UMLS:C0016382 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0016382 (flushing)
6,387 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiology has demonstrated that alcoholic beverages are causally related to oropharyngolaryngeal, esophageal, liver, colorectal, and female breast cancer. Among Japanese male alcoholics screened by endoscopy combined with esophageal iodine staining and immunofecal occult blood tests, 4.2% had esophageal squamous cell carcinoma (SCC); 1.2%, oropharyngolaryngeal SCC; 1.4%, stomach adenocarcinoma; 1.9%, colorectal adenocarcinoma. The inactive form of aldehyde dehydrogenase-2 (ALDH2), encoded by the gene ALDH2*1/2*2, which is prevalent in Asians, exposes them to higher levels of acetaldehyde after drinking and was a strong risk factor for these cancers among Japanese heavy drinkers. Inactive ALDH2 was also associated with synchronous and metachronous multiple esophageal cancers. These results suggest a general role of acetaldehyde, an established animal carcinogen, in carcinogenesis of the human alimentary tract. The oropharyngolarynx and esophagus lack ALDH2 activity, suggesting that after exposure to acetaldehyde derived from systemic, mucosal, salivary, or bacterial production or alcoholic beverages, these organs' inefficient degradation of acetaldehyde enhances the chances for local acetaldehyde-associated carcinogenesis. The normal alcohol dehydrogenase-2 (ADH2), encoded by ADH2*1/2*1, is another risk factor for oropharyngolaryngeal and esophageal cancer in Japanese alcoholics. For patients with both normal ADH2 and inactive ALDH2, the risks for oropharyngolaryngeal and esophageal cancer are enhanced in a multiplicative fashion. The responses to a simple questionnaire about both current and past facial flushing after drinking a glass of beer can indicate an individual's ALDH2 phenotype fairly well. Use of this questionnaire to obtain information on ALDH2-associated cancer susceptibility could contribute to the prevention of alcohol-related cancer in Asians.
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PMID:[Alcohol and oropharyngolaryngeal and digestive tract cancer]. 1182 13

Alcoholic beverages are causally related to cancer of the oral cavity, pharynx, larynx and esophagus. Ethanol is oxidized to acetaldehyde and then to acetate by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), both of which have genetic polymorphisms. A review of case-control studies of the effects of ALDH2, ADH2 and ADH3 genotypes shows consistently positive associations between inactive heterozygous ALDH2 and the less-active ADH2 genotypes and the risk for esophageal cancer in East Asian heavy drinkers and this enzyme-related vulnerability may extend to light-to-moderate drinkers. Some studies suggest similar associations with the risk for head and neck cancer in moderate-to-heavy-drinking Japanese. An established carcinogen in experimental animals, acetaldehyde can interact with human DNA. ALDH2-associated cancer susceptibility fits into a scenario in which acetaldehyde plays a critical role in the development of human cancer. Alcohol flushing and drinking behavior may partly explain this carcinogenic effect in carriers of less-active ADH2 genotypes. Whether the ADH3 genotype influences head and neck cancer risk in Western nations is controversial. Professional and public education about risky conditions connected to the ALDH2 and ADH2 genotypes and environmental factors is important in a new strategic approach to the prevention of alcohol-related cancers in East Asians. The use of simple tests to identify inactive ALDH2 on the basis of alcohol flushing responses could benefit many people, by helping them to identify their own cancer risks. Such testing could also help clinicians diagnose esophageal cancer earlier, through the use of endoscopic screening in the high-risk population.
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PMID:Genetic polymorphisms of alcohol and aldehyde dehydrogenases and risk for esophageal and head and neck cancers. 1267 87

High alcohol sensitivity among Asians is mainly due to a genetic polymorphism in the low Km aldehyde dehydrogenase (ALDH2) gene. Strong correlations between the ALDH2 genotype and alcohol sensitivity or alcohol drinking habits have been reported. Another prevalent polymorphism in the alcohol dehydrogenase beta-subunit (ADH2 gene) among Asians appears to modify skin flushing reactions after exposure to ethanol but does not influence alcohol drinking behavior. Both the ADH2 and ALDH2 genotypes have been significantly correlated with the risk of alcoholism. In a Japanese occupational population, a gene-environment interaction of the ALDH2 genotype and daily hassles scores for development of problem drinking behavior was observed. Habitual drinkers with the ALDH2*1/*2 genotype had higher frequencies of sister-chromatid exchange in cultured lymphocytes and higher 8-OHdG levels in polymorphonuclear leukocytes than those with the ALDH2*1/*1 genotype. Alcoholics and heavy drinkers with the ALDH2*1/*2 genotype have been shown to have significantly elevated risks for esophageal and multiple cancers in upper digestive organs than those with the ALDH2*1/*1 genotype. In Japan, bronchial asthma patients with the ALDH2*1/*2 genotype have been shown to have a significantly elevated risk for experiencing alcohol-induced asthma compared with the ALDH2*1/*1 genotype. Providing services to determine these genotypes would be of great help for each individual to make a plan for tailor-made health promotion.
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PMID:[Gene-environmental interactions in alcohol-related health problems--contributions of molecular biology to behavior modifications]. 1280 63

Enzymes encoded by two gene families, alcohol dehydrogenase ( ADH) and aldehyde dehydrogenase ( ALDH), mediate alcohol metabolism in humans. Allelic variants have been identified that alter metabolic rates and influence risk for alcoholism. Specifically, ADH1B*47His (previously ADH2-2) and ALDH2-2 have been shown to confer protection against alcoholism, presumably through accumulation of acetaldehyde in the blood and a resultant 'flushing response' to alcohol consumption. In the current study, variants at ADH1B (previously ADH2), ADH1C (previously ADH3), and ALDH2 were assayed in DNA extracts from participants belonging to a Southwest American Indian tribe ( n=490) with a high prevalence of alcoholism. Each subject underwent a clinical interview for diagnosis of alcohol dependence, as well as evaluation of intermediate phenotypes such as binge drinking and flushing response to alcohol consumption. Detailed haplotypes were constructed and tested against alcohol dependence and related intermediate phenotypes using both association and linkage analysis. ADH and ALDH variants were also assayed in three Asian and one African population (no clinical data) in order to provide an evolutionary context for the haplotype data. Both linkage and association analysis identified several ADH1C alleles and a neighboring microsatellite marker that affected risk of alcohol dependence and were also related to binge drinking. These data strengthen the support for ADH as a candidate locus for alcohol dependence and suggest further productive study.
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PMID:Allelic variation at alcohol metabolism genes ( ADH1B, ADH1C, ALDH2) and alcohol dependence in an American Indian population. 1288

Early esophageal squamous cell carcinoma detected by esophageal iodine staining can be easily treated by endoscopic mucosectomy, and identifying its predictors is important in better selecting candidates to screen for this high-mortality cancer. The common etiologies of elevated mean corpuscular volume (MCV) and esophageal cancer, including folate deficiency, smoking, drinking and high acetaldehyde exposure, suggest testing MCV as such a predictor. Japanese alcoholic men with (n = 65) and without (n = 206) esophageal squamous cell carcinomas, excluding those with liver cirrhosis, were assessed for MCV within 7 days of their last drink, alone or in combination with findings from either the alcohol flushing questionnaire or genotyping to identify inactive aldehyde dehydrogenase-2 (ALDH2*1/2*2) and the less-active form of alcohol dehydrogenase-2 (ADH2*1/2*1), which pose risks for esophageal squamous cell carcinoma. MCV was higher in cancer patients than in the control group. MCV was higher in both groups in those who were heavier smokers, had lower body mass index (BMI), experienced alcohol flushing, and had ALDH2*1/2*2. After adjusting for age, drinking and smoking habits, BMI and ALDH2/ADH2 genotypes, macrocytosis of MCV > or =106 fl was associated with increased risk for esophageal cancer (OR = 2.75). Men with both MCV > or =106 fl and alcohol flushing had an even higher cancer risk (OR = 5.51). The combinations of MCV > or =106 fl with ALDH2*1/2*2 or ADH2*1/2*1 alone, and both ALDH2*1/2*2 and ADH2*1/2*1 (ORs = 11.44, 21.22 and 319.7, respectively) showed consistently higher risk than the corresponding group with MCV <106 fl (ORs = 7.24, 4.71 and 27.01, respectively). In conclusion, MCV measurement, alone or in combination with the markers of alcohol sensitivity, provides a new means of predicting risk for esophageal squamous cell carcinoma in Japanese alcoholic men.
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PMID:Macrocytosis, a new predictor for esophageal squamous cell carcinoma in Japanese alcoholic men. 1294 54

Alcohol flushing after light drinking is triggered mainly by severe acetaldehydemia in individuals possessing inactive aldehyde dehydrogenase (ALDH)-2. Inactive ALDH2 encoded by ALDH2*1/2*2 and the low-activity form of alcohol dehydrogenase (ADH)-2 encoded by ADH2*1/2*1 enhance the risk for esophageal cancer in Japanese light to heavy drinkers, a significant association that emphasizes the importance of screening tests for inactive ALDH2 based on alcohol flushing. The objectives of the present report were (a). to evaluate the reliability of a simple questionnaire that asks about both current and past flushing for detecting inactive ALDH2 and (b). to predict cancer risk based on flushing in a case-control manner. The study subjects consisted of 233 Japanese men with esophageal squamous cell carcinoma and 610 cancer-free Japanese men. When current or former flushing individuals were considered to have inactive ALDH2, the sensitivity and specificity of the test were 84.8% and 82.3%, respectively, for the cases and 90.1% and 88.0%, respectively, for the controls. To clarify the characteristics of men who had genetically inactive ALDH2 but did not report alcohol flushing, we analyzed individuals possessing the ALDH2*1/2*2 genotype and found that those who also had ADH2*1/2*1 (both cases and controls) tended not to report current flushing, and those who did not report current flushing (controls only) tended to be heavier drinkers. As compared with overall never or rare drinking, the cancer risks for light (1-8.9 units/week; 1 unit = 22 g of ethanol), moderate (9-17.9 units/week), and heavy (18+ units/week) drinkers with current or former flushing (odds ratio = 6.69, 42.66, and 72.86, respectively) significantly exceeded the risks for those who had never flushed (odds ratio = 1.27, 10.12, and 15.61, respectively), even after adjustment for age, smoking, and diet. The flushing questionnaire may be used in large-scale epidemiological studies as a surrogate marker of ALDH2 genotype to predict individual cancer risk.
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PMID:Alcohol flushing, alcohol and aldehyde dehydrogenase genotypes, and risk for esophageal squamous cell carcinoma in Japanese men. 1465 86

This article summarizes a symposium that was organized by Dr. Kim Fromme and presented at the 2003 annual meeting of the Research Society on Alcoholism in Ft. Lauderdale, Florida. The four presentations illustrate the emerging technologies and methods that are now being used to investigate the genetic basis of differential sensitivity to alcohol and their behavioral manifestations. Combining human genotyping with laboratory measures of behavior and subjective reports, these presentations represent state-of-the-art approaches to crossing the bridge from the Decade of the Brain to the Decade of Behavior. Dr. De Wit's paper describes her research on the neurobiological basis for individual differences in sensitivity to the stimulant and sedative effects of alcohol. Evidence suggests that activity of the dopaminergic and GABAergic neurotransmitters underlie these stimulant and sedative effects, respectively. Both Drs. Hutchison's and Corbin's papers describe their research on polymorphisms for the serotonin transporter (SLC6A4) as a determinant of the subjective effects of alcohol challenge. Dr. Hutchinson's and Ms. Ray's findings indicate that individuals with the short form of the SLC6A4 alleles (S) demonstrated a low level of response to alcohol, thus supporting previous research that the S allele may be associated with increased risk for alcohol dependence. In contrast, Dr. Corbin did not find a reliable association between the SLC6A4 genotype and subjective response to alcohol. Mr. Cook's and Dr. Wall's paper adds another dimension to this article by presenting research on both the aldehyde dehydrogenase (ALDH2) and alcohol dehydrogenase (ADH2) genetic variants and their association with the alcohol-related flushing response that is prevalent in Asian populations. Dr. David Goldman provides concluding remarks.
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PMID:Biological and behavioral markers of alcohol sensitivity. 1511 32

Alcoholism is a chronic relapsing/remitting disease that is frequently unrecognized and untreated, in part because of the partial efficacy of treatment. Only approximately one-third of patients remain abstinent and one-third have fully relapsed 1 year after withdrawal from alcohol, with treated patients doing substantially better than untreated [1]. The partial effectiveness of strategies for prevention and treatment, and variation in clinical course and side effects, represent a challenge and an opportunity to better understand the neurobiology of addiction. The strong heritability of alcoholism suggests the existence of inherited functional variants of genes that alter the metabolism of alcohol and variants of other genes that alter the neurobiologies of reward, executive cognitive function, anxiety/dysphoria, and neuronal plasticity. Each of these neurobiologies has been identified as a critical domain in the addictions. Functional alleles that alter alcoholism-related intermediate phenotypes include common alcohol dehydrogenase 1B and aldehyde dehydrogenase 2 variants that cause the aversive flushing reaction; catechol-O-methyltransferase (COMT) Val158Met leading to differences in three aspects of neurobiology: executive cognitive function, stress/anxiety response, and opioid function; opioid receptor micro1 (OPRM1) Asn40Asp, which may serve as a gatekeeper molecule in the action of naltrexone, a drug used in alcoholism treatment; and HTTLPR, which alters serotonin transporter function and appears to affect stress response and anxiety/dysphoria, which are factors relevant to initial vulnerability, the process of addiction, and relapse.
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PMID:Alcoholism: genes and mechanisms. 1558 75

Pharmacokinetic models for ethanol metabolism have contributed to the understanding of ethanol clearance in human beings. However, these models fail to account for ethanol's toxic metabolite, acetaldehyde. Acetaldehyde accumulation leads to signs and symptoms, such as cardiac arrhythmias, nausea, anxiety, and facial flushing. Nevertheless, it is difficult to determine the levels of acetaldehyde in the blood or other tissues because of artifactual formation and other technical issues. Therefore, we have constructed a promising physiologically based pharmacokinetic (PBPK) model, which is an excellent match for existing ethanol and acetaldehyde concentration-time data. The model consists of five compartments that exchange material: stomach, gastrointestinal tract, liver, central fluid, and muscle. All compartments except the liver are modeled as stirred reactors. The liver is modeled as a tubular flow reactor. We derived average enzymatic rate laws for alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), determined kinetic parameters from the literature, and found best-fit parameters by minimizing the squared error between our profiles and the experimental data. The model's transient output correlates strongly with the experimentally observed results for healthy individuals and for those with reduced ALDH activity caused by a genetic deficiency of the primary acetaldehyde-metabolizing enzyme ALDH2. Furthermore, the model shows that the reverse reaction of acetaldehyde back into ethanol is essential and keeps acetaldehyde levels approximately 10-fold lower than if the reaction were irreversible.
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PMID:A physiologically based model for ethanol and acetaldehyde metabolism in human beings. 1592 32

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.
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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

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