Human stomach alcohol and aldehyde dehydrogenases: Comparison of expression pattern and activities in alimentary tract

Sj, Yin; Liao, C. S.; Cw, Wu; Tt, Li; Chen, LL; Lai, Ching‐Long; Ty, Tsao

doi:10.1053/gast.1997.v112.pm9041238

Cited by 115 publications

(108 citation statements)

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“…41 Since the activity of ALDH2 enzyme in the UADT was found to be markedly weak, the inefficient degradation of acetaldehyde in the alimentary tract enhances the carcinogenetic consequence of a high level of acetaldehyde. 42 As shown in Table III, a mild difference in HRs between lowto-moderate and heavy drinkers with the same genotypes was discerned. Heavy amount of ethanol intake seem only to confer a modest independent influence on the age of ESCC presentation.…”

Section: Discussionmentioning

confidence: 84%

“…As discussed previously, ADH1B Arg/Arg polymorphism and ALDH2 Lys variant were associated with an increased concentration of acetaldehyde in the saliva and blood. 36,42 In one recent in vivo study, a 7-folds higher salivary acetaldehyde has been documented in association with active smoking. 38 High levels of acetaldehyde with regard to the use of tobacco and alcohol, and genetic susceptibility might be an important explanation for the earlier mucosa tumorigenesis of this site of malignancy.…”

Section: Discussionmentioning

confidence: 99%

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Genetic modulation of ADH1B and ALDH2 polymorphisms with regard to alcohol and tobacco consumption for younger aged esophageal squamous cell carcinoma diagnosis

Lee¹,

Wu²,

Wu³

et al. 2009

Intl Journal of Cancer

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Genetic variants in alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) genes modulate acetaldehyde removal upon alcohol ingestion. Although these genetic vulnerabilities have been linked to higher esophageal squamous cell carcinoma (ESCC) risks, it is unclear whether they also determine the time of malignancy presentation. The purpose of this investigation was to unravel genotoxic effects of the two alcohol-metabolizing genes with regard to alcohol and tobacco consumption on the age at ESCC diagnosis and tumor dissemination. ADH1B/ALDH2 genotyping was performed on lymphocyte DNA specimens taken from 406 consecutively registered incident patients with pathology-proven ESCC. To fully utilize individual genetic and survival information, survival analyses and gene-longevity applied approaches were introduced. Among heavy drinkers, the ADH1B Arg/Arg (55 years) and ALDH2 Glu/Lys genotypes (54 years) were found to confer a 15 and 16 years earlier carcinoma diagnosed age than His/His and Glu/Glu nondrinkers (both 70 years), respectively. For drinkers, 1-year age advancement was, separately, associated with a 0.977 and 0.953-fold stepwise reduced likelihood of being ADH1B Arg homozygote and ALDH2 Lys variant. Noticeably elevated hazard-ratio (HR) for drinkers of ADH1B slow-form genotype and ALDH2 inactive-form allele were identified in smokers (HR 5 2.3-2.6), but no in nonsmokers. In smokers, appreciably higher cumulative cancer onset risks were correspondingly recognized from the age of 45 and 49 upward among any 1 Lys allele and Arg/Arg 1 Glu/Glu combined-ADH1B/ALDH2-genotype drinkers than nondrinkers. In conclusion, consumption of tobacco and alcohol, coupled with genetic susceptibilities associated with acetaldehyde elimination, as modulated by ADH1B and ALDH2 genotypes, determines a substantial magnitude of tumorigenetic effect on earlier age ESCC diagnosis. ' 2009 UICC Key words: age factor; alcohol drinking; alcohol dehydrogenase; aldehyde dehydrogenase; areca; esophageal neoplasms; smoking Carcinoma stemming from the esophagus ranks as the eighth most common cancer in the world and is one of the deadliest and, yet, most neglected forms of cancer.1 Given the insidious nature of this neoplasm, it has been found that more than 50% of the eventual patients already have unresectable and/or metastatic conditions at the time of tumor presentation.2 Although recent advances in the diagnosis, staging and treatment of esophageal cancer have brought about noteworthy improvement toward some manner of survival, 75% of the patients still die within 1 year of diagnosis, and currently just 5-14% of such patients survive at least 5 years.2,3 Due, in part, to the high case fatality rate, younger esophageal carcinoma onset has been linked to a shorter life expectancy. This leads to a number of challenging health-related issues for the respective family, as well as to substantial work productivity losses for the country.Alcohol intake is a well-recognized determinant for squamous cell carcinoma (SCC) of the esopha...

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Genetic modulation of ADH1B and ALDH2 polymorphisms with regard to alcohol and tobacco consumption for younger aged esophageal squamous cell carcinoma diagnosis

Lee¹,

Wu²,

Wu³

et al. 2009

Intl Journal of Cancer

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“…Some investigators have found no correlation between gastric ADH activity and FPM (Brown et al 1995). Importantly, the total ADH activity in the stomach, calculated based on the mass of the mucosa and its ADH activity, does not account for the amount of ethanol metabolized, as indicated by the observed differences between the AUC of oral and intravenous alcohol (Yin et al 1997). Furthermore, the human and rat s-ADH have markedly different kinetic properties.…”

Section: Gastrointestinal Absorption and First-pass Metabolismmentioning

confidence: 99%

“…Several groups have reported that ALDH2 deficiency is associated with increased risk of oesophageal and oropharyngeal cancer (Yokoyama et al 1996a,b,c). The activity of ADH is considerably higher than that of ALDH in the oesophagus, which would predispose this tissue to injury during ethanol oxidation (Yin et al 1993(Yin et al , 1997. It is also possible that the phenomenon reflects increased exposure of the oropharynx and oesophagus to acetaldehyde in the saliva (Vakevainen et al 2000(Vakevainen et al , 2001.…”

Section: Aldehyde Dehydrogenasementioning

confidence: 99%

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

et al. 2004

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Alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH2) are responsible for metabolizing the bulk of ethanol consumed as part of the diet and their activities contribute to the rate of ethanol elimination from the blood. They are expressed at highest levels in liver, but at lower levels in many tissues. This pathway probably evolved as a detoxification mechanism for environmental alcohols. However, with the consumption of large amounts of ethanol, the oxidation of ethanol can become a major energy source and, particularly in the liver, interferes with the metabolism of other nutrients. Polymorphic variants of the genes for these enzymes encode enzymes with altered kinetic properties. The pathophysiological effects of these variants may be mediated by accumulation of acetaldehyde; high-activity ADH variants are predicted to increase the rate of acetaldehyde generation, while the low-activity ALDH2 variant is associated with an inability to metabolize this compound. The effects of acetaldehyde may be expressed either in the cells generating it, or by delivery of acetaldehyde to various tissues by the bloodstream or even saliva. Inheritance of the high-activity ADH β2, encoded by the ADH2*2 gene, and the inactive ALDH2*2 gene product have been conclusively associated with reduced risk of alcoholism. This association is influenced by gene–environment interactions, such as religion and national origin. The variants have also been studied for association with alcoholic liver disease, cancer, fetal alcohol syndrome, CVD, gout, asthma and clearance of xenobiotics. The strongest correlations found to date have been those between the ALDH2*2 allele and cancers of the oro-pharynx and oesophagus. It will be important to replicate other interesting associations between these variants and other cancers and heart disease, and to determine the biochemical mechanisms underlying the associations.

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“…High level of exposure and inefficient degradation of acetaldehyde in the UADT may be associated with multifocal cancerization in the UADT. High-K m ADH4 (previously called ADH7) is strongly expressed in the UADT and is active in producing acetaldehyde upon exposure to a locally high dose of ethanol, whereas ALDH2 activity in the UADT is extremely weak (19). After ethanol ingestion, acetaldehyde levels in saliva are markedly higher than in blood (20), especially in inactive ALDH2 heterozygotes (21).…”

Section: Introductionmentioning

confidence: 99%

Risk of Squamous Cell Carcinoma of the Upper Aerodigestive Tract in Cancer-Free Alcoholic Japanese Men: An Endoscopic Follow-up Study

Yokoyama

Omori²,

Yokoyama

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Asian case-control studies have shown a strong relationship between the development of squamous cell carcinoma (SCC) of the esophagus and alcohol consumption combined with inactive aldehyde dehydrogenase-2 (ALDH2*1/*2), lessactive alcohol dehydrogenase-1B (ADH1B*1/*1), high mean corpuscular volume (MCV), and self-reported facial flushing in response to alcohol. However, little is known about whether these risk factors prospectively influence cancer development in cancer-free alcoholics. Between 1993 and 2005, 808 Japanese alcoholic men diagnosed as cancer-free by an initial endoscopic screening examination received followup examinations ranging from 1 to 148 months (median, 31 months) later, and SCC of the upper aerodigestive tract was diagnosed in 53 of them (esophagus in 33 and oropharyngolarynx in 30). Cox proportional hazards analysis showed that the age-adjusted relative hazard for SCC was 11.55 [95% confidence interval (95% CI), 5.73-23.3] in ALDH2*1/*2 heterozygotes compared with ALDH2*1/*1 homozygotes, 2.02 (95% CI, 1.02-4.02) in ADH1B*1/*1 homozygotes compared with ADH1B*1/*2 heterozygotes or *2/*2 homozygotes, 2.64 (95% CI, 1.49-4.67) in patients with flushing compared with those who had never experienced flushing, 2.91 (95% CI, 1.63-5.20) in those with an MCV z 106 compared with those with an MCV < 106, 2.52 (95% CI, 1.22-5.22) in those who smoked z30 cigarettes per day compared with those who smoked 0 to 19 cigarettes per day, 7.26 (95% CI, 3.99-13.23) in those with esophageal dysplasia compared with those without distinct iodine-unstained lesions z5 mm, and 0.28 (95% CI, 0.09-0.85) in those with body mass index z 23.2 (highest quartile) compared with those with body mass index < 19.0 (lowest quartile). These predictors are useful for selecting appropriately patients for careful follow-up examinations. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2209 -15)

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Human stomach alcohol and aldehyde dehydrogenases: Comparison of expression pattern and activities in alimentary tract

Cited by 115 publications

References 3 publications

Genetic modulation of ADH1B and ALDH2 polymorphisms with regard to alcohol and tobacco consumption for younger aged esophageal squamous cell carcinoma diagnosis

Genetic modulation of ADH1B and ALDH2 polymorphisms with regard to alcohol and tobacco consumption for younger aged esophageal squamous cell carcinoma diagnosis

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

Risk of Squamous Cell Carcinoma of the Upper Aerodigestive Tract in Cancer-Free Alcoholic Japanese Men: An Endoscopic Follow-up Study

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