Effects of alcohol consumption on DNA methylation reactions and gene expression: implications for increased cancer risk.
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Animals↗
Biomedical subjects
A J Garro
Publications and source records attributed to A J Garro.
Alcohol metabolism in the upper digestive tract: its implications with respect to carcinogenesis.
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Alcoholism↗
Ethanol consumption inhibits fetal DNA methylation in mice: implications for the fetal alcohol syndrome.
Acute ethanol administration (3 g/kg twice a day) to pregnant mice, from the 9th thru the 11th day of gestation, resulted in hypomethylation of fetal deoxyribonucleic acid (DNA). Nuclei isolated from the fetuses of the ethanol-treated mice had lower levels of methylase activity relative to controls even in the presence of excess S-adenosylmethionine, which serves as the methyl donor for the enzyme DNA methyltransferase. Acetaldehyde, at concentrations as low as 3 to 10 microM, inhibited DNA methyltransferase activity in vitro. Since DNA methylation is thought to play an important role in the regulation of gene expression during embryogenesis, ethanol-associated alterations in fetal DNA methylation may contribute to the developmental abnormalities seen in the fetal alcohol syndrome.
5-Methylcytosine↗
Mutagenic activity in gastric juice and urine of subjects with chronic atrophic gastritis, gastric epithelial dysplasia and gastric cancer.
Gastric juice and urine samples from consecutive patients who underwent endoscopy for upper GI tract complaints were examined for the presence of mutagens. Patients endoscopically and histologically diagnosed as having either chronic atrophic gastritis (CAG) or gastric cancer (GC) had higher than normal levels of mutagens in their gastric juice and urine. The gastric juice pH of these patients was also elevated and, in the case of the CAG patients, contained detectable levels of nitrites. No correlation was however found between gastric mutagen levels and urinary mutagen excretion in the individuals examined.
Adult↗
Effects of chronic ethanol consumption on carcinogen activating and detoxifying systems in rat upper alimentary tract tissue.
The effect of chronic ethanol consumption on enzyme systems directly involved in carcinogen activation and detoxification were studied in rat upper alimentary tract tissue. Microsomal cytochrome P-450 (P-450) levels and glutathione levels as well as glutathione transferase and UDP-glucuronic acid transferase (UDPGT) activities were measured in mucosa scraped from esophagus, forestomach and glandular stomach of rats which had been pair-fed ethanol or dextrimaltose-containing diets. Esophageal and forestomach P-450 levels were increased in the ethanol-fed rats. The ethanol diet also produced a small but significant increase in esophageal glutathione transferase levels. Glutathione levels and UDPGT activity were unaffected. Since P-450 is directly involved in the activation of many chemical carcinogens, these results are consistent with the hypothesis that the increase in upper alimentary tract cancer risk associated with alcohol abuse is due, at least in part, to ethanol's altering the balance between carcinogen activation and detoxification.
Alcohol Drinking↗
Chronic ethanol consumption inhibits repair of dimethylnitrosamine-induced DNA alkylation.
Chronic ethanol consumption causes a DNA repair deficiency. This was demonstrated in Sprague-Dawley rats injected with 14C-labeled dimethylnitrosamine after being pair-fed isocaloric, ethanol, or carbohydrate control diets for 4 weeks. Hepatic DNA was isolated from rats killed at intervals over a 36 hour period after administration of the nitrosamine and concentrations of alkylated guanine derivatives were measured. While N7-methylguanine was lost at equivalent rates from the DNA of both diet groups, 06methylguanine, a promutagenic lesion, persisted at higher levels for longer periods of time in the DNA from the alcohol-fed animals.
Alcoholism↗
In vitro and in vivo inhibitory effect of ethanol and acetaldehyde on O6-methylguanine transferase.
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.
Acetaldehyde↗
The effects of chronic ethanol consumption on carcinogen metabolism and on O6-methylguanine transferase-mediated repair of alkylated DNA.
This article presents a review and update of recent experiments conducted in collaboration with Dr. C. S. Lieber on mechanisms underlying the increased cancer risk associated with alcohol abuse. Ethanol has been found to be a potent inducer of microsomal enzymes involved in carcinogen metabolism in a variety of rat tissues including liver, esophagus, lungs, and intestines. In some of these tissues, ethanol's inductive effect on microsomal cytochrome P-450 enzyme activity may result in enhanced levels of electrophilic metabolites of procarcinogens which are not readily detoxified. In addition, chronic ethanol feeding has been found to depress the activity of O6-methylguanine transferase, an enzyme involved in the repair of carcinogen-induced DNA alkylation. The effects of ethanol on carcinogen metabolism and on DNA repair would be expected to enhance the initiation phase of chemically induced cancers.
Alcoholism↗
Nucleotide sequence of the immunity region of Bacillus subtilis bacteriophage phi 105: identification of the repressor gene and its mRNA and protein products.
A gene involved in the regulation of lysogeny in the temperate Bacillus subtilis phage phi 105 has been identified and isolated. A plasmid, pDC4, was constructed that contains a 740-bp HindIII-PvuII fragment that is derived from the phi 105 immunity region and is capable of rendering B. subtilis immune to infection by phi 105. Three different hybrid plasmids that contain the 740-bp fragment, pAG101 [Cully and Garro, J. Virol. 34 (1980) 789-791], pDC1 and pDC2, were found to synthesize a common 18-kDal polypeptide in B. subtilis minicells and Escherichia coli maxicells. The nucleotide (nt) sequence of this region revealed three open reading frames (ORFs) that predict proteins with Mrs of 16521, 7332, and 5516. In vivo synthesized phi 105 prophage RNA was mapped by primer extension and shown to be transcribed from the DNA strand coding for the Mr 16521 protein. The 5' end of the phi 105 lysogen RNA was mapped to a region that contains conserved sequences for RNA polymerase recognition.
Amino Acid Sequence↗
Urinary mutagen levels in smokers.
Urinary mutagen levels were measured over an 8-week period in a group of 13 smokers. Individual urinary mutagen levels were observed to be relatively constant and while there was a general correlation between mutagen excretion levels and cigarette consumption, individuals' excretion levels could not be predicted on the basis of either the numbers of cigarettes smoked or the tar content of the cigarettes.
Dose-Response Relationship, Drug↗
Sex dependent effect of chronic ethanol consumption in rats on hepatic microsome mediated mutagenicity of benzo[a]pyrene.
The effect of chronic ethanol consumption by rats on hepatic microsomal metabolism of the procarcinogen benzo[a]pyrene (B[a]P) was investigated both with respect to induction of microsomal arylhydrocarbon hydroxylase (AHH) activity and activation of B[a]P to a mutagen. In female rats, chronic ethanol ingestion produced a 42% increase in AHH activity (P less than 0.01), as measured in isolated microsomes, and also resulted in a significantly enhanced capacity (P less than 0.01) of these microsomes to activate B[a]P to a mutagen detectable in the Ames bacterial mutagenesis assay. Hepatic microsomes from male rats on the other hand did not exhibit any significant differences, either in AHH activity or in their capacity to activate B[a]P to a mutagen after chronic ethanol feeding.
Alcoholism↗
Enhanced pulmonary and intestinal activation of procarcinogens and mutagens after chronic ethanol consumption in the rat.
Recent epidemiological surveys have indicated that alcoholics exhibit increased incidences of a variety of cancers. We have investigated, as a possible contributing factor to carcinogenesis in this population, the effect of chronic ethanol consumption on metabolic activation of procarcinogens by microsomes isolated from lungs and small intestine. These tissues are major sites through which procarcinogens enter the body and are also potential sites of procarcinogen metabolism. Rat litter-mates were pair-fed nutritionally adequate liquid diets which contained either ethanol as 36% of total energy or an equivalent energy content of carbohydrates in place of ethanol. Chronic ethanol consumption produced significant increases in pulmonary microsomal cytochrome P-450 and microsomal ethanol oxidation. The ethanol diet also enhanced the capacity of pulmonary microsomes to activate compounds present in tobacco pyrolyzates to mutagens detectable in the Ames Salmonella auxotroph reversion assay. The ethanol diet did not alter the capacity of pulmonary microsomes to hydroxylate benzo(a)pyrene (BaP) or to activate BaP to a mutagen. In contrast, microsomes from the upper small intestine of ethanol-fed rats did exhibit both higher levels of BaP hydroxylase activity and enhanced activation of BaP to a mutagen. The ethanol feeding also enhanced the capacity of the intestinal microsomes to activate to mutagens both tryptophan pyrolyzate and 2-aminofluorene but did not influence the metabolic activation of these promutagens by pulmonary microsomes. Chronic ethanol consumption thus influences carcinogen metabolism in the intestine and lung in a manner which varies with respect to both carcinogen and tissue.
Alcoholism↗
Enhancement of dimethylnitrosamine metabolism and activation to a mutagen following chronic ethanol consumption.
Chronic ethanol ingestion in rats results in an increase in hepatic microsomal dimethylnitrosamine (DMN) demethylase activity and in an increase in hepatic microsomal activation of DMN to a mutagen. These effects of ethanol on DMN metabolism were detectable in vitro at DMN concentrations as low as 0.3 to 1 mM and as high as 100 mM. This ability of ethanol to increase the rate of DMN metabolism over such a broad range of DMN concentrations is in marked contrast to the effects of other microsomal enzyme inducers, such as phenobarbital and 3-methylcholanthrene, which increase the rate of DMN metabolism only at relatively high DMN concentrations and repress its metabolism at low DMN concentrations.
Alcoholism↗
Detection of mutagen-induced lesions in isolated DNA by marker rescue of Bacillus subtilis phage phi 105.
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Acetaldehyde↗
Expression of superinfection immunity to bacteriophage phi 105 by Bacillus subtilis cells carrying a plasmic chimera of pUB110 and EcoRI fragment F of phi 105 DNA.
A 2.1-megadalton, EcoRI-generated fragment of Bacillus subtilis phage phi 105 DNA was cloned into plasmid pUB110. The hybrid plasmid produces a biologically active product which renders B. subtilis immune to infection by phi 105.
Bacillus subtilis↗
Bacterial fusion assayed by a prophage complementation test.
In previous studies of bacterial protoplast fusion, only the frequencies of cell wall regeneration and of bacterial recombination were determined. In this work the frequency of the heterozygous fusion products is measured by prophage complementation. Two multiply marked nonsuppressing strains of Bacillus subtilis, each lysogenic for a different Sus mutant of the phage phi 105, were induced by mitomycin C, protoplasted, fused, and, after dilution in hypertonic broth, incubated until plating with phi 105-sensitive indicator bacteria. When cell lysis was avoided, the frequency of the heterozygous fused cells could be determined from the number of infectious centers produced. The very high frequencies observed are in good agreement with those determined directly, with nonlysogenic strains, by electron microscopic examination of the fused protoplasts (C. Frehel, A. M. Lheritier, C. Sanchez-Rivas, and P. Schaeffer, J. Bacteriol. 137:1354--1361, 1979). Evidence is presented that fusion occurs in two steps, one polyethylene glycol dependent, the other energy requiring. The bacterial growth medium affects the ability of the protoplasts to fuse and to regenerate a cell wall. When experiments using different growth media were compared, an inverse relationship between these abilities was observed, and a direct relationship appeared between the heterozygotes (corrected for wall regeneration) and the recombinant bacteria that were found.
Bacillus subtilis↗
Alcohol-related diseases and carcinogenesis.
Possible mechanisms whereby alcohol abuse and alcohol-related diseases may promote the development of cancer are analyzed. The mechanisms discussed include: (a) contact-related local effects on the upper gastrointestinal tract; (b) the presence of low levels of carcinogens in alcoholic beverages; (c) induction of microsomal enzymes involved in carcinogen metabolism; (d) various types of cellular injury produced by ethanol and its metabolites and their relationship to cancer, particularly in the liver; (e) the nutritional disturbances frequently associated with alcohol abuse. The relationship between alcohol-induced cirrhosis and hepatocellular carcinoma is also discussed, and case histories of patients seen at the Bronx Veterans Administration Medical Center with hepatocellular carcinoma in the absence of cirrhosis are reviewed. Data are presented demonstrating the induction, by chronic ethanol consumption, of microsomal enzymes which convert procarcinogens to carcinogens. These data were derived from experiments in which the ability of microsomes isolated from liver, intestine, and lung tissues of ethanol-fed and control rats to activate several test carcinogens was examined in the Ames Salmonella-mutagenicity test. The hypothesis is presented that ethanol-mediated induction of enzyme systems which activate procarcinogens to carcinogens in various tissues contributes to the enhanced incidence of cancer in the alcoholic.
Alcoholism↗