Genetic Polymorphisms of Alcohol and Aldehyde Dehydrogenases and Risk for Esophageal and Head and Neck Cancers

Yokoyama, Akira; Omori, Tai

doi:10.1016/j.alcohol.2005.04.003

Cited by 107 publications

(120 citation statements)

References 0 publications

Supporting

Mentioning

114

Contrasting

Unclassified

Order By: Relevance

“…A mutant allele, ALDH2 AA, has a single point mutation (G→A transition in exon 12) at position 1510 of the active ALDH2 GA gene. This results in the substitution of glutamic acid 504 to lysine, and therefore produces inactive ALDH2 (4,9,10).…”

Section: Introductionmentioning

confidence: 99%

A variant allele of ADH1B and ALDH2, is associated with the risk of esophageal cancer

Gong

Ding

et al. 2012

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Abstract. Alcoholic beverages are causally related to esophageal cancer. The genetic polymorphisms of the alcohol-metabolizing enzymes ADH1B rs1229984 and ALDH2 rs671 may modulate individual differences in alcohol-oxidizing capability. A case-control study was conducted to evaluate the genetic effects of these two functional single nucleotide polymorphisms (SNPs) on the development of esophageal cancer. A total of 380 esophageal squamous cell carcinoma cases and 380 controls were recruited. Genotypes were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Variant alleles of the functional polymorphism ADH1B rs1229984 SNP were associated with an increased risk of esophageal cancer [adjusted odds ratio (OR)=2.39, 95% confidence interval (CI)=1.42-4.03 for ADH1B rs1229984 GG vs. AA]. There was a borderline-significantly decreased risk between the ALDH2 rs671 genotype and esophageal cancer (adjusted OR=0.47, 95% CI=0.22-1.00 for ALDH2 rs671 AA vs. GG). Stratified analyses indicated that both of these effects were more evident among male, younger subjects and smokers. In conclusion, the functional polymorphisms ADH1B rs1229984 and ALDH2 rs671 may contribute to susceptibility to esophageal cancer, particularly among male, younger subjects and smokers. IntroductionEsophageal cancer is an extremely aggressive cancer, of which China has high-incidence regions (1). Esophageal squamous cell carcinoma (ESCC) is a subtype of esophageal cancer which accounts for >90% of cases (2). Esophageal cancer is known to be associated with environmental carcinogens. Epidemiological studies indicate that use of tobacco and consumption of alcohol are major risk factors for esophageal cancer. However, only a subset of individuals exposed to tobacco and alcohol develop esophageal cancer, suggesting a role of host susceptibility factors in cancer development. The genetic basis of esophageal cancer is complex and appears to involve multiple genes. Some studies have suggested that genetic polymorphisms might explain individual differences in susceptibility to esophageal cancer (3).Alcohol intake may be 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. The genetic polymorphisms of alcohol-metabolizing enzymes modulate individual differences in alcohol-oxidizing capability and drinking behavior (4).In humans, the major enzymes involved in the alcohol-metabolizing pathways are alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2). Alcohol is first oxidized by ADH to acetaldehyde, which is oxidized to acetate by ALDH. These enzymes are mainly expressed in the liver, but are also present in the gastrointestinal tract (5). A variant allele of

show abstract

Section: Introductionmentioning

confidence: 99%

A variant allele of ADH1B and ALDH2, is associated with the risk of esophageal cancer

Gong

Ding

et al. 2012

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

show abstract

“…Acetaldehyde has been established as a carcinogen in experimental animals (8) and is suspected of playing a critical role in cancer development in humans (9). Case-control studies in Japanese (10)(11)(12)(13) and Taiwanese (13)(14)(15)(16) individuals and prospective studies in which esophageal iodine staining has been used in Japanese alcoholics (17)(18)(19) have consistently shown a very strong link between the risk of esophageal SCC and alcohol drinking in people possessing the ALDH2*1/*2 genotype. Alcohol drinking together with the ALDH2*1/*2 genotype has been reported to be a risk factor for multiple cancerization in the upper aerodigestive tract (13,17,(19)(20)(21) and for oropharyngolaryngeal SCC (13,18,20,22,23).…”

Section: Introductionmentioning

confidence: 99%

Health Risk Appraisal Models for Mass Screening of Esophageal Cancer in Japanese Men

Yokoyama

Kumagai³

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

Self Cite

View full text Add to dashboard Cite

Background: Because early squamous cell carcinoma (SCC) of the esophagus is detectable by endoscopic esophageal iodine staining with high accuracy and is easily treated by endoscopic mucosectomy, it is important to develop efficient methods for screening candidates for the endoscopic examination. Inactive aldehyde dehydrogenase-2 (ALDH2) is a very strong risk factor for esophageal SCC in alcohol drinkers and thus may be suitable as a screening tool. Purpose: To assess the performance of health risk appraisal (HRA) models in screening for esophageal SCC in the Japanese male population. Methods: Two types of HRA models were developed based on our previous case-control study, which included assessment of ALDH2 activity and selected risk factors (HRA-G and HRA-F: activities of ALDH2 assessed by genotype and questionnaire for alcohol flushing, respectively). Each individual's risk of

show abstract

“…Metabolism of CH to TCE-OH and TCA by HK 2# was about 50% less compared to HK1#, metabolism being reduced at all time points at 3mM/day reflecting the cytotoxicity observed. Although we have only examined two samples, others have reported marked genetic polymorphisms in alcohol dehydrogenase and aldehyde reductase (Mizo et al, 1994;Li et al, 2001;Yokoyama and Omori, 2005;Wall, 2005). Recent studies using 13 samples of cryopreserved human hepatocytes, and CH as substrate, reported a large variability in alcohol dehydrogenase and aldehyde dehydrogenase activity among these samples (Bronley-DeLancey et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Lack of formic acid production in rat hepatocytes and human renal proximal tubule cells exposed to chloral hydrate or trichloroacetic acid

et al. 2007

View full text Add to dashboard Cite

The industrial solvent trichloroethylene (TCE) and its major metabolites have been shown to cause formic aciduria in male rats. We have examined whether chloral hydrate (CH) and trichloroacetic acid (TCA), known metabolites of TCE, produce an increase in formic acid in vitro in cultures of rat hepatocytes or human renal proximal tubule cells (HRPTC). The metabolism and cytotoxicity of CH was also examined to establish that the cells were metabolically active and not compromised by toxicity. Rat hepatocytes and HRPTC were cultured in serum-free medium and then treated with 0.3-3mM CH for 3 days or 0.03-3mM CH for 10 days respectively and formic acid production, metabolism to trichloroethanol (TCE-OH) and TCA and cytotoxicity determined. No increase in formic acid production in rat hepatocytes or HRPTC exposed to CH was observed over and above that due to chemical degradation, neither was formic acid production observed in rat hepatocytes exposed to TCA. HRPTC metabolised CH to TCE-OH and TCA with a 12-fold greater capacity to form TCE-OH versus TCA. Rat hepatocytes exhibited a 1.6-fold and 3-fold greater capacity than HRPTC to form TCE-OH and TCA respectively. CH and TCA were not cytotoxic to rat hepatocytes at concentrations up to 3mM/day for 3 days. With HRPTC, one sample showed no cytotoxicity to CH at concentrations up to 3mM/day for 10 days, while in another cytotoxicity was seen at 1mM/ day for 3 days. In summary, increased formic acid production was not observed in rat hepatocytes or HRPTC exposed to TCE metabolites, suggesting that the in vivo response cannot be modelled in vitro. CH was toxic to HRPTC at millimolar concentrations/day over 10 days, while glutathione derived metabolites of TCE were toxic at micromolar concentrations/day over 10 days supporting the view that glutathione derived metabolites are likely to be responsible for nephrotoxicity.

show abstract

Genetic Polymorphisms of Alcohol and Aldehyde Dehydrogenases and Risk for Esophageal and Head and Neck Cancers

Cited by 107 publications

References 0 publications

A variant allele of ADH1B and ALDH2, is associated with the risk of esophageal cancer

A variant allele of ADH1B and ALDH2, is associated with the risk of esophageal cancer

Health Risk Appraisal Models for Mass Screening of Esophageal Cancer in Japanese Men

Lack of formic acid production in rat hepatocytes and human renal proximal tubule cells exposed to chloral hydrate or trichloroacetic acid

Contact Info

Product

Resources

About