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

It was previously reported that the properties of alcohol dehydrogenase of a rat hepatocellular carcinoma (Becker H-252), a tumor of intermediate growth rate, were different from those of the liver enzyme, suggesting different isozymes. To determine whether the degree of differentiation affected the isozyme of alcohol dehydrogenase, a fast-growing, poorly differentiated tumor and one that is well differentiated and of intermediate growth rate were studied. Alcohol dehydrogenase from Morris hepatoma 7288ctc, a fast-growing, poorly differentiated tumor, had properties similar to those found with the Becker-H-252 tumor, including a high Km for ethanol and acetaldehyde and the absence of substrate inhibition. By contrast, alcohol dehydrogenase from the well-differentiated Morris hepatoma 5123C had properties similar to those of the liver enzyme. Thus, alcohol dehydrogenase is another example of an enzyme the isozyme composition of which changes with neoplastic de-differentiation. Further studies, including gel electrophoresis, substrate specificity patterns, and interaction with antibodies to alcohol dehydrogenase, are required to determine the factors responsible for the biochemical defect that occurs at the molecular level during carcinogenesis and whether the alcohol dehydrogenase isozymes in the Becker H-252 and Morris 7288ctc hepatomas are identical. A survey of several normal rat tissues revealed that only the stomach contains this unique isozyme of alcohol dehydrogenase.
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PMID:Kinetic properties of alcohol dehydrogenase in hepatocellular carcinoma and normal tissues of rat. 17

The formation and stability of DNA-protein crosslinks (DPXLs) formed by incubation of pUC13 plasmid DNA and calf thymus histones with 1-100 mM acetaldehyde was studied using a filter binding assay. DPXLs were formed at a rate of 127 DPXLs/plasmid molecule/mmol acetaldehyde in a reaction containing 1 microgram of histones and 0.33 microgram of DNA at 37 degrees C for 1 h. Acetaldehyde-induced DPXLs were unstable at 37 degrees C, with loss of up to 75% by 8 h. Crosslink formation was significantly higher at lower pH, with 3- and 2-fold higher levels at pH 5 and 6 respectively than at pH 7.5. Induction of DPXL formation by 1-100 mM vinyl acetate in the presence of rat liver microsomes was observed at 37 degrees C over 3 h. DPXL accumulation followed S-phase enzymatic kinetics, with a rate of formation of 1.1 DPXLs/plasmid molecule/mmol vinyl acetate/microgram microsomal protein/microgram DNA. Vinyl acetate was unable to cause formation of DPXLs in the absence of microsomes. A carboxylesterase inhibitor, bis-(p-nitrophenyl) phosphate, was able to block DPXL formation by vinyl acetate and microsomes. This work supports the hypothesis that DPXL formation by vinyl acetate requires microsomal metabolism to acetaldehyde, which is the active crosslinking agent.
Carcinogenesis 1992 Nov
PMID:Reaction kinetics of DNA-histone crosslinking by vinyl acetate and acetaldehyde. 142 81

A mixture of 100 mM creatinine and 100 mM L-phenylalanine was heated at 60 or 37 degrees C in the presence of sugar or aldehyde. A mutagen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) formed in the model system was determined by reversed-phase HPLC. Any sugars tested induced the formation of PhIP when heated at 60 degrees C, though PhIP was not detected in a mixture without sugar. Among the sugars tested, D-erythrose and D-glyceraldehyde were more productive than pentose (D-arabinose and D-ribose) and hexose (D-glucose and D-galactose) in the yield of PhIP. Moreover, PhIP was formed even when a mixture of creatinine, L-phenylalanine and D-glucose or D-ribose was incubated at 37 degrees C for a long time. Both formaldehyde and acetaldehyde also induced the formation of PhIP, though PhIP was not detected in a mixture without sugar or aldehyde even when heated at 100 degrees C. These results indicate that PhIP can be formed at low-temperature heating and that either sugar or aldehyde is essential for PhIP formation in the model system. Our data also suggest that aldehydes may be a key reactant in the formation of PhIP in aqueous heating of the mixture of creatinine and L-phenylalanine.
Carcinogenesis 1992 May
PMID:Formation of PhIP in a mixture of creatinine, phenylalanine and sugar or aldehyde by aqueous heating. 158 94

N-Methyl N-formlhydrazine (1), a component of the mushroom Gyromitra esculenta, is a carcinogen. Its mode of action, however, is poorly understood. To determine the intermediates that may form during the metabolism of 1, we examined its oxidative chemistry, identified the products and inferred the intermediates on the basis of these products. The incubation of 1 with rat liver microsomes was also studied and the metabolites determined and quantified. Both the chemical and the microsome-mediated oxidation of 1 yielded formaldehyde and acetaldehyde. The formation of acetaldehyde requires (i) the oxidation of 1 to a diazenium ion (I) or diazene (II) and (ii) fragmentation of I/II to formyl and methyl radicals. It is suggested that these radical intermediates may be important in understanding and elucidating carcinogenesis by 1.
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PMID:Chemical oxidation and metabolism of N-methyl-N-formylhydrazine. Evidence for diazenium and radical intermediates. 199 5

Several species of fish from the genus Poeciliopsis differ dramatically in their response to the carcinogen N-nitrosodiethylamine (NDEA). The differential induction of tumors among genotypes exposed to NDEA may, in part, result from differences in liver cytochrome P450pj activity (the piscine equivalent of mammalian P450j). Evidence for the existence of cytochrome P450pj activity and mRNA expression has been found in several Poeciliopsis genotypes (species and strains). Biochemical evidence suggests that a microsomal cytochrome P450 enzyme catalyzes the metabolism of NDEA to acetaldehyde and other intermediates in Poeciliopsis. This reaction was inhibited by carbon monoxide, and required molecular oxygen and reducing equivalents (NADPH). Differences were found in maximal activity as well as temperature optima among genotypes. Poeciliopsis, a livebearing fish from desert streams of northwestern Mexico, appears to have thermal optima for cytochrome P450pj activity between 25 and 30 degrees C depending on the genotype. Western blot analysis (using anti-rat P450IIE1 antibodies) detected a 55-60 kd band in microsomes isolated from rat and Poeciliopsis. Using a 49mer probe specific for rat cytochrome P450j, Northern blots revealed a 3.3 kb mRNA from livers of a Poeciliopsis genotype and rat, but none in muscle mRNA from either organism. S1 nuclease protection assays, using the same probe, revealed that a mRNA fragment protected by the probe against digestion was induced on exposure of the whole organism to ethanol (via uptake from the aquatic environment). The assays also demonstrated that ethanol treatments both induced and suppressed this mRNA, depending on concentration and exposure time.
Carcinogenesis 1991 Apr
PMID:Nitrosodiethylamine metabolism in the viviparous fish Poeciliopsis: evidence for the existence of liver P450pj activity and expression. 201 28

Aldehydes constitute a group of relatively reactive organic compounds. They occur as natural (flavoring) constituents in a wide variety of foods and food components, often in relatively small, but occasionally in very large concentrations, and are also widely used as food additives. Evidence of carcinogenic potential in experimental animals is convincing for formaldehyde and acetaldehyde, limited for crotonaldehyde, furfural and glycidaldehyde, doubtful for malondialdehyde, very weak for acrolein and absent for vanillin. Formaldehyde carcinogenesis is a high-dose phenomenon in which the cytotoxicity plays a crucial role. Cytotoxicity may also be of major importance in acetaldehyde carcinogenesis but further studies are needed to prove or disprove this assumption. For a large number of aldehydes (relevant) data on neither carcinogenicity nor genotoxicity are available. From epidemiological studies there is no convincing evidence of aldehyde exposure being related to cancer in humans. Overall assessment of the cancer risk of aldehydes in the diet leads to the conclusion that formaldehyde, acrolein, citral and vanillin are no dietary risk factors, and that the opposite may be true for acetaldehyde, crotonaldehyde and furfural. Malondialdehyde, glycidaldehyde, benzaldehyde, cinnamaldehyde and anisaldehyde cannot be evaluated on the basis of the available data. A series of aldehydes should be subjected to at least mutagenicity, cytogenicity and cytotoxicity tests. Priority setting for testing should be based on expected mechanism of action and degree of human exposure.
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PMID:Aldehydes: occurrence, carcinogenic potential, mechanism of action and risk assessment. 201 17

The generation of superoxide and related free radicals and the mobilization of catalytic iron due to ethanol metabolism have been suggested as mechanisms of alcohol-induced liver injury as well as of the increased risk of cancer observed in alcoholics. Cleavage of double stranded DNA is produced by both free radicals as well as by catalytic iron. The effects of ethanol metabolism on DNA cleavage were therefore studied in vitro as well as in vivo in isolated hepatocytes. Intactness of double stranded DNA was studied by measuring ethidium bromide fluorescence after DNA electrophoresis. In vitro, the metabolism of acetaldehyde by aldehyde oxidase caused cleavage of Lambda phage DNA. Cleavage was inhibited by both superoxide dismutase and desferrioxamine indicating the role of superoxide radicals and catalytic iron respectively. Studies with HIND III digests of the Lambda phage indicate a lack of specificity in the breaks with respect to nucleotide sequences. Addition of EDTA greatly enhanced cleavage. In vivo, ethanol metabolism caused minimal breakage in hepatocyte DNA and addition of acetaldehyde (100 microM) markedly enhanced cleavage; all cleavage was inhibited by desferrioxamine. The metabolism of ethanol to acetaldehyde and the further metabolism of acetaldehyde by aldehyde oxidase generates free radicals and mobilizes iron; these may contribute to alcohol-induced injury and carcinogenesis.
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PMID:DNA cleavage during ethanol metabolism: role of superoxide radicals and catalytic iron. 217 Jul 94

Prospective epidemiologic studies have reported an increased risk of rectal cancer following chronic ethanol ingestion. The effect of ethanol on chemically induced colorectal carcinogenesis is controversial depending on the experimental conditions. In the present study the effect of chronic ethanol administration on acetoxymethylmethylnitrosamine-induced rectal cancer and the possible role of acetaldehyde in this process were investigated. Chronic ethanol administration resulted in an earlier occurrence of rectal tumors in this animal model. Because the concomitant administration of cyanamide, a potent acetaldehyde dehydrogenase inhibitor, showed a positive trend toward increased incidences of tumors, acetaldehyde could be involved in the ethanol-associated carcinogenesis. To measure colonic acetaldehyde, 12 chronically ethanol-fed and control rats received an acute dose of ethanol (2.5 g/kg body wt). The mucosal concentration of acetaldehyde was significantly higher in the rectum compared with the cecum (198 +/- 23 vs. 120 +/- 23 nmoles.g colon-1, p less than 0.05), but was not affected by chronic ethanol feeding. Furthermore, 6 germ-free rats had significantly lower acetaldehyde concentrations in the rectum (84 +/- 11 vs. 234 +/- 33 nmoles.g colon-1, p less than 0.01) and in the cecum (59 +/- 13 vs. 121 +/- 33 nmoles.g colon-1, p less than 0.05) compared with 6 conventional animals, and this was paralleled by the number of fecal bacteria in the 2 intestinal segments. In addition, to determine the effect of chronic ethanol feeding on colorectal cell turnover, 30 animals were pair-fed liquid diets. Using the metaphase-arrest technique, alcohol feeding induced rectal (19.1 +/- 2.0 vs. 9.1 +/- 1.8 cells.crypt-1.h-1, p less than 0.01), but not cecal (18.9 +/- 1.3 vs. 22.2 +/- 3.3 cells.crypt-1.h-1, p greater than 0.05) hyperregeneration. This was accompanied by an increase in the crypt proliferative compartment and increased mucosal ornithine decarboxylase activity (63 +/- 18 vs. 22 +/- 6 pmoles.hr-1.mg protein-1, p less than 0.05). The data show that chronic ethanol ingestion accelerates chemically induced rectal carcinogenesis and raise the possibility that acetaldehyde probably generated through bacterial ethanol oxidation may be involved in this process. The secondary hyperregeneration of the mucosa, observed after alcohol feeding, could by itself favour carcinogenesis.
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PMID:Possible role of acetaldehyde in ethanol-related rectal cocarcinogenesis in the rat. 229 96

The oxidative metabolism of diethylnitrosamine (DEN) was investigated by acetaldehyde determination using microsomes from nasal mucosa and liver of Sprague-Dawley rats and nasal mucosa and liver of Syrian Golden hamsters, to establish the role of metabolic activation in the organo-targets for the carcinogenicity of the nitrosamine. The hepatic microsomal de-ethylation of DEN followed simple and biphasic Michaelis-Menten kinetics for rat liver and hamster liver, respectively. Both de-ethylations were inducible by phenobarbital (PB) and the DEN-de-ethylase activities and the Michaelis constants were determined. Microsomes from hamster liver showed a higher metabolic rate (Vmax) and a better affinity (Km) towards DEN with respect to microsomes from rat liver. In hamster, microsomes from nasal tissue biotransformed DEN at a rate and affinity quite similar to those of liver. In contrast, nasal mucosa of rat metabolized DEN poorly. The effect of metyrapone, a classical inhibitor of P-450 monooxygenases, on DEN de-ethylation was studied. It inhibited both hepatic and nasal DEN-de-ethylase activity, with greater affinity towards the latter. In addition metyrapone had a greater inhibitory effect on the hepatic P-450 isozymes induced in PB-treated animals. These results correlate well with the organotrophy of DEN carcinogenesis in the nasal region of hamster, but not of rat. They suggest that for the nose the metabolic activation of DEN in situ is necessary to elicit its carcinogenic effect.
Carcinogenesis 1986 Aug
PMID:Metabolism of diethylnitrosamine by nasal mucosa and hepatic microsomes from hamster and rat: species specificity of nasal mucosa. 308 39

Human and rat O6-methylguanine transferase (O6MeGT) are inhibited in vitro by ethanol at concentrations of 10 to 50 mM and by acetaldehyde, the first metabolite of ethanol, at concentrations as low as 0.01 microM. Several other enzymes, including glyceraldehyde-3-phosphate dehydrogenase and yeast alcohol dehydrogenase, which like O6MeGT have cysteines in their active sites, were not inhibited by acetaldehyde at the levels that inhibited O6MeGT. Disulfiram, an acetaldehyde dehydrogenase inhibitor, enhanced the inhibitory effect of ethanol in vivo. These results indicate that the inhibitory effect of ethanol on O6MeGT activity is mediated primarily via its metabolite, acetaldehyde.
Carcinogenesis 1988 May
PMID:In vitro and in vivo inhibitory effect of ethanol and acetaldehyde on O6-methylguanine transferase. 336 37


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