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

The ability of the highly reactive aldehyde acrolein to affect growth, membrane integrity, differentiation, and thiol status and to cause DNA damage has been studied at serum- and thiol-free conditions using cultured human bronchial epithelial cells. Acrolein markedly decreases colony survival at 3 microM whereas about 10-fold higher concentrations are required to increase membrane permeability, measured as uptake of trypan blue dye. Acrolein at micromolar concentrations also causes epithelial cells to undergo squamous differentiation as indicated by decreased clonal growth rate, dose-dependent increased formation of cross-linked envelopes, and increased cell planar surface area. Acrolein causes a marked and dose-dependent cellular depletion of total and specific free low-molecular-weight thiols as well as protein thiols. Exposure to acrolein did not cause oxidation of glutathione indicating that thiol depletion occurred by direct conjugation of reduced glutathione to acrolein without concomitant generation of active oxygen species. Furthermore, acrolein is genotoxic and causes both DNA single strand breaks and DNA protein cross-links in human bronchial epithelial cells. The results indicate that acrolein causes several cytopathic effects that relate to multistage carcinogenesis in the human bronchial epithelium.
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PMID:Pathobiological effects of acrolein in cultured human bronchial epithelial cells. 334 53

Chloral (trichloroacetaldehyde), the major metabolite of trichloroethylene (TCE), was investigated for its potential to form DNA-protein cross-links (DPX), a lesion produced by other aldehydes. Chloral did not form DPX in rat liver nuclei at concentrations up to 250 mM for 30 min at 37 degrees C, while chloroacetaldehyde (47 mM) and acetaldehyde (200 mM) did form cross-links. Experiments with the aldehyde-trapping reagents thiosemicarbazide and semicarbazide showed that chloral did not react, in contrast with aldehydes that form DPX. This indicates a very strong hydration of chloral. Mice given 800 mg/kg [14C]chloral after pretreatment with 1500 mg/kg TCE for 10 days had no detectable covalent binding of 14C to DNA in the liver. These results do not support a genotoxic theory of carcinogenesis for TCE mediated through chloral.
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PMID:Mechanistic studies on chloral toxicity: relationship to trichloroethylene carcinogenesis. 340 60

Six alkylnitrosamino ethanols (R-N(NO)-CH2CH2OH; R = Me, nBu, sBu, iBu, tBu, HOCH2CH2-), including the potent carcinogen N-nitrosodiethanolamine, have been shown to undergo efficient liver alcohol dehydrogenase catalyzed oxidation to their corresponding alpha-nitrosamino aldehydes. Five structurally representative nitrosamino-ethanals (R-N(NO)CH2CHO, R = 4-ClC6H4-, CH3-, nBu-, tBu-, HOCH2CH2-) have been synthesized. Each of these compounds demonstrates the unusual property of facile transnitrosation to a secondary amine. Transnitrosation to dimethylamine, pyrrolidine, morpholine and N-methylaniline has been shown. This reaction occurs rapidly at room temperature in organic solvents but is somewhat slower in aqueous buffer due to extensive equilibrium formation of gem diols by hydration of the aldehyde group. In aqueous media the transnitrosation rate increases with increasing pH from 7 to 9 and does not occur at pH 4. Transnitrosation to primary amines results in deamination (benzylamine----benzyl alcohol). The transnitrosation reaction is accompanied by the formation of imines of glyoxal (R - N = CH - CH = N - R) which appear as primary amines and glyoxal in aqueous solution. Other products have also been characterized as well. These chemical and biochemical data, taken together with results in other laboratories, provide strong support for our hypothesis that certain beta-oxidized nitrosamines can be activated to proximate or ultimate carcinogens by biochemical oxidation to produce highly reactive nitrosamines.
Carcinogenesis 1987 Jul
PMID:Nitroso transfer from alpha-nitrosamino aldehydes: implications for carcinogenesis. 359 27

Acetaldehyde and formaldehyde have been found to induce nasal cancer in two species of rodents. To understand the mechanism of carcinogenesis by acetaldehyde, studies were carried out to determine whether acetaldehyde can react with DNA in target tissues of the rat nasal cavity. When fresh homogenates of the nasal respiratory mucosa were incubated with acetaldehyde (distilled under N2) at concentrations of 10, 100, or 500 mM, followed by solubilization and extraction with a strongly denaturing aqueous-immiscible organic solvent mixture, a decrease was observed in the amount of DNA partitioned into the aqueous phase at the two higher acetaldehyde concentrations. The absent DNA was recovered from the interfacial layer by proteolytic digestion. Similarly, incubation of calf thymus nucleohistones with acetaldehyde (100, 300, Similarly, incubation of calf thymus nucleohistones with acetaldehyde (100, 300, or 1000 mM) or with formaldehyde (10, 30, or 100 mM) followed by precipitation of the DNA with H2SO4 and analysis of the supernatants by sodium dodecyl sulfate-polyacrylamide gel electrophoresis resulted in concentration-dependent decreases in the quantities of histone proteins released from the DNA. These results indicate that acetaldehyde as well as formaldehyde can form DNA-protein crosslinks in vitro. A single 6-hr exposure of male Fischer-344 rats to acetaldehyde (100, 300, 1000, or 3000 ppm) resulted in a significant increase relative to air-exposed controls in the percent interfacial DNA from the nasal respiratory mucosa at concentrations equal to or greater than 1000 ppm. No increase in the interfacial DNA from the olfactory mucosa was detected after a single 6-hr exposure (1000 or 3000 ppm), but a significant increase was found in rats hr/day for 5 days) to acetaldehyde (1000 ppm). Thus, evidence has been obtained hr/day for 5 days) to acetaldehyde (1000 ppm). Thus, evidence has been obtained for the formation of DNA-protein crosslinks by acetaldehyde in target tissues of the rat nasal cavity at concentrations similar to those that induced nasal cancer.
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PMID:Decreased extractability of DNA from proteins in the rat nasal mucosa after acetaldehyde exposure. 369 37

Nitrosatable precursors of mutagens that show mutagenicity to Salmonella typhimurium TA100 without S9 mix after treatment with nitrite at pH 3 were found in various foods. From Chinese cabbage, three indole compounds, indole-3-acetonitrile, 4-methoxyindole-3-acetonitrile, and 4-methoxyindole-3-aldehyde, were identified as mutagen precursors. 1-Methylindole and 2-methylindole, which are present in cigarette smoke showed strong mutagen precursor activity. Escherichia coli WP2 uvrA/pKM101 is more sensitive than S. typhimurium TA100 to nitrosatable precursors in soy sauce after treatment with 1-3 mM nitrite. The mutagenicity of soy sauce towards E. coli WP2 uvrA/pKM101 is partly explained by 1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (MTCA) and tyramine reported previously. Oral administration of soy sauce and nitrite to male Fischer 344 rats for 2 years induced basal cell proliferation of the forestomach and intestinal metaplasia of the glandular stomach, but did not induce cancers in any organ. 3-Diazotyramine, a mutagenic nitrosation product of tyramine that is present at high concentrations in various foods induced squamous cell carcinomas of the oral cavity of rats when given in their drinking water. The carcinogenesis by N-benzylmethylamine, a nitrosatable precursor and nitrite was prevented by thioproline.
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PMID:Nitrosatable precursors of mutagens in vegetables and soy sauce. 391 6

Administration of the hepatotoxin and carcinogen, inorganic hydrazine, to rodents results in the formation of 7-methylguanine and O6-methylguanine in liver DNA; co-administration of [methyl-14C]methionine or [14C]formate with the hydrazine labels the methylguanines, suggesting involvement of the 1-carbon pool in the methylation process. The present study investigates the proposal that the methylation mechanism involves reaction of hydrazine with endogenous formaldehyde to yield formaldehyde hydrazone, which could be metabolized to the potent methylating agent diazomethane. Hamsters were pretreated with methanol, ethanol or cyanamide to alter the endogenous hepatic aldehyde levels prior to administration of hydrazine. Formaldehyde levels were refractory to the pretreatments; hepatic acetaldehyde levels were increased, but hydrazine administration under such conditions did not result in the formation of ethylated guanines in DNA. Methanol and ethanol inhibited hydrazine-induced methylation of DNA. Hydrazine incubated with liver S9 fraction and calf thymus DNA induced the formation of 7-methylguanine and O6-methylguanine when formaldehyde was present in the incubation system; substitution of formaldehyde with acetaldehyde in the incubation medium did not result in any detectable alkylation of DNA. Both liver microsomal and cytosolic fractions demonstrated heat-labile activity in supporting the hydrazine-induced methylation process. Tetraformyltrisazine, or a similar reaction product of hydrazine and formaldehyde, may be a more important intermediate than formaldehyde hydrazone in the hydrazine-induced methylation of DNA.
Carcinogenesis 1986 Mar
PMID:The role of formaldehyde in hydrazine-induced methylation of liver DNA guanine. 394 26

The activities of aldehyde dehydrogenases using benzaldehyde and propionaldehyde as substrates and NADP and NAD as coenzymes were determined in normal liver, hepatocyte nodules and hepatocellular carcinomas from male Wistar rats. Hepatocyte nodules were produced by intermittent exposure of rats to 0.05% 2-acetylaminofluorene or by initiation with diethylnitrosamine followed by selection using 2 weeks of dietary exposure to 0.02% 2-acetylaminofluorene and partial hepatectomy. The activities of propionaldehyde:NAD and benzaldehyde:NADP aldehyde dehydrogenases were increased in hepatocyte nodules of all types as well as in most hepatocellular carcinomas. The most prominent elevation of enzyme activity was found in the cytosol of persistent hepatocyte nodules (35-60 times) and some hepatocellular carcinomas (92 times) using benzaldehyde and NADP. The benzaldehyde:NADP aldehyde dehydrogenase activity varied considerably between different nodules suggesting the existence of a subpopulation of hepatocyte nodules with very high enzymatic activities. The activity of propionaldehyde:NAD aldehyde dehydrogenase activity as well as of gamma-glutamyltransferase did not show substantial internodular variations. The activity of benzaldehyde:NADP aldehyde dehydrogenase in individual carcinomas investigated in these experiments varied extensively. The data did not support the idea that all hepatomas had been developed from pre-neoplastic nodules with very high activity of this enzyme.
Carcinogenesis 1985 Dec
PMID:Aldehyde dehydrogenase activities in hepatocyte nodules and hepatocellular carcinomas from Wistar rats. 406 45

Lipid peroxidation aldehydes of the 4-hydroxy-alpha, beta-unsaturated type, as well as the tobacco-smoke related alpha, beta-unsaturated aldehyde, acrolein, were highly cytotoxic and decreased the intracellular thiol content in cultured human bronchial fibroblasts after treatment with micromolar concentrations. In comparison, formaldehyde and acetaldehyde were less toxic and 100- to 300-fold higher doses were required to affect cell survival or thiol levels. The unsaturated aldehydes also markedly inhibited the DNA repair enzyme O6-methylguanine-DNA methyltransferase known to have a cysteine residue in its active site, but had no effect on the activity of uracil-DNA glycosylase. Our results indicate that reactive aldehydes of either exogenous or endogenous origin have direct cytotoxic effects and may also make cells more susceptible to other toxic chemicals due to an impairment in cellular defense mechanisms, e.g., DNA repair and detoxification by systems requiring glutathione.
Carcinogenesis 1985 Dec
PMID:Cytotoxicity, thiol depletion and inhibition of O6-methylguanine-DNA methyltransferase by various aldehydes in cultured human bronchial fibroblasts. 406 50

A potent tumour promoter on mouse skin, phorbol-9-myristate-9a-acetate, induces certain clones of Friend erythroleukemia cells to become adhesive to the surface of tissue culture dishes, whereas in the absence of this compound, these cells grow in suspension. We have quantitatively tested 20 other phorbol esters and related compounds for this effect. When the results are expressed as the concentrations of compounds which show half-maximum effect on cell adhesion, the decreasing order of potency is: phorbol-9-myristate-9a-acetate (3.6 x 10(-10) M) approximately equal to gnilatimacrin greater than milliamine A approximately equal to phorbol-9,9a-didecanoate approximately equal to mezerein approximately equal to gnidilatin approximately equal to ingenol-3,20-dibenzoate greater than phorbol-9-myristate-9a-acetate greater than phorbol-9,9a-dibutyrate approximately equal to phorbol-9-9a-dibenzoate greater than 4a-O-methyl-phorbol-9-myristate-9a-acetate greater than phorbol-9-myristate-9a-acetate-3-aldehyde greater than phorbol-9,9a-diacetate greater than 2,3-dihydrophorbol-9-myristate-9a-acetate. Phorbol, 4a alpha-phorbol-9,9a-didecanoate, phorbol-3,9,9a-triacetate, phorbol-9-myristate, phorbol-9-monoacetate and phorbol-9a-monoacetate were inactive in this assay when tested at concentrations as high as 1 microgram/ml (10(-6) M). None of these 20 compounds induced adhesion when they were tested with a variant clone of Friend erythroleukemia cells which is resistant to the induction of adhesion and several other effects of phorbol-myristate-acetate. When the relative potencies of these compounds in the adhesion assay were compared to available in vivo data on tumour promoting activity on mouse skin, there was, in general, a good qualitative correlation. A better but not perfect quantitative correlation was obtained when the results from the adhesion assay were compared with reported inflammatory activity on mouse ear. When several other tumour promoters and cocarcinogens which differ structurally from the phorbol esters and related plant diterpenes were tested, none of these induced adhesion in this assay.
Carcinogenesis 1981
PMID:Induction of erythroleukemia cell adhesion by plant diterpene tumour promoters: a quantitative study and correlation with in vivo activities. 694 62

A significant change in hepatic aldehyde dehydrogenase activity has been observed in normal Sprague-Dawley rat liver during the promotion phase of hepatocarcinogenesis induced by brief feeding of 2-acetylaminofluorene (2-AAF) followed by tumor promotion using dietary phenobarbital (PB) exposure. Animals receiving only 2-AAF or PB do not possess this new aldehyde dehydrogenase activity. The phenotype is characterized by the appearance of a new cytosolic isozyme kinetically, electrophoretically and immunochemically distinct from the normal liver aldehyde dehydrogenase isozymes and from aldehyde dehydrogenases inducible in 2-AAF-induced hepatomas. The new isozyme is NAD-dependent, disulfiram-sensitive and cross-reacts with antiserum to a normal liver aldehyde dehydrogenase inducible in several lines of rats by PB. However, the population of animals used in this study has been shown previously to be non-responsive to aldehyde dehydrogenase induction by dietary PB. Since no animals receiving only PB express this new isozyme, the carcinogen must play a significant role in its induction. Moreover, that not all animals receiving carcinogen and promoter possess the phenotype suggests this carcinogen/promoter interaction has a genetic basis.
Carcinogenesis 1982
PMID:Sequential 2-acetylaminofluorene--phenobarbital exposure induces a cytosolic aldehyde dehydrogenase during rat hepatocarcinogenesis. 709 12


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