UMLS:C0596263 - FACTA Search

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

Alcohol drinking and smoking are independent risk factors for upper digestive tract cancers. Furthermore, their combined use interacts in a multiplicative way on cancer risk. There is convincing evidence that acetaldehyde, the first metabolite of ethanol and a constituent of tobacco smoke, is a local carcinogen in humans. Therefore, we examined the combined effect of alcohol drinking and tobacco smoking on in vivo acetaldehyde concentration in saliva. Seven smokers and 6 nonsmokers participated in the study. First, to measure the effect of alcohol on salivary acetaldehyde, all volunteers ingested 0.8 g/kg body weight of ethanol and saliva samples were collected every 20 min for 160 min thereafter. After a 3-day washout period, smokers ingested again the same amount of ethanol and smoked one cigarette every 20 min and saliva samples were collected at 10 min intervals for 160 min. Acetaldehyde and ethanol concentrations were analyzed by headspace gas chromatograph. Firstly, smokers without concomitant smoking during ethanol challenge had 2 times higher in vivo salivary acetaldehyde concentrations than nonsmokers after ethanol ingestion (AUC 114.8 +/- 11.5 vs. 54.2 +/- 8.7 microM x hr, respectively; p = 0.002). Secondly, smokers with active smoking during ethanol challenge had 7 times higher in vivo salivary acetaldehyde levels than nonsmokers (AUC 369.5 +/- 12.2 vs. 54.2 +/- 8.7 microM x hr, respectively; p < 0.001). We conclude that this markedly increased exposure of upper digestive tract mucosa to carcinogenic salivary acetaldehyde of smoking and drinking subjects may explain the synergistic and multiplicative risk effect of alcohol drinking and tobacco smoking on upper gastrointestinal tract carcinogenesis.
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PMID:Synergistic effect of alcohol drinking and smoking on in vivo acetaldehyde concentration in saliva. 1523 23

Chronic ethanol consumption is associated with an increased risk for cancer of the colorectum. The highly toxic and carcinogenic compound is acetaldehyde, the product of ethanol metabolism. Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase (ADH) in colorectal mucosa and bacteria. The enzyme responsible for oxidation of acetaldehyde is aldehyde dehydrogenase. The aim of this study was to compare ADH isoenzymes and ALDH activity in colorectal cancer with the activity in normal colonic mucosa. Total ADH activity was measured by a photometric method with p-nitrosodimethylaniline (NDMA) as substrate, and ALDH activity by a fluorometric method with 6-methoxy-2-naphthaldehyde as a substrate. For measurement of the activity of class I and II isoenzymes we employed fluorometric methods, with class-specific fluorogenic substrates. The activity of class III ADH was measured by the photometric method with n-octanol as substrate, and class IV with m-nitrobenzaldehyde as substrate. Samples were taken surgically during routine operations of colorectal carcinomas from 32 patients. The activities of total ADH and, the most important in colon mucosa, class I ADH were significantly higher in cancer than in healthy tissues. The other tested classes of ADH had a tendency to higher-level activity in cancer cells than in healthy mucosa. ALDH activity was not significantly lower in the cancer cells. The activities of all tested enzymes and isoenzymes were not significantly higher in drinkers than in nondrinkers both in colorectal cancer and in normal mucosa. The differences in activities of total ADH and class I isoenzyme between cancer tissues and normal colon mucosa might be a factor for metabolic changes and disturbances in low-mature cancer cells and, additionally, might be a reason for the higher level of acetaldehyde, which can intensify carcinogenesis.
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PMID:The activity of class I, II, III, and IV alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in colorectal cancer. 1530 86

Because of potential exposure both in the workplace and from ambient air, the known carcinogen 1,3-butadiene (BD) is considered a priority hazardous air pollutant. BD and its 2-methyl analog, isoprene (ISO), are chemically similar but have very different toxicities, with ISO showing no significant carcinogenesis. Once released into the atmosphere, reactions with species induced by sunlight and nitrogen oxides convert BD and ISO into several photochemical reaction products. In this study, we determined the relative toxicity and inflammatory gene expression induced by exposure of A549 cells to BD, ISO, and their photochemical degradation products in the presence of nitric oxide. Gas chromatography and mass spectrometry analyses indicate the initial and major photochemical products produced during these experiments for BD are acrolein, acetaldehyde, and formaldehyde, and products for ISO are methacrolein, methyl vinyl ketone, and formaldehyde; both formed < 200 ppb of ozone. After exposure the cells were examined for cytotoxicity and interleukin-8 (IL-8) gene expression, as a marker for inflammation. These results indicate that although BD and ISO alone caused similar cytotoxicity and IL-8 responses compared with the air control, their photochemical products significantly enhanced cytotoxicity and IL-8 gene expression. This suggests that once ISO and BD are released into the environment, reactions occurring in the atmosphere transform these hydrocarbons into products that induce potentially greater adverse health effects than the emitted hydrocarbons by themselves. In addition, the data suggest that based on the carbon concentration or per carbon basis, biogenic ISO transforms into products with proinflammatory potential similar to that of BD products.
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PMID:Effects of 1,3-butadiene, isoprene, and their photochemical degradation products on human lung cells. 1553 32

There are many gaps in our knowledge of the molecular basis of alcohol toxicity and addiction. Metabolism affords mainly acetic acid via acetaldehyde. A minor metabolite, diacetyl (an alpha-dicarbonyl), arises from the aldehyde. We propose that this C(4) entity and/or its iminium derivatives from condensation with protein amino groups plays important roles in bioresponses. A review of the literature reveals substantial support for this premise. Reduction potentials for diacetyl and its iminium derivatives fall in the range favorable for catalytic electron transfer in vivo, which can generate oxidative stress via reactive oxygen species due to redox cycling. Oxidative stress and reactive oxygen species are linked to toxicity associated with major organs by alcohol. The alpha-dicarbonyl moiety in related substances is believed to induce various toxic responses, such as Alzheimer's disease, mutagenesis, and carcinogenesis. In addition to discussion of addiction and computational studies, potential applications for health improvement are suggested.
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PMID:Role of diacetyl metabolite in alcohol toxicity and addiction via electron transfer and oxidative stress. 1565 7

Chronic alcohol consumption is associated with an increased risk for cancers of many organs, such as oral cavity, pharynx, larynx, and esophagus; breast; liver; ovary; colon; rectum; stomach; and pancreas. An understanding of the underlying mechanisms by which chronic alcohol consumption promotes carcinogenesis is important for development of appropriate strategies for prevention and treatment of alcohol-associated cancers. The National Institute on Alcohol Abuse and Alcoholism, Office of Dietary Supplements, Office of Rare Diseases, National Cancer Institute, National Institute on Drug Abuse, and National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, sponsored an international symposium on Mechanisms of Alcohol-Associated Cancers in Bethesda, Maryland, USA, October 2004. The following is a summary of the symposium. Chronic ethanol consumption may promote carcinogenesis by (1) production of acetaldehyde, which is a weak mutagen and carcinogen; (2) induction of cytochrome P450 2E1 and associated oxidative stress and conversion of procarcinogens to carcinogens; (3) depletion of S-adenosylmethionine and, consequently, induction of global DNA hypomethylation; (4) induction of increased production of inhibitory guanine nucleotide regulatory proteins and components of extracellular signal-regulated kinase-mitogen-activated protein kinase signaling; (5) accumulation of iron and associated oxidative stress; (6) inactivation of the tumor suppressor gene BRCA1 and increased estrogen responsiveness (primarily in breast); and (7) impairment of retinoic acid metabolism. Nicotine may promote carcinogenesis through activation of extracellular signal-regulated kinase/cyclooxygenase-2/vascular endothelial growth factor signaling pathway.
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PMID:Mechanisms of alcohol-associated cancers: introduction and summary of the symposium. 1605 76

Alcoholic beverage consumption is classified as a known human carcinogen, causally related to an increased risk of cancer of the upper gastrointestinal tract. The formation of acetaldehyde from ethanol metabolism seems to be the major mechanism underlying this effect. Acetaldehyde is carcinogenic in rodents and causes sister chromatid exchanges and chromosomal aberrations in human cells. The best-studied DNA adduct from acetaldehyde is N(2)-ethyl-2'-deoxyguanosine, which is increased in liver DNA obtained from ethanol-treated rodents and in white blood cells obtained from human alcohol abusers. However, the carcinogenic relevance of this adduct is unclear in view of the lack of evidence that it is mutagenic in mammalian cells. A different DNA adduct, 1,N(2)-propano-2'-deoxyguanosine (PdG), can also be formed from acetaldehyde in the presence of histones and other basic molecules. PdG has been shown to be responsible for the genotoxic and mutagenic effects of crotonaldehyde. The PdG adduct can exist in either of two forms: a ring-closed form or a ring-opened aldehyde form. Whereas the ring-closed form is mutagenic, the aldehyde form can participate in the formation of secondary lesions, including DNA-protein cross-links and DNA interstrand cross-links. The formation of these types of complex secondary DNA lesions resulting from PdG may explain many of the observed genotoxic effects of acetaldehyde described above. Repair of PdG and its associated adducts is complex, involving multiple pathways. Inherited variation in the genes encoding the proteins involved in the repair of PdG and its secondary adducts may contribute to susceptibility to alcoholic beverage-related carcinogenesis.
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PMID:DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis. 1605 80

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

Breast cancer is the most common cancer in women in the United States, and it is second among cancer deaths in women. Results of most epidemiologic studies, as well as of most experimental studies in animals, have shown that alcohol intake is associated with increased breast cancer risk. Alcohol consumption may cause breast cancer through different mechanisms, including through mutagenesis by acetaldehyde, through perturbation of estrogen metabolism and response, and by inducing oxidative damage and/or by affecting folate and one-carbon metabolism pathways. Alcohol-metabolizing enzymes are present in human breast tissue. Acetaldehyde is a known, although weak, mutagen. However, results of some studies with human subjects implicate this agent in the context of genetic susceptibilities to increased ethanol metabolism. Reactive oxygen species, resulting from ethanol metabolism, may be involved in breast carcinogenesis by causing damage, as well as by generating DNA and protein adducts. Alcohol interferes with estrogen pathways in multiple ways, influencing hormone levels and effects on the estrogen receptors. With regard to one-carbon metabolism, alcohol can negatively affect folate levels, and the folate perturbation affects DNA methylation and DNA synthesis, which is important in carcinogenesis. Some study results indicate that genetic variants of one-carbon metabolism genes might increase alcohol-related breast cancer risk. For all these pathways, genetic polymorphisms might play a role in increasing further a woman's risk for breast cancer. Additional studies are needed to determine the relative importance of these pathways, as well as the modifying influence by genetic variation.
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PMID:The etiology of alcohol-induced breast cancer. 1605 83

Chronic and excessive alcohol intake is associated with an increased risk of a variety of cancers (e.g., oral cavity, larynx, esophagus, liver, lung, colorectal, and breast). Retinoids (vitamin A and its derivatives) are known to exert profound effects on cellular growth, cellular differentiation, and apoptosis, thereby controlling carcinogenesis. Lower hepatic vitamin A levels have been well documented in alcoholics. Substantial research has been done, investigating the mechanisms by which excessive alcohol interferes with retinoid metabolism. More specifically, (1) alcohol acts as a competitive inhibitor of vitamin A oxidation to retinoic acid involving alcohol dehydrogenases and acetaldehyde dehydrogenases; (2) alcohol-induced cytochrome P450 enzymes (CYP), particularly CYP2E1, enhance catabolism of vitamin A and retinoic acid; and (3) alcohol alters retinoid homeostasis by increasing vitamin A mobilization from liver to extrahepatic tissues. As a consequence, long-term and excessive alcohol intake results in impaired status of retinoic acid, the most active derivative of vitamin A and a ligand for both retinoic acid receptors and retinoid X receptors. Moreover, this alcohol-impaired retinoic acid homeostasis interferes with (1) retinoic acid signaling (e.g., down-regulates retinoid target gene expression) and (2) retinoic acid "cross-talk" with the mitogen-activated protein kinase [(MAPK), including Jun N-terminal kinase, extracellular signal-regulated kinase, and p38 kinase] signaling pathway. In addition, restoration of retinoic acid homeostasis by retinoic acid supplementation restored the normal status of both retinoid and MAPK signaling, thereby maintaining normal cell proliferation and apoptosis in alcohol-fed animals. These observations would have implications for the prevention of alcohol-promoted liver (and peripheral tissue) carcinogenesis. However, a better understanding of the alcohol-retinoid interaction and the molecular mechanisms involved is needed before retinoids can be pursued in the prevention of alcohol-related carcinogenesis in human beings, particularly regarding the detrimental effects of polar metabolites of vitamin A.
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PMID:Alcohol, vitamin A, and cancer. 1605 87

This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism in Mannheim, Germany, in October 2004. This symposium was dedicated to Charles S. Lieber in recognition of his contribution in alcohol research over the last 50 years. It was divided into two parts, namely effects of alcohol on the gastrointestinal tract and effects of alcohol on the liver. Major emphasis was given to recent discoveries elucidating mechanisms of alcohol-associated carcinogenesis. M. Salaspuro (Finland) discussed the role of acetaldehyde in the saliva and in the large intestine with respect to its role in the pathogenesis of alcohol-associated cancer, and H. K. Seitz (Germany) presented new data identifying individuals homozygous for the ADH1C&1 allele as high on risk for alcohol-associated upper aerodigestive tract cancer. M. Savolainen (Finland) discussed the role phosphatidylethanol as a bioactive lipid that can mediate beneficial and harmful effects of alcohol drinking. In the second part of the symposium, alcoholic liver disease was discussed. P. Haber (Australia) presented new data on hepatic transcriptome in alcoholic liver disease with the identification of new genes possibly involved in alcohol-initiated fibrogenesis of the liver, and H. Moshage (The Netherlands) described survival mechanisms of the cholestatic hepatocytes with implications for therapy in cholestatic liver disease. The role of the hepatic microsomal ethanol oxidizing system in the metabolism of alcohol in alcoholic liver disease was summarized by R. Teschke (Germany). H. Ishii (Japan) discussed the current status and treatment of alcoholic hepatitis in Japan. Finally, in a state-of-the-art lecture, Charles S. Lieber (USA) discussed the development of the understanding of the pathophysiology of alcoholic liver disease in the last 50 years. He emphasized the role of pathophysiology as an important prerequisite for better treatment strategies.
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PMID:From alcohol toxicity to treatment. 1608 98

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