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)

Chronic alcoholism and incidence of carcinoma of the oropharynx, the larynx, the esophagus and the liver (and probably as well of the pancreas and rectum) are correlated, as epidemiological studies have shown. In animal experiments ethanol is not carcinogenic, but it enhances carcinogenesis induced by other compounds; it may influence the initial as well as the promotional phase of carcinogenesis. A local effect could be the responsible mechanism in carcinogenesis of the upper gastrointestinal tract. Ethanol does influence regenerative, secretory, motility nd microbial patterns of the gastrointestinal tract. In addition changes of hormone, vitamin and mineral metabolism and of the immune system induced by ethanol may contribute to carcinogenesis. Ethanol enhances activation of a number of procarcinogens in the small intestine, in the liver and in the lung. It is also known that different alcoholic beverages contain carcinogens.
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PMID:[Ethanol and carcinogenesis]. 705 May 73

The effects of ethanol on the metabolism of nitrosamines by rat liver microsomes have been studied. Treatment of rats with 10 or 15% ethanol in drinking water for 3 days causes a 4- to 5-fold enhancement in microsomal N-nitrosodimethylamine demethylase (NDMAd) activity and a 40-60% increase in gross P-450 content. The enhancement is mainly due to the induction of a low Km form (Km = 0.07 mM) of NDMAd. The treatment induces protein species with molecular weights between 50000 and 52000, some of which are believed to be P-450 isozymes with high affinity to NDMA. In addition to NDMA, treatment with ethanol also enhances the metabolism of N-nitroso-N-methylethylamine, N-nitrosomethylaniline, and N-nitroso-N-methylbenzylamine. When added to the incubation mixture, ethanol and its homologs inhibit the demethylation of these nitrosamines by microsomes. Ethanol is a competitive inhibitor of the low Km NDMAd with a Ki of 0.31 mM and is less effective in inhibiting the metabolism of more lipophilic nitrosamines.
Carcinogenesis 1982
PMID:The induction and competitive inhibition of a high affinity microsomal nitrosodimethylamine demethylase by ethanol. 715 Dec 59

The paper presents results of the epidemiological, clinical and experimental data regarding the link between alcohol abuse and cancer that demonstrate an important role of ethanol in stomach cancerogenesis. The role of ethanol is more evident in stomach as it is the organ exposed more directly and often to higher ethanol concentrations. Ethanol may develop its detrimental activity in carcinogenesis through several mechanisms: by its solvent effects, by inducing alimentary and immunological deficiencies, by acting as a vehicle for carcinogens, by facilitating their activation or by inhibiting DNA repair.
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PMID:[Ethanol as a risk factor in the pathogenesis of precancerous states and changes in the gastric mucous membrane]. 759 92

A majority of epidemiological investigations report an association between risk for breast cancer in women and alcohol consumption. However, evidence for an enhancing effect of ethanol on chemically induced rat mammary tumorigenesis is limited and inconsistent. The present study was conducted to evaluate the influence of low to high ethanol intakes (15, 20 or 30% of calories) as part of a defined, liquid diet on both the initiation and promotion stages of N-methyl-N-nitrosourea (MNU)-induced rat mammary tumorigenesis. Ethanol consumed by rats at 15% of calories during either the initiation or promotion stages increased the number of mammary adenocarcinomas compared to isocaloric controls. Ethanol intake at 20% of calories only during the promotion stage resulted in an increase in the number of mammary adenocarcinomas compared to controls. No enhancing effect of dietary ethanol at 30% of calories on either stage of tumorigenesis was observed in comparison to isocaloric controls. Therefore, ethanol at specific intakes can enhance the initiation and promotion stages of MNU-induced rat mammary tumorigenesis. There was not, however, a corresponding increase in mammary tumor development at the highest intake of ethanol evaluated. Possible reasons for this latter lack of effect of ethanol are discussed.
Carcinogenesis 1995 Apr
PMID:Enhancement by chronic ethanol intake of N-methyl-N-nitrosourea-induced rat mammary tumorigenesis. 772 81

The loss of HLA antigens by neoplastic cells may allow tumors to escape immune surveillance. We observed reduced expression of HLA antigens during human colon carcinogenesis. Since ethanol, which is associated with human colonic carcinogenesis, modulates the expression of HLA genes, we examined whether it affects the expression of HLA class I genes in human colon adenocarcinoma cell lines. Ethanol (1.7 x 10(-10) M to 1.7 x 10(-1) M), had no effect on the expression of HLA class I antigens on these colonocytes, the corresponding mRNA levels, or the expression of HLA constructs. Our findings do not support the hypothesis that ethanol may modulate the expression of HLA class I genes in human colon cancer cells.
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PMID:The effect of ethanol on the expression of HLA class I genes in human colon adenocarcinoma cell lines. 801 85

Alcohol consumption and cigarette smoking are synergistic etiologic factors for squamous cell carcinoma of the esophagus in Western countries. Catechol, a constituent of cigarette smoke, was previously found to be a co-carcinogen with methyl-n-amylnitrosamine (MNAN) for esophageal tumors in rats, when it was given in the diet. Here we tested whether the inclusion of ethanol in a similar system had an additional promoting effect on esophageal carcinogenesis. Male MRC - Wistar rats were injected three times i.p. with 25 mg MNAN/kg starting from 7 weeks of age. A second group of rats was injected similarly with MNAN and treated for life with 10% ethanol and 0.2% catechol in the drinking water, starting at 6 weeks of age. One or more test chemicals were omitted in other groups. The rats were maintained until they died and were necropsied. The number of esophageal papillomas/rat was 2.18 +/- 0.36, 4.27 +/- 0.53, 2.54 +/- 0.48 and 3.21 +/- 0.52 (mean +/- SE) in groups treated with MNAN alone, MNAN + ethanol + catechol, MNAN + ethanol and MNAN + catechol, respectively. Esophageal carcinomas showed a similar trend, with the number of carcinomas/rat equal to 0.23 +/- 0.08 in the MNAN alone group and 0.50 +/- 0.14 in the MNAN + ethanol + catechol group. Tumor multiplicities for the esophageal papillomas and carcinomas were significantly (P < 0.05) greater in the MNAN + ethanol + catechol group than in the MNAN group. These findings indicate that, in the esophagus, catechol alone was not significantly co-carcinogenic with MNAN when it was given in the drinking water (unlike when given in the diet in our previous study), but that ethanol + catechol given in the water was co-carcinogenic with MNAN. Seven of 19 rats given ethanol + catechol without MNAN developed esophageal papillomas, as compared to zero incidence in untreated controls (P = 0.06). Forestomach papillomas occurred in 22% of all rats given catechol. Hence, for esophageal tumor induction, ethanol and catechol were co-carcinogenic with MNAN and appeared to be tumorigenic when given without MNAN. Ethanol and catechol could have increased the carcinogenicity because they affected MNAN metabolism. As a partial test of this possibility, the effect of feeding these compounds for 5-7 weeks separately or together was examined on 2-, 3-, 4-and 5-hydroxy-MNAN (HO-MNAN) production from MNAN by the esophagus and liver slices from freshly killed rats.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1994 May
PMID:Effect of catechol and ethanol with and without methylamylnitrosamine on esophageal carcinogenesis in the rat. 820 91

The inducibility of a cytochrome P450 isoform, CYP2E1 (cyp2e-1), was compared in colonic epithelium of selected inbred mice. Mice were chosen for study on the basis of reported susceptibility to 1,2-dimethylhydrazine (DMH)-induced colorectal tumor formation. DBA/2J (resistant), C57BL/6J (intermediate) and SWR/J (susceptible) mice were exposed to acetone (1% v/v) in drinking water for 10 days. SWR/J mice sustained the largest increase in colonic cyp2e-1, although protein levels, assessed by Western analysis, were markedly increased in mucosal tissue obtained from C57BL/6J mice as well. Further evidence for colonic cyp2e-1 induction is supported by elevated (3.5-fold) chlorzoxazone 6-hydroxylase activity in response to acetone. To more fully characterize these changes in colon, the tumor-sensitive SWR/J mice were chosen for further evaluation. Mice were treated with a panel of agents established to induce this protein in liver, including isoniazid (0.1% v/v) and ethanol (10% v/v) in drinking water and pyrazole (300 mg/kg), given intraperitoneally. With the exception of ethanol, each compound produced a marked (1.5- to 3-fold) elevation of cyp2e-1 in colon and liver. Overall balance between phase I and II metabolism may be a critical factor in determining tumor susceptibility. Therefore, glutathione S-transferase (GST) activity was also examined. In liver, basal GST levels varied less than 2-fold between strains, while in colon, levels were 5-10% of corresponding hepatic levels. Although acetone treatment did not significantly alter hepatic GST, a 30-60% decline in activity was observed in colons of SWR/J and C57BL/6J mice. Further examination of colonic GST revealed compound-specific effects. Ethanol exposure markedly (60%) lowered GST levels in colon, whereas pyrazole produced a 2-fold increase. None of these agents significantly altered hepatic GST activity. These studies demonstrate the ability of mouse colon to undergo an increase in immunoreactive cyp2e-1 in response to a panel of xenobiotics known to elevate this protein in liver. Further characterization of cyp2e-1 and GSTs in inbred mice may provide important information on the role of colonocytes in direct activation of ingested procarcinogens to DNA-reactive metabolites.
Carcinogenesis 1994 Jan
PMID:Induction of cyp2e-1 protein in mouse colon. 829 51

Seventy-five percent of esophageal cancers are alcohol related, yet alcohol is not a carcinogen. Ethanol may promote carcinogenesis via increased free radical products during its metabolism, as indicated by data from this and other studies. Ethanol is oxidized to acetaldehyde by alcohol dehydrogenase, catalase and the microsomal ethanol oxidizing system (MEOS). Free radicals (FR) are released during the oxidation of ethanol by the MEOS. An increased formation of FR in tissues would increase their oxidative stress and may increase their susceptibility for developing chemically induced cancers. FR and some FR products can rapidly react with biological materials, i.e. lipids, proteins and nucleic acids, forming toxic products. This study focuses on the effects of FR and/or FR products on cancer promotion during alcohol metabolism. Eight groups of mice were fed nutritionally adequate diets supplemented with vitamin E and/or ethanol. Some groups of mice were also orally gavaged with N-nitrosomethylbenzylamine (NMBzA), an esophageal carcinogen. Following the feeding of the various diets for 22 weeks, livers and esophagi were removed and the FR burden in the liver measured by the presence of lipid peroxide products and the number of tumors in each esophagus determined. These studies indicate that a linear relationship exists between the increasing number of esophageal tumors and increasing levels of lipid peroxide products that are formed during FR activity. These results show that FR and/or FR products are the cancer promoters during ethanol metabolism, since diets supplemented with high levels of vitamin E, which inhibits ethanol-induced FR activity and the formation of FR products, suppress the promotion of cancer by ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of cancer growth by vitamin E and alcohol. 847 Oct 82

Chronic alcoholism is associated with increased cancer risk that may be related to ethanol-induced alterations in methionine and deoxynucleotide metabolism. These metabolic relationships were studied in micropigs fed diets for 12 months that contained 40% ethanol or cornstarch control with adequate folate. Ethanol feeding altered methionine metabolism without changing mean terminal liver folate levels. After initial equilibration to diet, ethanol feeding significantly increased monthly serum homocysteine levels while reducing serum methionine levels over the time course of the experiment. After 12 months, hepatic methionine synthase activity and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) were significantly reduced in ethanol-fed animals, whereas the ratio of liver deoxyuridine triphosphate (dUTP) to deoxythymidine triphosphate (dTTP) was increased and correlated inversely with methionine synthase activity. These findings were associated with increased frequency of hepatocytes with apoptotic bodies and positivity for proliferating cell nuclear antigen (PCNA) in livers from ethanol-fed minipigs. These studies suggest that chronic ethanol feeding perturbs methionine metabolism by impairment of methionine synthase activity, resulting in deoxynucleoside triphosphate (dNTP) imbalance, increased apoptosis, and regenerative proliferation. These biochemical alterations may provide a promoting environment for carcinogenesis during long-term ethanol exposure.
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PMID:Ethanol feeding of micropigs alters methionine metabolism and increases hepatocellular apoptosis and proliferation. 861 29

Ethanol is oxidised not only in the liver, but also in the gastrointestinal tract. Although this ethanol metabolism is less than that of the liver, it has some important relevance with respect to the first pass metabolism of alcohol and to ethanol induced tissue toxicity. In the gastrointestinal tract, ethanol can be metabolised not only in the mucosal cell via alcohol dehydrogenase (ADH) and microsomal ethanol oxidising system (MEOS), but also in a great variety of bacteria. Depending on the gastrointestinal location, one or the other metabolic pathway of alcohol may be predominant. The metabolism of ethanol by gastric ADH, the so called first pass metabolism, influences ethanol blood concentrations not only in the portal vein and thus in the liver, but also in the systemic circulation. As gastric ADH activity is decreased in younger women, in the elderly, in the alcoholic, during fasting and after treatment with certain H-2-receptor antagonists, increased blood ethanol concentrations may occur in these situations after oral intake of ethanol. However, this first pass metabolism of alcohol is influenced not only by ADH activity but also by the speed of gastric emptying (e.g. slow gastric emptying leads to increased first pass metabolism). Finally, gastric morphology also determines first pass metabolism. Chronic atrophic gastritis and Helicobacter pylori associated gastric injury lead to a decrease of gastric ADH activity, and thus possibly to a decreased first pass metabolism of alcohol. In addition, the local production of acetaldehyde from ethanol in the oesophagus, where significantly more sigma-ADH is present, may contribute to tissue injury and this may lead to the well known ethanol associated oesophageal cancer development. Various isoenzymes of ADH exist in the colorectum and they are also capable of producing acetaldehyde in amounts sufficient to injure the mucosa. Besides ADH, the MEOS, a mixed function oxidase, also metabolises ethanol. This system is inducible by chronic alcohol consumption and is involved in the metabolism of various xenobiotics including drugs and procarcinogens. Thus, an increased activation of dietary procarcinogens by this enzyme system may also contribute to carcinogenesis in the alcoholic. Finally, a great variety of gastrointestinal bacteria are capable of metabolising ethanol to acetaldehyde. This is possibly of major importance in the colorectum where faecal bacteria, especially anaerobes in the rectum, can produce high amounts of acetaldehyde, and this correlates with mucosal hyperregeneration suggesting an acetaldehyde mediated mucosal damage.
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PMID:Ethanol metabolism in the gastrointestinal tract and its possible consequences. 897 30


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