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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1,N6-Ethenoadenine (epsilon A) and 3,N4-ethenocytosine (epsilon C) are formed when electrophilic vinyl chloride (VC) metabolites, chloroethylene oxide (CEO) or chloroacetaldehyde (CAA) react with adenine and cytosine residues in DNA. They were assayed for their miscoding properties in an in vitro system using Escherichia coli DNA polymerase I and synthetic templates prepared by reaction of poly(dA) and poly(dC) with increasing concentrations of CEO or CAA. Following the introduction of etheno groups, an increasing inhibition of DNA synthesis was observed. dGMP was misincorporated on CAA- or CEO-treated poly(dA) templates and dTMP was misincorporated on CAA- or CEO-treated poly(dC) templates, suggesting that epsilon A and epsilon C may miscode. The error rates augmented with the extent of reaction of CEO or CAA with the templates. Base-pairing models are proposed for the epsilon A.G. and epsilon C.T pairs. The potentially miscoding properties of epsilon A and epsilon C may explain why metabolically-activated VC and its reactive metabolites specifically induce base-pair substitution mutations in Salmonella typhimurium. Promutagenic lesions may represent one of the initial steps in VC- or CEO-induced carcinogenesis.
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PMID:Studies on the miscoding properties of 1,N6-ethenoadenine and 3,N4-ethenocytosine, DNA reaction products of vinyl chloride metabolites, during in vitro DNA synthesis. 701 Mar 14

Chloroacetaldehyde, a rearranged metabolic product of the human carcinogen vinyl chloride, reacts with the DNA-like polymers poly(dA-dT) and poly(dC-dG) to form etheno-adducts of the adenine and cytosine bases. These treated polymers, when used as templates for E. coli DNA polymerase I in an in vitro assay, show a decreased ability to direct DNA synthesis. At the same time, increased relative levels of non-complementary nucleotides are incorporated. With the poly(dA-dT) templates 1 dGMP residue is incorporated for every approx 60 ethenoadenine residues present whilst no increased misincorporation of dCMP was detected. With the poly(dC-dG) templates 1 misincorporation of dAMP or dTMP occurred in the presence of approx 30 and 80 ethenocytosine residues respectively. A nearest neighbour analysis shows that with the modified poly(dC-dG) templates the majority of the errors were incorporated opposite cytosine (or modified cytosine) bases.
Carcinogenesis 1981
PMID:The induction of errors during in vitro DNA synthesis following chloroacetaldehyde-treatment of poly(dA-dT) and poly(dC-dG) templates. 702 22

The reaction of chloroacetaldehyde, a reactive metabolic of the carcinogen vinyl chloride, with DNA produces in addition to the hitherto known adducts, 1,N6-ethenoadenine and 3,N4-ethenocytosine, an ethenoguanine adduct, namely N2,3-ethenoguanine. This adduct is formed in the reaction of chloroacetaldehyde with the free base as well. After DNA hydrolysis followed by isolation of this new adduct by h.p.l.c., its mass spectrum and fluorescence spectrum are identical with those published in the literature for the chemically synthesized N2,3-ethenoguanine. The formation of only this guanine derivative out of several theoretically possible reaction products allows the formulation of a reaction scheme. The absence of 7-(2-oxoethyl)-guanine, another recently detected DNa adduct of vinyl chloride, in chloroacetaldehyde-treated DNA suggests its origin from the other reactive metabolic of vinyl chloride, chloroethylene oxide. The potential of N2,3-ethenoguanine to lead to misincorporation of deoxythymidine monophosphate opposite of guanine and the high fluorescence of this adduct provide it with potentially high biological significance and ease of analytical monitoring.
Carcinogenesis 1982
PMID:Detection of N2,3-ethanoguanine in DNA after treatment with chloroacetaldehyde in vitro. 711 60

Hepatocarcinogens cause marked biochemical changes in the liver at short intervals after administration. The studies described were designed to investigate the effects of hepatocarcinogens and hepatotoxicants on the microsomal mixed function oxidase system. DT-diaphorase and epoxide hydrolase. Following 5 day p.o. treatment of male F-344 rats with aflatoxin B1 (AFB), 2-acetylaminofluorene (AAF), technical grade dinitrotoluene (DNT), or 2,4-diaminotoluene, microsomal cytochrome P450 dependent enzyme activities were depressed while epoxide hydrolase activity was markedly elevated (3-8 times control). Diethylnitrosamine (DEN) given at 5 mg/kg/day and DL-ethionine at 1000 mg/kg/day failed to increase epoxide hydrolase. 3-Methylcholanthrene, methylnitrosourea, carbon tetrachloride, bromobenzene and vinyl chloride all failed to increase epoxide hydrolase activity. Using 3 daily i.p. injections, dose-response relationships for increases in epoxide hydrolase were generated for the hepatocarcinogens. With the exception of p-dimethylaminoazobenzene (DAB) and DEN, the carcinogens studied produced log-linear dose response curves for increase in epoxide hydrolase. Both DEN and DAB caused increases in epoxide hydrolase but classical sigmoidal dose-response curves were not obtained. The order of potency for increasing epoxide hydrolase was AFB greater than AAF greater than 2,6-dinitrotoluene greater than 3'-methyl-N,N-dimethyl-4-aminoazobenzene greater than DNT greater than 2, 4-dinitrotoluene. The slopes of the linear portions of the log dose-response curves were not statistically different from the slope of the dose-response curve obtained with AAF suggesting that structurally diverse carcinogens elicit increases in epoxide hydrolase by a common mechanism.
Carcinogenesis 1982
PMID:Effect of hepatocarcinogens on epoxide hydrolase and other xenobiotic metabolizing enzymes. 711 69

Reaction of deoxyguanosine in glacial acetic acid with chloroethylene oxide, a proposed reactive metabolite of vinyl chloride, led to a single, strongly fluorescent product in nearly quantitative yield. The u.v. spectra indicated alkylation of N-7 of guanine, which was confirmed following reduction of the reaction product by sodium borohydride to 7-(2-hydroxyethyl)guanine, and the synthesis of the same modified guanine via a stereoselective 7-N hydroxy alkylation using 2,3-epoxy-1-propanol. In agreement with the expected structure 7-(2-oxoethyl)guanine reacted with the carbonyl specific reagent 2,4-dinitrophenylhydrazine (2,4-DNPH). However, its i.r. and proton n.m.r. spectra did not support the existence of a simple aldehyde group. Moreover, the 2,4-dinitrophenylhydrazone was labile, 7-(2-oxoethyl)guanine being produced when excess 2,4-DNPH was removed. This instability was interpreted as being due to the reversible formation of a hemiacetal ring between O6 of the guanine residue and the aldehyde carbon of the 2-oxoalkyl group resulting in O6,7-(1'-hydroxyethano)guanine. This conformation was supported by the occurrence in field desorption mass spectra of the ions of m/e = 175 and 292 which are interpreted as O6,7-ethenoguanine and O6,7-ethenodeoxyguanosine resulting from the elimination of H2O of the hydroxyethano residue. O6,7-(1'-hydroxyethano)guanine might be expected to cause faulty base pairing during replication of DNA, which may be the molecular basis of the carcinogenicity of vinyl chloride.
Carcinogenesis 1981
PMID:Modification of deoxyguanosine by chloroethylene oxide. 727 47

Chronic administration of several chemical carcinogens to laboratory animals induces a variety of tumours which arise from specific cell populations within the liver. In the rat, diethylnitrosamine induces hepatocellular carcinomas, dimethylnitrosamine induces both angiosarcomas and hepatocellular carcinomas, vinyl chloride primarily induces angiosarcomas, and 1,2-dimethylhydrazine induces malignant haemangioendotheliomas. One of the principal mechanisms thought to be involved in initiating carcinogenesis is the alkylation of specific sites on DNA, such as the O(6) position of guanine. Previous investigations of alkylation and repair have, however, analysed DNA prepared from whole liver. This approach does not localize alkylation or repair capacity in the different cell types which give rise to neoplasia. Furthermore, although hepatocytes account for more than 90% of the liver's mass, they only comprise 60-70% of its cells. The nonparenchymal cell (NPC) population, which consists almost entirely of endothelial and Kupffer cells, accounts for the remaining 30-40% and contains 10-20% of the DNA. Therefore, we decided to investigate the alkylation and repair of O(6)-and 7-methylguanine in the target and non-target cells following oral administration of 1,2-dimethylhydrazine. We report here that although initial alkylation was slightly less in NPCs, removal of O(6)-methylguanine was significantly slower. This led to a preferential accumulation of O(6)-methylguanine in NPC 24 h after administering a second daily dose. In contrast, 7-methylguanine decreased at similar rates, resulting in a 28-fold greater O(6)-methylguanine/7-methylguanine ratio in the target cell population.
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PMID:Differential repair of O(6)-methylguanine in DNA of rat hepatocytes and nonparenchymal cells. 743 20

Angiosarcomas of the liver are rare, malignant cancers composed of neoplastic blood vessels. Human hapatic angiosarcomas have been associated with liver cirrhosis or exposure to vinyl chloride, Thorotrast or arsenic. A recent analysis of six hepatic angiosarcomas associated with vinal chloride exposure found three mutations and all were A:T --> T:A transversions, which are otherwise uncommon in human cancers. To test the specificity of this mutation spectrum, we analyzed 21 hepatic angiosarcomas not associated with vinyl chloride exposure. Four cases were exposed to Thorotrast, none had a history of arsenic exposure and the rest were sporadic. Exons 5-8 of the p53 gene were amplified by polymerase chain reaction, and the products were sequenced directly. Two G:C --> A:T transitions were found in two tumors: TGCstop in codon 136. Neither mutation was associated with Thorotrast exposure. These data indicate that p53 mutations are uncommon in sporadic hepatic angiosarcomas (2/21, 9%), and the mutational profile is consistent with endogenous mechanisms. Both features support the evidence linking vinyl chloride exposure to hepatic angiosarcomas containing an increased frequency of p53 mutations with a mutational spectrum (i.e. A:T --> T:A transversions) characteristic of chloroethylene oxide, a carcinogenic metabolite of vinyl chloride.
Carcinogenesis 1995 Nov
PMID:p53 mutations in primary hepatic angiosarcomas not associated with vinyl chloride exposure. 758 14

The etheno-bridged exocyclic DNA adducts 1,N6-ethenodeoxyadenosine (epsilon dA) and 3,N4-ethenodeoxycytine (epsilon dC) can be formed by several structurally diverse carcinogens and mutagens that include vinyl chloride and urethane. In order to investigate the occurrence and persistence of these adducts in rodents exposed to such DNA-damaging agents, an ultra-sensitive detection method has been developed. It is based on immunoaffinity purification of the etheno adducts and subsequent 32P-postlabelling followed by separation as 5'-monophosphates on polyethyleneimine-cellulose-coated thin-layer plates. Normal nucleotides in the DNA samples were quantitated by HPLC. Optimal conditions for enzymatic hydrolysis of DNA are described: deoxyuridine 3'-monophosphate was used as internal standard to correct for labelling efficiency of the etheno adducts. The method had a detection limit of 25 amol of epsilon dA and epsilon dC for a 50 micrograms DNA sample. Using this technique, analysis of liver DNA from humans with unknown exposure revealed the presence of epsilon dA and epsilon dC residues in the range of 0-27 adducts per 10(9) parent bases. Liver DNA obtained from untreated mice and rats was also shown to contain similar low but variable levels of these etheno adducts. In vitro studies indicated that these promutagenic DNA lesions could arise from endogenously formed lipid peroxidation products.
Carcinogenesis 1995 Mar
PMID:1,N6-ethenodeoxyadenosine and 3,N4-ethenodeoxycytine in liver DNA from humans and untreated rodents detected by immunoaffinity/32P-postlabeling. 769 21

3,N4-Etheno, 3,N4-ethano, and 3-(2-hydroxyethyl)derivatives of 2'-deoxycytidine arise in mammalian DNA that has been exposed to the metabolic products of either vinyl chloride or the antitumor drug bis(chloroethyl)nitrosourea. These chemically-related adducts are thought to be associated with both mutagenesis and carcinogenesis. In this paper we report reliable syntheses of these deoxynucleosides and incorporation of the latter into oligodeoxynucleotides by the phosphoramidite route, using automated methods. It was found that 3-(2-hydroxyethyl)-2'-deoxycytidine is unstable in aqueous solution and undergoes an autoinduced hydrolysis to 3-(2-hydroxyethyl)-2'-deoxyuridine. The rate of this hydrolysis was found to be pH-dependent, having a maximum around pH 8, and a half-life of approximately 5 h. At higher or lower acidities, the reaction rate falls, indicating that the process involves a general acid-base catalysis. Thus in this case, oligomers were obtained that possessed 3-(2-hydroxyethyl)-2'-deoxyuridine residues, rather than the cytidine analogue. It is likely that the former represents the longer-lived species in DNA under physiological conditions. Representative oligomers containing these chemical lesions were analyzed by mass spectrometric and enzymatic degradation methods to confirm their structures.
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PMID:Synthesis of 3,N4-etheno, 3,N4-ethano, and 3-(2-hydroxyethyl) derivatives of 2'-deoxycytidine and their incorporation into oligomeric DNA. 770 59

Vinyl chloride is a DNA-damaging carcinogen which induces liver angiosarcomas in humans and animals. Activation of the Ki-ras 2 gene by a GC-->AT transition at the second base of codon 13 in human liver angiosarcomas associated with occupational exposure to vinyl chloride has been reported recently. In order to compare the molecular pathways of carcinogenesis in humans and animals, Sprague-Dawley rats were exposed to vinyl chloride and hepatic tumors, including two hepatocellular carcinomas and five liver angiosarcomas, were investigated for mutations at codons 12, 13 and 61 of the Ha-ras, Ki-ras and N-ras genes. High molecular weight DNA was amplified by the polymerase chain reaction and point mutations were analyzed by allele specific oligonucleotide hybridization, direct sequencing of polymerase chain reaction products and sequencing after cloning. None of the tumors exhibited a mutation in codons 12, 13 and 61 of the Ki-ras gene, nor in codons 12 of the Ha-ras gene or 61 of the N-ras gene. However, an activating AT-->TA transversion at base 2 of codon 61 of the Ha-ras gene was detected in the two hepatocellular carcinomas. Mutations involving codon 13 (GGC-->GAC) and codon 36 (ATA-->CTA) of the N-ras A gene were detected in two liver angiosarcomas, suggesting that the nature of the ras gene affected by a given carcinogen depends on host factors specific to cell types. Several additional base pair substitutions were found in exon 1 of the N-ras B and C sequences. NIH 3T3 transfection assays and Southern blot analysis of DNA from transformed NIH 3T3 cells confirmed the presence of a dominant activated N-ras gene. These results emphasize the differences in the molecular pathways leading to tumors in humans and rats and within a given species between different cell types.
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PMID:Mutagenesis of ras proto-oncogenes in rat liver tumors induced by vinyl chloride. 792 62


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