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)

Findings obtained from numerous prospective cohort and case-control studies on alcohol consumption and pancreatic cancer risk have been inconsistent, with many confounding variables present in various investigations. However, heavy alcohol consumption has been known to be a major cause of chronic pancreatitis and a risk factor for type 2 diabetes mellitus, both of which are linked to pancreatic cancer. It has been established that an extensive normal interaction exists between the exocrine and endocrine pancreas, as well as in inflammatory processes and carcinogenesis. Alcohol and its metabolites (acetaldehyde and fatty acid ethyl esters) can alter metabolic pathways involved in the inflammatory response and carcinogenesis, and they are mediated by one or more of the following mechanisms: (1) premature activation of zymogens; (2) induction of the inflammatory response through activation of nuclear transcription factors, including nuclear factor-kappa and activation protein 1; (3) increased production of reactive oxygen species, resulting in oxidative DNA damage and altered effect of dietary antioxidants; (4) activation of pancreatic stellate cells, which leads to fibrosis; (5) gene mutation in enzymes related to cytochrome P450, glutathione S-transferase, aldehyde dehydrogenase, cationic trypsinogen, and pancreatic secretory trypsin inhibitor; (6) synergistic effects of ethanol and tobacco carcinogen on NNK [nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] metabolism; and (7) dysregulation of proliferation and apoptosis. These various metabolic effects of alcohol can lead to or interact with other risk factors (genetic, dietary, environmental, and lifestyle factors) that result in acute and chronic pancreatitis and diabetes mellitus and, ultimately, affect the multistep process of carcinogenesis toward the development of pancreatic cancer.
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PMID:Alcohol and pancreatic cancer. 1605 82

Alcohol consumption is recognized as a potential risk factor for colorectal cancer (CRC). Genetic polymorphisms, aldehyde dehydrogenase (ALDH2) Glu487Lys and alcohol dehydrogenase 2 (ADH2) His47Arg, which have a strong impact on alcohol metabolism, are common in Japanese population but their significance for CRC carcinogenesis remains to be clarified in detail. We, therefore, conducted a matched case-control study with 257 incident CRC cases and 771 non-cancer controls at Aichi Cancer Center, including analysis of interactions between polymorphisms, drinking and folate consumption. The ADH2 Arg allele was found to be associated with increased risk, the odds ratios (ORs) being 1.35 (95% confidence interval: 1.00-1.84) and 1.93 (1.06-3.53) for the His/Arg and Arg/Arg genotypes, respectively. In contrast, no apparent links were observed with the ALDH2 genotypes. Individuals having ALDH2 Glu/Glu with ADH2 Arg+, ALDH2 Lys+ with ADH2 His/His and ALDH2 Lys+ with ADH2 Arg+ showed ORs of 0.10(0.04-0.21), 0.10 (0.06-0.19) and 1.36 (0.94-1.97), respectively, compared with ALDH2 Glu/Glu with ADH2 His/His. Statistical gene-gene interaction was significant between the two polymorphisms for the risk of CRC (P< 0.001). The impact of ALDH2 Lys+ with ADH2 Arg+ was more evident in low folate consumer (OR = 2.32, 1.19-4.55) than high folate consumer (OR 1.38, 0.80-2.38). In conclusion, while we failed to find any significant association with the ALDH2 polymorphism itself, significant interaction between ALDH2 and ADH2 polymorphism was observed. Replication in the future study is warranted.
Carcinogenesis 2006 May
PMID:A gene-gene interaction between ALDH2 Glu487Lys and ADH2 His47Arg polymorphisms regarding the risk of colorectal cancer in Japan. 1633 25

Numerous experiments have shown that alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) play a significant role in the metabolism of many biological substances. Some metabolic disorders that can lead to breast carcinogenesis may be the cause of changes in ADH and ALDH activity. In previous experiments we found a changed level of class I ADH activity in breast cancer tissues. The changed level of this enzyme in cancer cells may be reflected by the enzyme's activity in the serum. Therefore, in this study we measured the activity of ADH isoenzymes and ALDH in the sera of patients with breast cancer. Serum samples were taken for routine biochemical investigation from 45 women with breast cancer before treatment. Among all tested classes of ADH isoenzymes, only class I had higher activity in the serum of patients with breast cancer in stage IV. The total ADH and ALDH activities were not significantly higher in patients with breast cancer than in healthy controls. The changes in activity, especially in class I ADH, appear to be caused by isoenzymes being released from the organ damaged by metastatic disease.
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PMID:Activity of alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) in the sera of patients with breast cancer. 1672 36

Synchronous multiple intra-esophageal squamous cell carcinomas (SCCs) or oropharyngolaryngeal SCCs are common in alcoholics with esophageal SCC, and more frequently found in those with inactive heterozygous aldehyde dehydrogenase-2 (ALDH2). p53 alterations have been suspected as key molecular events in such multifocal esophageal carcinogenesis. We studied 95 Japanese alcoholic men with Tis and mucosal invasive esophageal SCC and found very high levels of p53 protein accumulation occurring in early esophageal SCC. Synchronous cancer multiplicity in the upper aerodigestive tract was found in 40 patients. p53 expression was not correlated with either cancer multiplicity or ALDH2 genotype. The risk for cancer multiplicity was associated with inactive heterozygous ALDH2 alone (OR=4.22) among the risk factors investigated, which also included smoking, less-active alcohol dehydrogenase-1B, and macrocytosis, enhancing the validity of the link between acetaldehyde exposure and cancer multiplicity.
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PMID:p53 Protein accumulation, cancer multiplicity, and aldehyde dehydrogenase-2 genotype in Japanese alcoholic men with early esophageal squamous cell carcinoma. 1675 95

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) play a significant role in the metabolism of many biological substances. ADH participates in the metabolism of ethanol, retinoic acid, lipid peroxidation products, leukotriene and glutathione metabolism. ALDH is responsible for oxidation of acetaldehyde and other aldehydes and metabolism of histamine and retinoic acid. The aim of this study was to compare the metabolism in breast cancer cells and normal breast parenchyma by measuring ADH isoenzymes and ALDH activities in these tissues. Total ADH activity was measured by a photometric method with p-nitrosodimethylaniline (NDMA) as a substrate. For the measurement of the activity of ALDH and class I and II isoenzymes of ADH we employed the fluorometric methods, with class-specific fluorogenic substrates. The activity of class III alcohol dehydrogenase was detected by the photometric method with n-octanol and class IV with m-nitrobenzaldehyde as substrates. The samples were taken surgically during resection of breast carcinoma from 75 women. The activity of the class I ADH isoenzyme was significantly lower in breast cancer cells than in healthy tissues. The other tested classes of ADH had a tendency for higher levels of activity in cancer cells than in normal mammary tissue. The activity of total ADH and ALDH was also not significantly lower in the cancer cells. The decrease of activity of class I ADH isoenzyme in breast cancer tissues may be a factor of some disorders in metabolic pathways with participation of these isoenzymes that can lead to carcinogenesis.
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PMID:The activity of class I, II, III and IV alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in breast cancer. 1682 Sep 97

The genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2), alcohol dehydrogenase-1B (ADH1B, previously called ADH2), and ADH1C (previously called ADH3) affect the metabolism of alcohol. The inactive ALDH2 encoded by ALDH2*1/*2 and the less-active ADH1B encoded by ADH1B*1/*1 increase the risk of esophageal squamous cell carcinoma in East Asian drinkers. This case-control study involved 96 Japanese men with oral and pharyngeal squamous cell carcinoma (hypopharyngeal cancer in 43 patients and oral/oropharyngeal cancer in 53) and 642 cancer-free Japanese men. The risk of the cancers overall and of hypopharyngeal cancer was increased 3.61- and 10.08-fold, respectively, by ALDH2*1/*2 among moderate-to-heavy drinkers (9+ units/week; one unit = 22 g of ethanol), but the risk of oral/oropharyngeal cancer was not significantly affected by the ALDH2 genotype. The results obtained with a simple alcohol flushing questionnaire were essentially comparable with those obtained by ALDH2 genotyping. Among moderate-to-heavy drinkers, men with the less-active ADH1B*1/*1 had a significantly higher risk of the cancers overall, of hypopharyngeal cancer, and of oral/oropharyngeal cancer (OR = 5.56, 7.21 and 4.24, respectively). In view of the linkage disequilibrium between ADH1B and ADH1C, the ADH1C genotype does not significantly affect cancer risk. The significant independent risk factors for oral and pharyngeal cancer overall among moderate-to-heavy drinkers were inactive ALDH2*1/*2, less-active ADH1B*1/*1, frequent drinking of strong alcohol beverages straight, smoking, and lower intake of green-yellow vegetables. Educating these risks for cancer of the upper aerodigestive tract could be a useful new strategic approach to the prevention of these cancers in Japanese.
Carcinogenesis 2007 Apr
PMID:Genetic polymorphisms of alcohol and aldehyde dehydrogenases, and drinking, smoking and diet in Japanese men with oral and pharyngeal squamous cell carcinoma. 1707 28

The metabolism of cancer is in many way different than in healthy cells. Increased metabolism of several carcinogenic substances may take place in cancer cells. The one of them was ethanol, that is oxidized by alcohol dehydrogenase (ADH) to high concentration of acetaldehyde, a toxic and carcinogenic compound. The enzyme responsible for oxidation of acetaldehyde is aldehyde dehydrogenase (ALDH). The aim of this study was to compare the capacity for ethanol metabolism measured by ADH isoenzymes and ALDH activity between gastric cancer and normal gastric mucosa. Total ADH activity was measured by photometric method with p-nitrosodimethylaniline (NDMA) as a substrate and ALDH activity by the fluorometric method with 6-methoxy-2-naphtaldehyde as a substrate. For the measurement of the activity of class I isoenzymes, we used fluorometric methods, with class-specific fluorogenic substrates. The activity of class III ADH was measured by the photometric method with n-octanol and class IV with m-nitrobenzaldehyde as a substrate. The samples were taken surgically during routine operations of gastric carcinomas from 55 patients. The activities of total ADH, and the most important in gastric mucosa, class IV ADH were significantly higher in cancer cells than in healthy tissues. The other tested classes of ADH and ALDH showed a tendency toward higher activity in cancer than in healthy mucosa. The activities of all tested enzymes and isoenzymes were not significantly higher in men than in women in wither gastric cancer tissues or normal mucosa. The increased ADH IV activity may be 1 of the factors intensifying carcinogenesis by the increased ability to acetaldehyde formation from ethanol.
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PMID:The activity of class I, III, and IV of alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in gastric cancer. 1721 7

N2-ethylidene-2'-deoxyguanosine (N2-ethylidene-dG) is a major DNA adduct induced by acetaldehyde. Although it is unstable in the nucleoside form, it is relatively stable when present in DNA. In this study, we analyzed three acetaldehyde-derived DNA adducts, N2-ethylidene-dG, N2-ethyl-2'-deoxyguanosine (N2-Et-dG) and alpha-methyl-gamma-hydroxy-1,N2-propano-2'-deoxyguanosine (alpha-Me-gamma-OH-PdG) in the liver DNA of aldehyde dehydrogenase (Aldh)-2-knockout mice to determine the influence of alcohol consumption and the Aldh2 genotype on the levels of DNA damage. In control Aldh2+/+ mice, the level of N2-ethylidene-dG adduct in liver DNA was 1.9 +/- 0.7 adducts per 10(7) bases and was not significantly different than that of Aldh2+/- and -/- mice. In alcohol-fed mice (20% ethanol for 5 weeks), the adduct levels of Aldh2+/+, +/- and -/- mice were 7.9 +/- 1.8, 23.3 +/- 4.0 and 79.9 +/- 14.2 adducts per 10(7) bases, respectively, and indicated that adduct level was alcohol and Aldh2 genotype dependent. In contrast, an alcohol- or Aldh2 genotype-dependent increase was not observed for alpha-Me-gamma-OH-PdG, and N2-Et-dG was not detected in any of the analyzed samples. In conclusion, the risk of formation of N2-ethylidene-dG in model animal liver in vivo is significantly higher in the Aldh2-deficient population and these results may contribute to our understanding of in vivo adduct formation in humans.
Carcinogenesis 2007 Nov
PMID:Increased formation of hepatic N2-ethylidene-2'-deoxyguanosine DNA adducts in aldehyde dehydrogenase 2-knockout mice treated with ethanol. 1736 Oct 10

We reported earlier that exposure of rats to 3-methylcholanthrene (MC) causes sustained induction of hepatic cytochrome P450 (CYP)1A expression for up to 45 days by mechanisms other than persistence of the parent MC (Moorthy, J. 2000. Pharmacology. Exp. Ther. 294, 313-322). The CYP1A genes are members of the Ah gene battery that also encode CYP1B1 and phase II enzymes such as glutathione S-transferase (GST-alpha), UDP glucuronyl transferase (UGT)1A, NAD(P)H (nicotinamide adenine dinucleotide phosphate, reduced):quinone oxidoreductase I (NQO1), aldehyde dehydrogenase (ALDH), etc. Therefore, in this investigation, we tested the hypothesis that MC elicits persistent induction of CYP1B1 and phase II genes, which are in part regulated by the Ah receptor (AHR). Female Sprague-Dawley rats were treated with MC (100 mumol/kg), ip, once daily for 4 days, and expression of CYP1B1 and several phase II (e.g., GST-alpha, NQO1) genes and their corresponding proteins were determined in lung and liver. The major finding was that MC persistently induced (3- to 10-fold) the expression of several phase II enzymes, including GST-alpha, NQO1, UGT1A1, ALDH, and epoxide hydrolase in both tissues for up to 28 days. However, MC did not elicit sustained induction of CYP1B1. Our results thus support the hypothesis that MC elicits coordinated and sustained induction of phase II genes presumably via persistent activation of the AHR, a phenomenon that may have implications for chemical-induced carcinogenesis and chemopreventive strategies in humans.
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PMID:Persistent induction of hepatic and pulmonary phase II enzymes by 3-methylcholanthrene in rats. 1820 89

Epidemiological data have identified chronic alcohol consumption as a significant risk factor for cancer in humans. The exact mechanism of ethanol-associated carcinogenesis has remained unknown. The metabolism of ethanol leads to generation of acetaldehyde (AA), which is highly toxic and carcinogenic. The amount of acetaldehyde to which cells or tissues are exposed after alcohol ingestion may be of great importance and may, among others, affects carcinogenesis. Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase (ADH). The enzyme responsible for oxidation of acetaldehyde is aldehyde dehydrogenase (ALDH). Both formation and degradation of acetaldehyde depends on the activity of these enzymes. The total alcohol dehydrogenase activity is significantly higher in cancer tissues than in this healthy organs (e.g. liver, stomach, esophagus, colorectum). Moreover the activity of ADH is much higher than the activity of ALDH. This suggests that cancer cells have a greater capability for ethanol oxidation but less ability to remove acetaldehyde than normal tissues. In addition significant differences of ADH isoenzymes activities between cancer tissues and healthy organs may be a factor intensifying carcinogenesis by the increased ability to acetaldehyde formation from ethanol and disorders in metabolism of some biologically important substances (e.g. retinoic acid). The changes in activity of particular ADH isoenzymes in the sera of patients with different cancers, seem to be caused by release of these isoenzymes from cancer cells, and may be useful for diagnostics of this cancer. The particular isoenzymes of ADH present in the serum may indicate the cancer localization.
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PMID:Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in the cancer diseases. 1850 83


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