Alcohol and aldehyde dehydrogenase genotypes in Korsakoff syndrome

BACKGROUND: Previous studies have suggested a genetic predisposition to the development of Wernicke-Korsakoff syndrome (WKS), a neuropsychiatric syndrome commonly associated with alcoholism; however, little is known about this genetic risk factor. METHODS: To test the hypothesis that altered alcohol or aldehyde regulation is related to the development of WKS, the genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2) and alcohol dehydrogenase-2 (ADH2) were examined in 47 alcoholic subjects with WKS and compared with those of 342 alcoholic subjects without any WKS symptoms and 175 nonalcoholic controls. RESULTS: Although the frequencies of the ALDH2 genotypes and alleles did not differ significantly between alcoholic subjects with WKS and alcoholics without WKS, the ADH2*1/2*1 genotype and ADH2*1 allele were significantly increased in WKS. CONCLUSIONS: These findings suggest that the ADH2*1/2*1 genotype is a risk factor for the development of WKS in alcoholic patients.     

Alcohol intake, type of beverage, and risk of breast cancer in pre- and postmenopausal women

BACKGROUND: Most studies of the relation between alcohol consumption and breast cancer have shown a modestly increased risk, although the results are still conflicting. METHODS: The aim of this prospective population-based cohort study was to assess the influence of alcohol intake and type of beverage (beer, wine, or spirits) on breast cancer risk in relation to menopausal status. Among 13,074 women aged 20 to 91 years, we examined the relationship between breast cancer risk, total alcohol intake, and type of alcohol in relation to menopausal status. The women were classified as premenopausal or as postmenopausal at younger than 70 years or 70 years or more. RESULTS: During follow-up, 76 premenopausal and 397 postmenopausal women developed breast cancer. Premenopausal women who had an intake of more than 27 drinks per week had a relative risk of breast cancer of 3.49 (95% confidence limits, 1.36-8.99) compared with light drinkers (p = 0.011), whereas there were no differences in risk in the lower-intake categories. The increased risk of breast cancer among premenopausal women was independent of the type of alcohol. Postmenopausal women older than 70 years of age who had an intake of more than six drinks per week of spirits had a relative risk of breast cancer of 2.43 (95% confidence limits, 1.41-4.20) compared with women who consumed less than one drink of spirits per week (p = 0.0014). CONCLUSIONS: Total alcohol intake of more than 27 drinks per week increases breast cancer risk in premenopausal women independently of the type of alcohol. Among postmenopausal women, an intake of spirits of more than six drinks per week increases breast cancer risk.     

Alcohol and aldehyde dehydrogenase gene polymorphisms influence susceptibility to esophageal cancer in Japanese alcoholics

BACKGROUND: Studies have consistently demonstrated that inactive aldehyde dehydrogenase-2 (ALDH2), encoded by ALDH2*1/2*2, is closely associated with alcohol-related carcinogenesis. Recently, the contributions of alcohol dehydrogenase-2 (ADH2) polymorphism to alcoholism, esophageal cancer, and the flushing response have also been described. METHODS: To determine the effects of ALDH2 and ADH2 genotypes in genetically based cancer susceptibility, lymphocyte DNA samples from 668 Japanese alcoholic men more than 40 years of age (91 with and 577 without esophageal cancer) were genotyped and the results were expressed as odds ratios (ORs). This study also tested 82 of the alcoholics with esophageal cancer to determine whether cancer susceptibility is associated with patients' responses to simple questions about current or former flushing after drinking a glass of beer. RESULTS: The frequencies of ADH2*1/2*1 and ALDH2*1/2*2 were significantly higher in alcoholics with, than in those without, esophageal cancer (0.473 vs. 0.289 and 0.560 vs. 0.099, respectively). After adjustment for drinking and smoking, the analysis showed significantly increased cancer risk for alcoholics with either ADH2*1/2*I (OR = 2.03) or ALDH2*1/2*2 (OR = 12.76). For those having ADH2*1/2*1 combined with ALDH2*1/2*2, the esophageal cancer risk was enhanced in a multiplicative fashion (OR = 27.66). Responses to flushing questions showed that only 47.8% of the ALDH2*1/2*2 heterozygotes with ADH2*1/ 2*1, compared with 92.3% of those with ALDH2*1/2*2 and the ADH2*2 allele, reported current or former flushing. Genotyping showed that for alcoholics who reported ever flushing, the questionnaire was 71.4% correct in identifying ALDH2*1/2*2 and 87.9% correct in identifying ALDH2*1/2*1. CONCLUSION: Japanese alcoholics can be divided into cancer susceptibility groups on the basis of their combined ADH2 and ALDH2 genotypes. The flushing questionnaire can predict high risk ALDH2*1/2*2 fairly accurately in persons with ADH2*2 allele, but a reliable screening procedure for the highest risk gene combination (ADH2*1/2*1 and ALDH2*1/2*2) will require further investigation.     

Alcohol and Colorectal Cancer: The Role of Alcohol Dehydrogenase 1C Polymorphism

Background:  Chronic alcohol consumption is a risk factor for colorectal cancer. Animal experiments as well as genetic linkage studies in Japanese individuals with inactive acetaldehyde dehydrogenase leading to elevated acetaldehyde concentrations following ethanol ingestion support the hypothesis that acetaldehyde may be responsible for this carcinogenic effect of alcohol. In Caucasians, a polymorphism of alcohol dehydrogenase 1C ( ADH1C ) exists resulting in different acetaldehyde concentrations following ethanol oxidation.
Methods:  To evaluate whether the association between alcohol consumption and colorectal tumor development is modified by ADH1C polymorphism, we recruited 173 individuals with colorectal tumors diagnosed by colonoscopy and 788 control individuals without colorectal tumors. Genotyping was performed using genomic DNA extracted from whole blood followed by polymerase chain reaction.
Results:  Genotype ADH1C*1/1 was more frequent in patients with alcohol-associated colorectal neoplasia compared to patients without cancers in the multivariate model controlling for age, gender, and alcohol intake (odds ratio = 1.674, 95% confidence interval = 1.110–2.524, 2-sided p from Wald test = 0.0139). In addition, the joint test of the genetic effect and interaction between ADH1C genotype and alcohol intake (2-sided p  = 0.0007) indicated that the difference in ADH1C*1 polymorphisms between controls and colorectal neoplasia is strongly influenced by the alcohol consumption and that only individuals drinking more than 30 g ethanol per day with the genotype ADH1C*1/1 had an increased risk for colorectal tumors.
Conclusions:  These data identify ADH1C homozygosity as a genetic risk marker for colorectal tumors in individuals consuming more than 30 g alcohol per day and emphasize the role of acetaldehyde as a carcinogenic agent in alcohol-related colorectal carcinogenesis.     

Alcohol and Cancer

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Helmut K. Seitz and Shohei Matsuzaki. The presentations were (1) Alcohol dehydrogenase-2 and aldehyde dehydrogenase-2 genotype and cancer risk for upper aerodigestive tract in Japanese alcoholics, by Akira Yokoyama; (2) The role of acetaldehyde in alcohol-associated carcinogenesis, by Nils Homann; (3) High salivary acetaldehyde levels after a moderate dose of alcohol in ALDH2-deficient subjects, by Satu Väkeväinen; (4) Alcohol and vitamin A interactions, by Xian Dong Wang; and (5) Alcohol and colorectal cancer, by Helmut K. Seitz.     

Effects of variation at the ALDH2 locus on alcohol metabolism, sensitivity, consumption, and dependence in Europeans

BACKGROUND: The low-activity variant of the aldehyde dehydrogenase 2 (ALDH2) gene found in East Asian populations leads to the alcohol flush reaction and reduces alcohol consumption and risk of alcohol dependence (AD). We have tested whether other polymorphisms in the ALDH2 gene have similar effects in people of European ancestry. METHODS: Serial measurements of blood and breath alcohol, subjective intoxication, body sway, skin temperature, blood pressure, and pulse were obtained in 412 twins who took part in an alcohol challenge study. Participants provided data on alcohol reactions, alcohol consumption, and symptoms related to AD at the time of the study and subsequently. Haplotypes based on 5 single-nucleotide polymorphisms (SNPs) were used in tests of the effects of variation in the ALDH2 gene on alcohol metabolism and alcohol's effects. RESULTS: The typed SNPs were in strong linkage disequilibrium and 2 complementary haplotypes comprised 83% of those observed. Significant effects of ALDH2 haplotype were observed for breath alcohol concentration, with similar but smaller and nonsignificant effects on blood alcohol. Haplotype-related variation in responses to alcohol, and reported alcohol consumption, was small and not consistently in the direction predicted by the effects on alcohol concentrations. CONCLUSIONS: Genetic variation in ALDH2 affects alcohol metabolism in Europeans. However, the data do not support the hypothesis that this leads to effects on alcohol sensitivity, consumption, or risk of dependence.     

Effects of vitamin A deficiency on rat liver alcohol dehydrogenase expression and alcohol elimination rate in rats

BACKGROUND: Vitamin A has been suggested to regulate the expression of liver alcohol dehydrogenase (ADH) in humans. There are few studies on the ability of retinoic acid to affect ADH expression in vivo and none on its effects on alcohol metabolic rate. METHODS: Male Sprague Dawley rats were used for isolation of hepatocytes or were rendered vitamin A deficient by feeding a deficient diet for 7 weeks. ADH, retinoic acid receptor beta, and retinoid X receptor alpha protein levels were analyzed by Western blotting. Alcohol elimination rate was determined by following blood alcohol levels after administering a 1.5 g/kg dose of ethanol intraperitoneally. RESULTS: Retinoic acid had no effect on ADH protein in cultured hepatocytes. In the vitamin A deficient rats, retinol was not detectable in serum or liver at the time animals were killed. ADH and retinoid X receptor alpha protein levels were unchanged in the deficient group compared with a vitamin A sufficient control group, whereas retinoic acid receptor beta levels increased 40%. The deficient rats had a reduced volume of distribution of alcohol, but this largely was accounted for by their smaller body size. The alcohol elimination rates were lower in the deficient animals, but this was accounted for by reduced body and liver weights. CONCLUSIONS: Severe vitamin A deficiency did not alter liver ADH protein expression or rates of alcohol elimination when expressed per gram of body or liver weight.     

The association of ADH and ALDH gene variants with alcohol drinking habits and cardiovascular disease risk factors

Background: Genetic variation in ethanol metabolism may have an influence on both alcohol drinking habits and the susceptibility to health effects of alcohol drinking. Such influences are likely to bias exposure‐disease associations in epidemiologic studies of health effects of alcohol drinking. In a Caucasian population, we examined the association of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genetic variants with alcohol drinking habits, biomarkers of alcohol exposure, and risk factors for cardiovascular disease. Methods: The study population consisted of 1,216 Danish men and women aged 15–77 years participating in a health examination in 1998. The health examination included a self‐administered questionnaire (alcohol drinking habits), a physical examination (blood pressure), and various blood tests [alanine aminotransferase (ALAT), erythrocyte mean corpuscular volume (E‐MCV), and lipids]. ADH and ALDH gene variants were determined by standard techniques. Data were analyzed by regression analyses adjusted for relevant confounders. Results: Self‐reported alcohol drinking was significantly associated with increasing levels of ALAT, E‐MCV, high‐density lipoprotein cholesterol, and blood pressure. The ALDH1b ala69val variant was associated with nondrinking and total alcohol intake. The ALDH2 promoter variant was associated with binge‐drinking, and the ALDH1b1 ala69val polymorphism was associated with diastolic blood pressure. We did not find any statistically significant interactions between any of the gene variants and alcohol consumption in relation to the various outcomes. Conclusions: In this Caucasian population sample, we found evidence to support that genetic variation in ethanol metabolism may influence drinking habits, but no statistically significant gene‐environment interactions. More large‐scale epidemiologic studies are needed to confirm theses results and to further investigate genetic susceptibility to the effects of alcohol drinking.     

Alcohol consumption and the risk of breast cancer

Epidemiologic studies addressing the association of alcohol consumption with breast cancer consistently suggest a modest association and a dose-response relationship. The epidemiologic evidence does not point to a single mechanism to explain the association, and several mechanisms have been proposed. Alcohol consumption is shown to increase levels of endogenous estrogens, known risk factors for breast cancer. This hypothesis is further supported by data showing that the alcohol-breast cancer association is limited to women with estrogen-receptor positive tumors. Products of alcohol metabolism are known to be toxic and are hypothesized to cause DNA modifications that lead to cancer. Recent research has focused on genes that influence the rate of alcohol metabolism, with genes that raise blood concentrations of acetaldehyde hypothesized to heighten breast cancer risk. Mounting evidence suggests that antioxidant intake(e.g.folate)mayreducealcohol-associatedbreast cancer risk, because it neutralizes reactive oxygen species, a second-stage product of alcohol metabolism. Diets lacking sufficient antioxidant intake, as a result, may further elevate the risk of breast cancer among alcohol consumers. Given that alcohol consumption is increasing worldwide and especially among women in countries of rapid economic growth, a greater understanding of the mechanisms underlying the known alcohol-breast cancer association is warranted. Avoiding overconsumption of alcohol is recommended, especially for women with known risk factors for breast cancer.     

Alcohol metabolism in human cells causes DNA damage and activates the Fanconi anemia-breast cancer susceptibility (FA-BRCA) DNA damage response network

Background: We recently reported that exposure of human cells in vitro to acetaldehyde resulted in the activation of the Fanconi anemia–breast cancer susceptibility (FA‐BRCA) DNA damage response network. Methods: To determine whether intracellular generation of acetaldehyde from ethanol metabolism can cause DNA damage and activate the FA‐BRCA network, we engineered HeLa cells to metabolize alcohol by expression of human alcohol dehydrogenase (ADH) 1B. Results: Incubation of HeLa‐ADH1B cells with ethanol (20 mM) resulted in acetaldehyde accumulation in the media, which was prevented by co‐incubation with 4‐methyl pyrazole (4‐MP), a specific inhibitor of ADH. Ethanol treatment of HeLa‐ADH1B cells produced a 4‐fold increase in the acetaldehyde–DNA adduct and N²‐ethylidene‐dGuo and also resulted in the activation of the FA‐BRCA DNA damage response network, as indicated by a monoubiquitination of FANCD2 and phosphorylation of BRCA1. Ser 1524 was identified as 1 site of BRCA1 phosphorylation. The increased levels of DNA adducts, FANCD2 monoubiquitination, and BRCA1 phosphorylation were all blocked by 4‐MP, indicating that acetaldehyde, rather than ethanol itself, was responsible for all 3 responses. Importantly, the ethanol concentration we used is within the range that can be attained in the human body during social drinking. Conclusions: Our results indicate that intracellular metabolism of ethanol to acetaldehyde results in DNA damage, which activates the FA‐BRCA DNA damage response network.     

Characteristics of Japanese Alcoholics with the Atypical Aldehyde Dehydrogenase 2*2.I. A Comparison of the Genotypes of ALDH2, ADH2, ADH3, and Cytochrome P-4502E1 Between Alcoholics and Nonalcoholics

We examined the genotypes of the aldehyde dehydrogenase (ALDH)-2 , alcohol dehydrogenase (ADH)-2, ADH3 , and P-4502E1 loci of 53 alcoholics and 97 nonalcoholics. All of the subjects fulfilled the DSM-III-R criteria for alcohol dependence. The control group consisted of 97 subjects who were either hospital staff or students. We also compared the frequencies of homozygous ALDH2*1/1 and heterozygous ALDH2*1/2 genotypes in alcoholics. Our study revealed differences in the allelic frequencies of the ALDH2, ADH2 , and ADH3 loci between alcoholics and nonalcoholics. For alcoholics with both homozygous ALDH2*1/1 and heterozygous ALDH2*1/2 genotypes, it was found that ADH2 and ADH3 played important roles. Alcoholics with the heterozygous ALDH2*1/2 genotype showed a significantly higher frequency of ADH2*1/1 than ones with the homozygous ALDH2*1/1 genotype. We assume ADH2*1 plays an important role in the development of alcoholism in alcoholics with the heterozygous ALDH2*1/2 genotype.     

Polymorphisms of alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 and colorectal cancer risk in Chinese males

AIM： To evaluate the relationship between drinking and polymorphisms of alcohol dehydrogenase 2 （ADH2） and/or aldehyde dehydrogenase 2 （ALDH2） for risk of colorectal cancer （CRC） in Chinese males. METHODS： A case-control study was conducted in 190 cases and 223 population-based controls. ADH2 Arg47His （G-A） and ALDH2 Glu487Lys （G-A）genotypes were identified by PCR and denaturing high-performance liquid chromatography （DHPLC）. Information on smoking and drinking was collected and odds ratio （OR） was estimated. RESULTS= The ADH2 A/A and ALDH2 G/G genotypes showed moderately increased CRC risk. The age- and smoking-adjusted OR for ADH2 A/A relative to G/A and G/G was 1.60 （95% CI=1.08-2.36）, and the adjusted OR forALDH2 G/G relative to G/A and A/A was 1.79 （95% CI= 1.19-2.69）. Significant interactions between ADH2, ALDH2 and drinking were observed. As compared to the subjects with ADH2 G and ALDH2 A alleles, those with ADH2 A/A and ALDH2 G/G genotypes had a significantly increased OR （3.05, 95% CI= 1.67-5.57）. The OR for CRC among drinkers with the ADH2 A/A genotype was increased to 3.44 （95% CI= 1.84-6.42） compared with non-drinkers with the ADH2 G allele. The OR for CRC among drinkers with the ALDH2 G/G genotype was also increased to 2.70 （95% CI= 1.57-4.66） compared with non-drinkers with the ALDH2 A allele. CONCLUSION： Polymorphisms of the ADH2 and ALDH2 genes are significantly associated with CRC risk. There are also significant gene-gene and gene-environment interactions between drinking and ADH2 and ALDH2 polymorphisms regarding CRC risk in Chinese males.     

Influence of age, sex, and Helicobacter pylori infection before and after eradication on gastric alcohol dehydrogenase activity

BACKGROUND: Gastric alcohol dehydrogenase may contribute to the metabolism of orally ingested ethanol and decrease the bioavailability of the drug. The aims of this study were to assess the impact of Helicobacter pylori infection and its eradication on gastric alcohol dehydrogenase activity and to relate the findings to gastric histology. Furthermore, the role of age- and sex-related differences in gastric alcohol dehydrogenase activity were studied. METHODS: A total of 76 subjects (39 women and 37 men) underwent upper gastrointestinal endoscopy, and biopsies were obtained from the corpus and antrum. The specimens were used for determining gastric alcohol dehydrogenase activity, histological examination, and urease testing. Subjects with H. pylori infection (n = 36) received medication to eradicate the infection, and repeat biopsies were taken 2 and 12 months later. RESULTS: No significant difference in gastric alcohol dehydrogenase activity was found between men and women (p > 0.05). Gastric alcohol dehydrogenase activity did not differ significantly between the subjects older than 50 years (n = 39) and those 50 years or younger (n = 37). In subjects with H. pylori infection, gastric alcohol dehydrogenase activity was significantly reduced in the antrum (p < 0.05). After eradication of H. pylori, alcohol dehydrogenase activity in the antrum increased significantly within 2 months (p < 0.01). Antral biopsies with the most pronounced inflammation and histological changes had significantly decreased alcohol dehydrogenase activity (p < 0.05). In contrast, no significant differences were found in corpus. CONCLUSIONS: H. pylori infection is associated with decreased antral alcohol dehydrogenase activity, which seems to be related to the severity of the inflammatory changes in the mucosa. Eradication of H. pylori normalizes antral alcohol dehydrogenase activity within 2 months.     

Association of alcohol dehydrogenase genes with alcohol-related phenotypes in a Native American community sample

Background: Previous linkage studies, including a study of the Native American population described in the present report, have provided evidence for linkage of alcohol dependence and related traits to chromosome 4q near a cluster of alcohol dehydrogenase (ADH) genes, which encode enzymes of alcohol metabolism. Methods: The present study tested for associations between alcohol dependence and related traits and 22 single‐nucleotide polymorphisms (SNPs) spanning the 7 ADH genes. Participants included 586 adult men and women recruited from 8 contiguous Native American reservations. A structured interview was used to assess DSM‐III‐R alcohol dependence criteria as well as a set of severe alcohol misuse symptoms and alcohol withdrawal symptoms. Results: No evidence for association with the alcohol dependence diagnosis was observed, but an SNP in exon 9 of ADH1B (rs2066702; ADH1B*3) and an SNP at the 5′ end of ADH4 (rs3762894) showed significant evidence of association with the presence of withdrawal symptoms (p = 0.0018 and 0.0012, respectively). Further, a haplotype analysis of these 2 SNPs suggested that the haplotypes containing either of the minor alleles were protective against alcohol withdrawal relative to the ancestral haplotype (p = 0.000006). Conclusions: These results suggest that variants in the ADH1B and ADH4 genes may be protective against the development of some symptoms associated with alcohol dependence.     

Alcohol Dehydrogenase Activities in the Human Gastric Mucosa: Effects of Helicobacter pylori Infection, Sex, Age, and the Part of the Stomach

Background: Human gastric mucosa contains three alcohol dehydrogenase (ADH) isozymes (classes I, III, and IV). Various factors such as Helicobacter pylori infection, sex, age, and the part of the stomach involved have been suggested to affect alcohol dehydrogenase activities, although these views are controversial. In this study, these unsettled issues were reexamined.
Methods: Activities of class I and IV ADHs were evaluated in the cytosolic fraction of human gastric mucosa samples by reduction of their preferred substrates, namely acetaldehyde and m-nitrobenzaldehyde, and activities of class III were evaluated by oxidation of its preferred substrate, formaldehyde. Then, effects of Helicobacter pylori infection, sex, age, and the part of the stomach involved were examined.
Results: Class I, III, and IV ADH activities were 17.5 ± 8.4, 4.2 ± 2.5, and 8.9 ± 3.9 nmol of nicotinamide adenine dinucleotide oxidation per minute per milligram of protein, respectively, for the entire population. Helicobacter pylori infection significantly reduced class I and IV ADH activities but did not affect activity of class III. In the samples without Helicobacter pylori infection and severe gastritis, sex did not affect class I, III, or IV ADH activities. In the same series, class IV ADH activity significantly decreased with age ( p = 0.006), whereas no correlation was found between age and ADH activity of class I and III ADHs. The level of class IV ADH activity was significantly higher in the upper body than in the lower regions, whereas no such heterogeneity was observed in class I and III ADH.
Conclusions: Various factors affect human gastric ADH activities, such that careful interpretation of their significance is necessary.     

Alterations in ethyl alcohol pharmacokinetics during oral consumption of malt liquor beverages in African Americans

Background: Malt liquor (ML) beverages have become increasingly popular among urban minority groups, due partly to their inexpensive price and targeted advertising. We hypothesized that nonfermented by‐products contained in ML beverages will alter the pharmacokinetics (PK) and pharmacodynamic (PD) effects of its ethanol content. In addition, we determined the effect of alcohol dehydrogenase (ADH) genotypes on the PK following consumption of ML beverages. Methods: The study was conducted in 31 healthy adult African‐American social drinkers, mean ± SD age of 22.3 ± 1.3 years, and weight of 70.7 ± 10.9 kg. Participants were administered ethanol, in randomized order, 2‐weeks apart, in the form of oral ML beverage (6%v/v), or isocaloric solution of diet soda–ethanol (DS–Etoh) beverage (6%v/v). During each session the beverage was consumed over 4 minutes and breath alcohol concentrations (BrAC) as well as subjective and behavioral effects of ethanol were evaluated over 180 minutes. Pharmacokinetic parameters of ethanol were calculated using Michaelis–Menten elimination kinetics. The effect of ML and ADH genotype on PK was evaluated using the Wilcoxon rank‐sum test and the Wilcoxon signed rank test, respectively. Results: Results show a slower mean rate of absorption, K_a, (0.12 vs. 0.15 min^?1, p = 0.03) and a longer time to reach maximum concentration, T_max, (28 vs. 23 minute, p < 0.01) for the ML compared with DS–Etoh beverage. The ML beverage resulted in a larger area under the BrAC–time curve compared with DS–Etoh beverage (8.4 vs. 6.8 min g/dl, p = 0.02). There was no difference in the subjective PD effects between the 2 beverages. Conclusion: Results show that exposure to ethanol following the consumption of ML beverages is different compared to that following nonmalt beverages in African‐Americans. These differences may be related to nonfermented by‐products present in commercially available ML products. These PK differences do not appear to result in significant perceived alcohol PD changes, nor are they related to ADH genotype.     

Relationship between genetic polymorphisms of alcohol and aldehyde dehydrogenases and esophageal squamous cell carcinoma risk in males

AIM: To investigate the association between the genetic polymorphisms of ADH2 and ALDH2, lifetime alcohol consumption and esophageal cancer risk in the Taiwanese men. METHODS: Between August 2000 and June 2003, 134 pathologically-proven esophageal squamous cell carcinoma male patients and 237 male controls were recruited from Kaohsiung Medical University Hospital and Kaohsiung Veterans General Hospital in southern Taiwan. ADH2 and ALDH2 polymorphisms were genotyped using PCR-RFLP. RESULTS: Compared to those with ADH2*2/*2, individuals with ADH2*l/*2 and ADH2*1/*1 had 2.28-and 7.14-fold, respectively, increased risk of developing esophageal cancer (95%CI = 1.11-4.68 and 2.76-18.46) after adjusting for alcohol consumption and other covariates. The significant increased risk was also noted among subjects with ALDH2*l/*2 (adjusted OR (AOR) = 5.25, 95%CI = 2.47-11.19), when compared to those with ALDH2*1/*1. The increased risk of esophageal cancer was made greater, when subjects carried both ADH2*1/*1 and ALDH2*1/*2, compared to those with ADH2*1/*2 or ADH2*2/*2 and ALDH2*1/*1 (AOR = 36.79, 95%CI = 9.36-144.65). Furthermore, we found a multiplicative effect of lifetime alcoholic consumption and genotypes (ADH2 and ALDH2) on esophageal cancer risk. CONCLUSION: Our findings suggest that polymorphisms of ADH2 and ALDH2 can modify the influence of alcoholic consumption on esophageal cancer risk.     

Effect of aldehyde dehydrogenase-2 genotype on cardiac autonomic nervous responses to moderate alcohol ingestion

Background:  Asian people are divided into the individuals who can ingest alcohol and cannot because of the difference of aldehyde dehydrogenase-2 (ALDH2) genotype. The purpose of the present study was to investigate the effect of ALDH2 genotype on cardiac autonomic nervous responses to moderate alcohol ingestion.
Methods:  Subjects were 17 healthy male students at Kyoto University. According to the difference of ALDH2 genotype, they were divided into two groups: the STRONG ( n  = 10) and WEAK ( n  = 7) group. The subjects ingested 10 (the LITTLE trial) or 30 g (the MUCH trial) of pure alcohol on a separate day randomly. We collected ECG data and analyzed QT interval.
Results:  ECG QT interval, the important marker for sudden cardiac death in cardiac patients as well as healthy people, of the STRONG group were not prolonged after alcohol ingestion, but that of the WEAK group were significantly prolonged, compared to control. Moreover, with respect to the comparison of the change of QT interval between the LITTLE and MUCH trials, there were also no significant differences in the STRONG group. In the WEAK group, however, the change was more marked at MUCH trial.
Conclusions:  It is concluded that the cardiovascular response to alcohol ingestion is influenced by ALDH2 genotype and that the drinking assumed to be in moderation puts a strain on the hearts for the ALDH2-deficient individuals. The results of this investigation show that moderate drinking does not have a good effect on everybody with respect to QT interval. This study also shows that moderate alcohol intake does not have a bad effect on the immune system regardless of ALDH2 genotype.     

ADH4-lacZ Transgenic Mouse Reveals Alcohol Dehydrogenase Localization in Embryonic Midbrain/ Hindbrain, Otic Vesicles, and Mesencephalic, Trigeminal, Facial, and Olfactory Neural Crest

Pursuit of endogenous functions for various members of the alcohol dehydrogenase (ADH) enzyme family has led to exploration of gene expression patterns. Herein, we have used transgenic mice to examine the mouse gene encoding class IV ADH (ADH4), an enzyme that is weakly effective as an ethanol dehydrogenase, but highly effective as a retinol dehydrogenase in vitro. ADH4 promoter and upstream regulatory sequences were fused to lacZ and stably introduced into mice so that embryonic expression of ADH4 could be easily monitored by examination of β-galactosidase activity in situ. Several independent founder mice carrying ADH4-lacZ transgenes with either 2.7 or 9.0 kb of upstream regulatory sequences produced embryos in which expression was highly localized in the brain and craniofacial region at stages E8.5 to 9.5 during neurulation. Expression in the brain was limited to the ventral midbrain and its boundary with the hindbrain. At stage E8.5, ADH4-lacZ expression was noticed in several dispersed regions throughout the head, and by stage E9.5 it was evident that these regions corresponded to the otic vesicles and migrating neural crest cells, particularly the mesencephalic, trigem-inal, facial, and olfactory neural crest. ADH4-lacZ expression in the trigeminal neural crest appeared as long fibers emanating from the midbrain/hindbrain boundary and extending to the first branchial arch following the tract of the trigeminal nerve. These findings support the hypothesis that ADH4 may normally function in retinoic acid synthesis needed for brain and neural crest development and that it participates in the mechanism of ethanol-induced brain and craniofacial birth defects.