Initiators are generally considered mutagens while promoters have previously been shown not to induce either DNA damage or mutations. 2,4-Dinitrofluorobenzene (2,4-DNFB), a compound used in the identification of N-terminal amino acids of polypeptides, had been previously reported to be a tumor promoter in mouse skin, while other investigators have found it to be a mutagen in bacteria and yeast. To investigate this apparent discrepancy, we chose to study the carcinogenic potential of 2,4-DNFB utilizing various methods available in V79 Chinese hamster cells. 2,4-DNFB exposure did not result in any unscheduled DNA synthesis a measure of DNA excision repair, nor did it increase the frequency of sister chromatid exchanges in V79 cells either in the presence or absence of rat liver postmitochondrial supernatant (S-15). Forward mutations in V79 cells, either to ouabain or 6-thioguanine resistance, were not induced by 2,4-DNFB, in the presence or absence of S-15. 2,4-DNFB was, however, able to induce reversions in methionine-requiring E. coli auxotrophs in a dose-dependent fashion. Phylogenetic differences between lower organisms and mammals may account for this discordance. 2,4-DNFB was found to inhibit metabolic cooperation, in a dose dependent manner, in V79 cells. This property has previously been shown to be correlated with tumor promoting ability in mouse skin. Therefore, we conclude that the carcinogenic potential of 2,4-DNFB might reside in its ability as a tumor promoter and not as a carcinogenic initiator. Furthermore, these studies serve to illustrate the need for caution when extrapolating bacterial data for risk assessment in humans.
Carcinogenesis 1982
PMID:Evaluation of the carcinogenic potential of 2,4-dinitrofluorobenzene and its implications regarding mutagenicity testing. 703 54

The modulation of gene expression accompanying neoplastic transformation has been assessed by computerized microdensitometry or autoradiographic patterns of [35S]methionine labeled polypeptides separated by two-dimensional polyacrylamide gel electrophoresis. Nearly 1000 polypeptide species of parent diploid human fibroblasts (KD strain) and clonally-derived malignant fibroblasts (HUT-14 strain) were compared. HUT-14 fibroblasts express a mutation in one of the two functional beta-actin genes and possess properties that distinguish them as neoplastic cells. Of the 700 more abundant polypeptides measured, 13 were lost and 14 were gained following this neoplastic transformation. It is estimated that less than or equal to 2% of the genes expressing abundant polypeptides were either activated or shut off, but at least 32% were modulated quantitatively as a consequence of this neoplastic transformation. Classes of "highly variable" and "marginally variable" polypeptides were assigned. Among the "highly variable" polypeptides, two related species barely detectable in KD parental cells were synthesized at a 25-31-fold higher rate in the transformed cells, and the cell-associated and extracellular matrix forms of fibronectin were each diminished by greater than 90%. Principles emerging from this study may form a basis for interpretation of the role of individual genes in the expression of neoplastic characteristics of HUT-14 cells.
Carcinogenesis 1982
PMID:Changes in gene expression accompanying chemically-induced malignant transformation of human fibroblasts. 706 38

Nuclear protein methylation was studied in regenerating rat liver by giving [methyl-3H]methionine 45 h after partial hepatectomy. Ethionine, a liver carcinogen, has been shown to alter the methylation patterns in a basic protein (histone) fraction, as well as an acidic protein (non-histone) fraction present in a 0.25 N HCl nuclear extraction. The proteins present in the 0.25 N HCl extraction were separated by chromatography using a Bio-Rex 70 cation exchange column. Polyacrylamide gel electrophoresis and total amino acid analysis showed the first protein fraction contained acidic large molecular weight non-histone proteins, while the second fraction contained basic small molecular weight histone proteins. Both fractions were then hydrolyzed, and the amino acids chromatographed on an Aminex A-5 cation exchange column. The histones were found to contain epsilon-N-mono, di and trimethyllysine derivatives; whereas the non-histone fraction contained these lysine derivatives and additional basic amino acid identified as NG,NG-dimethylarginine. Ethionine (0.5 mg/g body weight) was found to inhibit in vivo methylation of lysine to form epsilon-N-mono, di and trimethyllysine, 46, 52 and 68%, respectively. The formation of NG,NG-dimethylarginine was inhibited by 85%. Ethylation of these proteins was also studied by giving [ethyl-3H]ethionine. After hydrolysis, the non-histones were found to contain a labeled lysine and arginine derivative, but in the histone fraction only labeled lysine was found.
Carcinogenesis 1982
PMID:Ethionine inhibits in vivo methylation of nuclear proteins. 709 6


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