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PubMed2005

Paired acute inhalation test reveals that acetaldehyde toxicity is higher in aldehyde dehydrogenase 2 knockout mice than in wild-type mice.

Aldehyde dehydrogenase 2 (ALDH2) is an important enzyme that oxidizes acetaldehyde. Approximately 45% of Chinese and Japanese individuals have the inactive ALDH2 genotypes (ALDH2*2/*2 and ALDH2*1/*2); acute inhalation toxicity of acetaldehyde has not been evaluated in these populations. We compared the toxicity between wild-type (Aldh2+/+) and Aldh2-inactive transgenic (Aldh2-/-) mice by using the paired acute inhalation test modified from the acute toxic class method (OECD TG433). Blood acetaldehyde level was measured 4 hr after the inhalation. A pair of Aldh2+/+ and Aldh2-/- mice was put into a chamber and was exposed to 5000 ppm of acetaldehyde. At the start of the inhalation, the mice exhibited hypoactivity and closing of the eyes. Subsequently, symptoms such as crouching, bradypnea, and piloerection were observed. Flushing was observed only in the Aldh2+/+ mice. Symptoms such as tears, straggling gait, prone position, pale skin, abnormal deep respiration, dyspnea, and one case of death were observed only in the Aldh2-/- mice. The symptoms did not change 1 hr after inhalation in the Aldh2+/+ mice. In contrast, in the Aldh2-/- mice, the symptoms became more severe until the end of the inhalation. The blood acetaldehyde level in the Aldh2-/- mice was approximately twice that in the Aldh2+/+ mice 4 hr after inhalation. The Aldh2-/- mice evidently showed more severe toxicity as compared with the Aldh2+/+ mice due to acute inhalation of acetaldehyde at a concentration of 5000 ppm. Acetaldehyde toxicity in Aldh2+/+ and Aldh2-/- mice was estimated and classified one class different. Based on this study, acetaldehyde inhalations were inferred to pose a higher risk to ALDH2-inactive human individuals.

Acetaldehyde↗
PubMed2002

Chaperonin GroESL mediates the protein folding of human liver mitochondrial aldehyde dehydrogenase in Escherichia coli.

An efficient bacterial expression system for the human mitochondrial aldehyde dehydrogenase (ALDH2) was developed using co-overexpression of heat shock chaperone gene GroESL. On the basis of the ALDH2 amino acid sequence and cDNA sequences a full-length cDNA encoding wild-type ALDH2 was cloned from a human liver library. A mutant-type ALDH2 (ALDH2(2)) was developed using site-directed mutagenesis of the ALDH2 cDNA and also cloned. Both types of ALDH2 cDNA were subcloned for expression in Escherichia coli (E. coli), recombinant ALDH2 and ALDH2(2) were successfully expressed as soluble active enzymes following co-expression with a second plasmid construct producing GroES and GroEL, E. coli chaperonin proteins. Purified wild-type ALDH2 and mutant ALDH2(2) had a K(m) for acetaldehyde of 0.65 and 25.73 microM, respectively. Co-expression of ALDH2 with ALDH2(2) in the presence of E. coli chaperonins produced a soluble enzyme with a K(m) for acetaldehyde of 8.79 microM, suggesting that the product was a heteromer. Mitochondrial matrix hsp60 and hsp10 chaperonins are then thought to act on imported ALDH2 and are essential for accurate protein folding and multisubunit formation. Protein-protein interactions between ALDH2s and various chaperones were investigated using the yeast two-hybrid system. The wild-type and mutant-type enzymes strongly interacted with each other and GroEL and ALDH2s also interacted but only weakly. Chaperone hsp10 also interacted with hsp60 and ALDH2(1) and ALDH2(2), but again the interactions were weak ones.

Aldehyde Dehydrogenase↗
PubMed2003

Mean corpuscular volume and the aldehyde dehydrogenase-2 genotype in male Japanese workers.

BACKGROUND: Increased mean corpuscular volume (MCV) is common in alcohol abusers and alcoholics. MCV is higher in Japanese heavy drinkers with inactive aldehyde dehydrogenase-2 (ALDH2) encoded by ALDH2*1/2*2 than among those with active ALDH2 encoded by ALDH2*1/2*1. Inactive ALDH2 dramatically increases blood acetaldehyde levels after alcohol intake. Because moderate and heavy drinkers with ALDH2*1/2*2 have very high risks for esophageal cancer, MCV might serve as an indicator of these high-risk drinkers. METHODS: In this investigation of the association of red cell values with the ALDH2 genotype and possible confounding factors, the drinking, smoking, and dietary habits reported on a structured questionnaire by 163 Japanese working men were subjected to multivariate analyses. RESULTS: Aging, lower body mass index (BMI), more alcohol consumption, and more smoking were positively associated with increased MCV. Among moderate to heavy drinkers (>or=9 units/week; 1 unit = 22 g of ethanol), both MCV and mean corpuscular hemoglobin were higher and the red cell count was lower in those with ADLH2*1/2*2 than in those with ALDH2*1/2*1. Multiple linear regression analysis after adjustment for age, BMI, and smoking revealed that a positive relationship between the amount of drinking and MCV but inverse relationships for drinking and red cell count, as well as hemoglobin and hematocrit values, were significantly stronger for men with ALDH2*1/2*2 than for those with ALDH2*1/2*1, demonstrating a gene-environment interaction. Drinking accounted for 19.9% of interindividual MCV variance among men with ALDH2*1/*2*2 but for only 1.3% of variance among those with ALDH2*1/2*1. Age, BMI, drinking, and smoking accounted for 52.1 and 34.7% of the variation among those with ALDH2*1/2*2 and ALDH2*1/2*1, respectively. Macrocytosis (MCV >or=100.0 fl) was observed in 18 subjects (11.0%), and use of macrocytosis as a biomarker of moderate to heavy drinkers with ALDH2*1/2*2 had a sensitivity of 54.5% (6 of 11) and a specificity of 92.1% (140 of 152). CONCLUSIONS: Alcohol-related red cell value changes associated with inactive ALDH2 in Japanese men suggest the importance of acetaldehyde's role in increasing MCV and the potential for using MCV as a marker for high-risk drinkers for esophageal cancer.

Adult↗
PubMed2006

The UChA and UChB rat lines: metabolic and genetic differences influencing ethanol intake.

Ethanol non-drinker (UChA) and drinker (UChB) rat lines derived from an original Wistar colony have been selectively bred at the University of Chile for over 70 generations. Two main differences between these lines are clear. (1) Drinker rats display a markedly faster acute tolerance than non-drinker rats. In F2 UChA x UChB rats (in which all genes are 'shuffled'), a high acute tolerance of the offspring predicts higher drinking than a low acute tolerance. It is further shown that high-drinker animals 'learn' to drink, starting from consumption levels that are one half of the maximum consumptions reached after 1 month of unrestricted access to 10% ethanol and water. It is likely that acquired tolerance is at the basis of the increases in ethanol consumption over time. (2) Non-drinker rats carry a previously unreported allele of aldehyde dehydrogenase-2 (Aldh2) that encodes an enzyme with a low affinity for Nicotinamide-adenine-dinuclectide (NAD+) (Aldh2(2)), while drinker rats present two Aldh2 alleles (Aldh2(1) and Aldh2(3)) with four- to fivefold higher affinities for NAD+. Further, the ALDH2 encoded by Aldh2(1) also shows a 33% higher Vmax than those encoded by Aldh2(2) and Aldh2(3). Maximal voluntary ethanol intakes are the following: UChA Aldh2(2)/Aldh2(2) = 0.3-0.6 g/kg/day; UChB Aldh2(3)/Aldh2(3) = 4.5-5.0 g/kg/day; UChB Aldh2(1)/Aldh2(1) = 7.0-7.5 g/kg/day. In F2 offspring of UChA x UChB, the Aldh2(2)/Aldh2(2) genotype predicts a 40-60% of the alcohol consumption. Studies also show that the low alcohol consumption phenotype of Aldh2(2)/Aldh2(2) animals depends on the existence of a maternally derived low-activity mitochondrial reduced form of nicotinamide-adenine-dinucleotide (NADH)-ubiquinone complex I. The latter does not influence ethanol consumption of animals exhibiting an ALDH2 with a higher affinity for NAD+. An illuminating finding is the existence of an 'acetaldehyde burst' in animals with a low capacity to oxidize acetaldehyde, being fivefold higher in UChA than in UChB animals. We propose that such a burst results from a great generation of acetaldehyde by alcohol dehydrogenase in pre-steady-state conditions that is not met by the high rate of acetaldehyde oxidation in mitochondria. The acetaldehyde burst is seen despite the lack of differences between UChA and UChB rats in acetaldehyde levels or rates of alcohol metabolism in steady state. Inferences are drawn as to how these studies might explain the protection against alcoholism seen in humans that carry the high-activity alcohol dehydrogenase but metabolize ethanol at about normal rates.

Alcohol Drinking↗
PubMed2006

Monoamine metabolism and behavioral responses to ethanol in mitochondrial aldehyde dehydrogenase knockout mice.

BACKGROUND: It is widely accepted that, in addition to removing acetaldehyde produced during the metabolism of ethanol, mitochondrial aldehyde dehydrogenase (ALDH2) functions in the pathway by which aldehyde metabolites of the monoamines dopamine (DA) and serotonin (5-HT) are converted to their acidic metabolites. Moreover, studies of ALDH2 inhibitors used for treating alcoholism suggest that their antidipsotropic effects may be related to inhibition of monoamine metabolism. Therefore, we examined the hypothesis that altered brain monoamine metabolism is related to the influence of ALDH2 on behavioral responses to ethanol. METHODS: Mice were generated with a gene-trap mutation of the ALDH2 gene. ALDH2 mRNA was absent in ALDH2-/- mice. Western blot analysis of liver mitochondria confirmed the absence of ALDH2 protein in the ALDH2-/- mice. Wild-type and ALDH2-deficient mice were tested for the effects of different doses of ethanol on locomotor activity, ataxia, and a 2-bottle ethanol-water preference test. RESULTS: Wild-type and ALDH2+/- mice preferred ethanol to water. However, ALDH2-/- mice drank significantly less ethanol than wild-type or ALDH2+/- mice. Locomotor activity and ataxia were significantly more affected by ethanol in ALDH2-/- mice than in wild-type or ALDH2+/- mice. There was no effect of genotype on levels of 5-HT, DA, or their precursors or metabolites in several brain regions, as measured by HPLCec. CONCLUSIONS: The results indicate that: (1) the effect of the mutant genotype on behavioral responses to ethanol is unrelated to altered brain monoamine metabolism and (2) ALDH2 is not required for the metabolism of brain monoamines in vivo.

Aldehyde Dehydrogenase↗
PubMed2005

Expression of aldehyde dehydrogenase 2 in the normal esophageal epithelium and alcohol consumption in patients with esophageal cancer.

Alcohol consumption is a risk factor for esophageal cancer. Acetaldehyde, a highly toxic intermediate produced from ethanol, is converted to acetic acid mainly by aldehyde dehydrogenase 2 (ALDH2) in the metabolic pathway of ethanol. Fifty percent of Japanese have inactive ALDH2 due to genetic polymorphism, which is considered to be a risk factor associated with esophageal cancer. In our previous study, we have demonstrated that ALDH2 is expressed in the esophagus with a considerable variation among individuals. In this study, we further investigated the expression of ALDH2 in esophagus and its relationship with risk factors of esophageal cancer. Tissue specimens resected from 51 patients with esophageal cancer were analyzed by immunohistochemistry using ALDH2-antibody. The immuno-staining of ALDH2 in the esophageal epithelium was compared with both the drinking habit and the occurrence of flushing that is closely associated with the ALDH2 deficiency. ALDH2 was not detectable in 8 (16%) among 51 specimens. All of the 8 patients were non- or light-drinkers but not heavy-drinkers. Among 18 patients showing the high level ALDH2 expression in the esophagus, 15 patients (83%) were heavy-drinkers. Although the relationship between the ALDH2 deficiency and drinking habit is not clear, the patients with ALDH2 deficiency tend to be non- or light drinkers while heavy-drinkers tend to have the active form of ALDH2. These results suggest that both inactive and active forms of ALDH2 are induced in the esophagus by heavy drinking and also support a hypothesis that ALDH2 deficiency might be a high-risk factor of esophageal cancer for the individuals having a heavy-drinking habit. To our knowledge, this is the first study demonstrating the induction of ALDH2 in the esophagus by ethanol consumption.

Alcohol Drinking↗
PubMed2005

Hangover susceptibility in relation to aldehyde dehydrogenase-2 genotype, alcohol flushing, and mean corpuscular volume in Japanese workers.

BACKGROUND: A study of Asian-American students suggested a positive association between inactive ALDH2*2 and susceptibility to hangover. A biomarker for moderate-to-heavy drinking in persons with inactive aldehyde dehydrogenase-2 (ALDH2) is increased mean corpuscular volume (MCV). METHODS: Associations between hangover and ALDH2 genotype, alcohol flushing, and MCV were examined for 251 Japanese workers (139 men, 112 women). RESULTS: Inactive ALDH2*1/2*2 heterozygotes drank less alcohol than active ALDH2*1/2*1 homozygotes (p < 0.0001), but the frequency of hangover did not significantly differ between the two groups for either gender. The amount of drinking reported to lead to hangover was significantly less for male and female ALDH2*1/2*2 heterozygotes than for their ALDH2*1/2*1 homozygous counterparts (p < 0.005). The proportion of men who had hangover three times or more during the past year increased significantly with increased daily alcohol consumption in men with the ALDH2*1/2*2 genotype (p = 0.0002) but not in those with the ALDH2*1/2*1 genotype. For men who usually consumed <44 g of ethanol/day, the median amount of drinking before hangover was significantly lower for ALDH2*1/2*2 men than for ALDH2*1/2*1 men reporting the same level of consumption. Hangover occurred with consistently high frequency among ALDH2*1/2*1 men, regardless of their daily consumption. Similar findings were observed in a comparison of men who never flushed and those who reported current or former flushing, a surrogate marker of inactive ALDH2. Assessment of hangover risk by quartiles of MCV showed that men with MCV of > or =96 had a significantly higher risk of hangover than did men with MCV of <91 (odds ratio = 5.56; 95% confidence interval = 1.69-18.25). CONCLUSIONS: Inactive heterozygous ALDH2, alcohol flushing, and increased MCV were positively associated with hangover susceptibility in Japanese workers, suggesting that acetaldehyde is etiologically linked to the development of hangover.

Adult↗
PubMed2000

Inactive aldehyde dehydrogenase 2 worsens glycemic control in patients with type 2 diabetes mellitus who drink low to moderate amounts of alcohol.

BACKGROUND: Alcohol intake can have hypoglycemic or hyperglycemic effects in patients with type 2 diabetes mellitus. The present study was designed to investigate the glycemic control of male patients with diabetes mellitus from the aspect of the genetic status of alcohol metabolism. METHODS: One hundred sixty-three men with type 2 diabetes mellitus were enrolled in the present study. They were all outpatients at the Diabetes Center of Saiseikai Central Hospital. The genotype of the aldehyde dehydrogenase 2 (ALDH2) gene of each patient was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and the patients were divided into those with active or inactive ALDH2 phenotype. We compared the amount of habitual alcohol intake and clinical data that included physical findings and blood chemistry of the patients in the active and inactive ALDH2 groups. The glycemic control of each patient was evaluated by the serum level of HbAlc. RESULTS: Of the 163 patients with type 2 diabetes mellitus, 90 patients had the active ALDH2 phenotype and 73 patients had the inactive ALDH2 phenotype. The mean HbA1c level of the active ALDH2 group was nearly the same as that of the inactive ALDH2 group. However, the HbA1c level of the light-to-moderate drinkers (1-400 g/week) in the inactive ALDH2 group was highest and was significantly higher than the HbA1c level of the light-to-moderate drinkers of the active ALDH2 group. The HbA1c of the patients with diabetic complications was higher than the HbAlc of those without diabetic complications in both the active and inactive ALDH2 groups. However, the HbA1c level of the light-to-moderate drinkers without diabetic complications in the inactive ALDH2 group was significantly higher and the incidence of 24 hr urinary C-peptide was higher than the respective level of the light-to-moderate drinkers without diabetic complications in the active ALDH2 group. CONCLUSIONS: Habitual light-to-moderate alcohol intake worsens glycemic control in diabetic patients who have the inactive ALDH2 phenotype. The data on 24 hr urinary C-peptide level suggested that increased acetaldehyde after light-to-moderate drinking by inactive ALDH2 diabetic patients may increase the HbA1c value by the insulin-resistant condition that resulted in hyperinsulinemia.

Adult↗
PubMed2002

Genetic polymorphisms of alcohol and aldehyde dehydrogenases and glutathione S-transferase M1 and drinking, smoking, and diet in Japanese men with esophageal squamous cell carcinoma.

The genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2), alcohol dehydrogenase-2 (ADH2), ADH3, and glutathione S-transferase M1 (GSTM1) influence the metabolism of alcohol and other carcinogens. The ALDH2*1/2*2 genotype, which encodes inactive ALDH2, and ADH2*1/2*1, which encodes the low-activity form of ADH2, enhance the risk for esophageal cancer in East Asian alcoholics. This case-control study of whether the enzyme-related vulnerability for esophageal cancer can be extended to a general population involved 234 Japanese men with esophageal squamous cell carcinoma and 634 cancer-free Japanese men who received annual health checkups. The GSTM1 genotype was not associated with the risk for this cancer. Light drinkers (1-8.9 units/week) with ALDH2*1/2*2 had an esophageal cancer risk 5.82 times that of light drinkers with ALDH2*1/2*1 (reference category), and their risk was similar to that of moderate drinkers (9-17.9 units/week) with ALDH2*1/2*1 (odds ratio = 5.58). The risk for moderate drinkers with ALDH2*1/2*2 (OR = 55.84) exceeded that for heavy drinkers (18+ units/week) with ALDH2*1/2*1 (OR = 10.38). Similar increased risks were observed for those with ADH2*1/2*1. A multiple logistic model including ALDH2, ADH2, and ADH3 genotypes showed that the ADH3 genotype does not significantly affect the risk for esophageal cancer. For individuals with both ALDH2*1/2*2 and ADH2*1/2*1, the risk of esophageal cancer was enhanced in a multiplicative fashion (OR = 30.12), whereas for those with either ALDH2*1/2*2 or ADH2*1/2*1 alone the ORs were 7.36 and 4.11. In comparison with the estimated population-attributable risks for preference for strong alcoholic beverages (30.7%), smoking (53.6%) and for lower intake of green and yellow vegetables (25.7%) and fruit (37.6%), an extraordinarily high proportion of the excessive risk for esophageal cancer in the Japanese males can be attributed to drinking (90.9%), particularly drinking by persons with inactive heterozygous ALDH2 (68.5%). Education regarding these risky conditions in connection with ALDH2 and ADH2 is vitally important in a new strategic approach aimed at preventing esophageal cancer in East Asians.

Adult↗
PubMed2005

Aldehyde dehydrogenase 2 gene targeting mouse lacking enzyme activity shows high acetaldehyde level in blood, brain, and liver after ethanol gavages.

BACKGROUND: Previously, we created an aldehyde dehydrogenase 2 gene transgenic (Aldh2-/-) mouse as an aldehyde dehydrogenase (ALDH) 2 inactive human model and demonstrated low alcohol preference. In addition, after a free-choice drinking test, no difference in the acetaldehyde level was observed between the Aldh2-/- and wild type (Aldh2+/+) mice. The actual amounts of free-choice drinking were so low that it is uncertain whether these levels are pharmacologically and/or behaviorally relevant in either strain. To elucidate this uncertainty, we compared the ethanol and acetaldehyde concentration in the blood, brain, and liver between the Aldh2-/- and Aldh2+/+ mice after ethanol gavages at the same dose and time. METHOD: We measured differences in the ethanol and acetaldehyde levels between the Aldh2-/- and Aldh2+/+ mice by headspace gas chromatography-mass spectrometry (GC-MS) after ethanol gavages at the same dose and time. RESULTS: Significantly higher blood acetaldehyde concentrations were found in the Aldh2-/- mice than in the Aldh2+/+ mice 1 hr after the administration of ethanol gavages at doses of 0.5, 1.0, 2.0, and 5.0 g/kg. The blood acetaldehyde concentrations in the two strains were 2.4 vs. 0.5, 17.8 vs. 1.9, 108.3 vs. 4.3, and 247.2 vs. 14.0 (microM), respectively. In contrast, no significant difference was observed in the blood ethanol concentrations between the Aldh2+/+ and Aldh2-/- mice. The aldehyde dehydrogenase 2 enzyme metabolized 94% of the acetaldehyde produced from the ethanol as calculated from the area under the curve (AUC) of acetaldehyde when ethanol was administered at a dose of 5.0 g/kg. CONCLUSIONS: These data indicate that mouse ALDH2 is a major enzyme for acetaldehyde metabolism, and the Aldh2-/- mice have significantly high acetaldehyde levels after ethanol gavages.

Acetaldehyde↗
PubMed2001

The N-terminal portion of mature aldehyde dehydrogenase affects protein folding and assembly.

Human liver cytosolic (ALDH1) and mitochondrial (ALDH2) aldehyde dehydrogenases are both encoded in the nucleus and synthesized in the cytosol. ALDH1 must fold in the cytosol, but ALDH2 is first synthesized as a precursor and must remain unfolded during import into mitochondria. The two mature forms share high identity (68%) at the protein sequence level except for the first 21 residues (14%); their tertiary structures were found to be essentially identical. ALDH1 folded faster in vitro than ALDH2 and could assemble to tetramers while ALDH2 remained as monomers. Import assay was used as a tool to study the folding status of ALDH1 and ALDH2. pALDH1 was made by fusing the presequence of precursor ALDH2 to the N-terminal end of ALDH1. Its import was reduced about 10-fold compared to the precursor ALDH2. The exchange of the N-terminal 21 residues from the mature portion altered import, folding, and assembly of precursor ALDH1 and precursor ALDH2. More of chimeric ALDH1 precursor was imported into mitochondria compared to its parent precursor ALDH1. The import of chimeric ALDH2 precursor, the counterpart of chimeric ALDH1 precursor, was reduced compared to its parent precursor ALDH2. Mature ALDH1 proved to be more stable against urea denaturation than ALDH2. Urea unfolding improved the import of precursor ALDH1 and the chimeric precursors but not precursor ALDH2, consistent with ALDH1 and the chimeric ALDHs being more stable than ALDH2. The N-terminal segment of the mature protein, and not the presequence, makes a major contribution to the folding, assembly, and stability of the precursor and may play a role in folding and hence the translocation of the precursor into mitochondria.

Aldehyde Dehydrogenase↗
PubMed1999

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.

Adult↗
PubMedDate not supplied

Aldehyde dehydrogenase-2 genotypes and HLA haplotypes in Japanese patients with esophageal cancer.

The aim of this study was to examine how aldehyde dehydrogenase-2 (ALDH2) genotypes and human leukocyte antigen (HLA) haplotypes contribute to the risk for esophageal cancer. We examined ALDH2 genotypes and HLA haplotypes in 29 Japanese patients with esophageal cancer. The ratio of patients who experienced current or former intense vasodilatation upon consuming alcohol (flushing type) was much higher in individuals with the inactive form of ALDH2 encoded by the ALDH2(2)/2(2) or ALDH2(1)/2(2) genotype than in those with the active form of ALDH2 encoded by the ALDH2(1)/2(1) genotype. The ratio of inactive ALDH2 was significantly higher in patients with esophageal cancer than in control normal subjects, suggesting that alcoholics with inactive ALDH2 were susceptible to esophageal cancer. HLA haplotypes A24, A26, B54, B61 and DR9 were prevalent in patients with esophageal cancer (82.8, 24.1, 34.5, 37.9 and 44.8%, respectively). HLA haplotype of A24 and inactive ALDH2 were simultaneously found in 58.6% of patients with esophageal cancer. Furthermore, we found other primary malignancies in 6 of 29 (20.7%) patients with esophageal cancer, and 4 of these 6 patients had both the inactive form of ALDH2 and the HLA A24 haplotype. The present study showed the high prevalence of the inactive form of ALDH2 and HLA haplotypes A24, A26, B54, B61 and DR9 in Japanese patients with esophageal cancer. Therefore, the examination of genotypes of ALDH2 loci and HLA haplotypes may allow the early detection of esophageal cancer in the Japanese population.

Adult↗
PubMed2002

Alcohol sensitivity in Taiwanese men with different alcohol and aldehyde dehydrogenase genotypes.

BACKGROUND AND PURPOSE: Previous studies demonstrated that ADH2*2, encoding for high-maximal velocity (Vmax) beta2-alcohol dehydrogenase (ADH) activity, and mutant ALDH2*2, encoding for null aldehyde dehydrogenase (ALDH) 2 activity, independently influence susceptibility to alcoholism. A single copy of the ALDH2*2 allele may protect less strongly than a single copy of ADH2*2 in individuals carrying only one copy of either ALDH2*2 or ADH2*2. Individuals with various ADH2 and ALDH2 gene status may exhibit different alcohol metabolism and alcohol sensitivity, which affects drinking behavior. To explore the underlying pharmacogenetic mechanism, alcohol metabolism and alcohol sensitivity were tested using ethanol challenge in Taiwanese men with different ADH2 and ALDH2 genotypes. METHODS: Twenty-four adults, matched by age, body mass index, nutritional state, and homozygosity at ADH3, were recruited from a population base of 304 men. Six individuals were chosen with each of the different ADH2 and ALDH2 genotypes: ADH2*1/*1, ALDH2*1/*1; ADH2*2/*2, ALDH2*1/*1; ADH2*1/*1, ALDH2*1/*2; and ADH2*2/*2, ALDH2*1/*2. After a low-to-moderate challenge with ethanol (0.3 g/kg), blood ethanol and acetaldehyde concentrations, heart rate, and facial capillary blood flow (FCBF) were measured for 130 minutes. RESULTS: All heterozygous ALDH2*2 individuals were found to be strongly responsive to low-to-moderate ethanol, as evidenced by pronounced increases in heart rate and FCBF. Conversely, there were no significant differences in alcohol metabolism and alcohol sensitivity between the ADH2*2 and ADH2*1 homozygotes with identical ALDH2 genotype. CONCLUSION: Individuals heterozygous for ALDH2*2 exhibit strong alcohol hypersensitivity caused by persistent accumulation of large amounts of acetaldehyde, but homozygosity for ADH2*2 is not dependent upon this pathway against alcoholism.

Adult↗
PubMed1996

Association of aldehyde dehydrogenase with inheritance of NIDDM.

To investigate the influence of the mitochondrial aldehyde dehydrogenase 2 (ALDH2) genotype on the clinical features of diabetes, 212 Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) (154 males and 58 females aged 17-83 years; mean age 58.2 years) were investigated. Genotyping of ALDH2 was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The pattern of inheritance of diabetes and various clinical parameters was compared between active and inactive ALDH2 groups. Of the 212 subjects, 120 had active ALDH2 and 92 had inactive ALDH2. The percentage of patients with a diabetic mother was higher in the inactive ALDH2 group (32.6%) than in the active ALDH2 group (19.2%) (p < 0.05). The prevalence of proliferative retinopathy was lower in the inactive ALDH2 group than in the active ALDH2 group (p < 0.05). However, other clinical parameters showed no difference. We conclude that maternal inheritance of diabetes was common in the inactive ALDH2 group. The finding is suggestive of a relationship between alcohol intolerance and inheritance of diabetes. We speculate that the interaction between mitochondrial DNA and ALDH2 inactivity causes an increase of mitochondrial DNA mutations or deletions, thereby inducing the maternal inheritance of diabetes. The relationship of the ALDH2 genotype with proliferative retinopathy is interesting, because it resembles that of chlorpropamide alcohol flushing with severe diabetic retinopathy. The interaction of aldehyde dehydrogenase isoenzymes might have an aetiological role, since aldehyde dehydrogenase 1 plays an important part in oxidation of retinal to retinoic acid. However, the number of affected patients with proliferative retinopathy was small, hence, our result should be considered as a preliminary finding.

Adolescent↗
PubMed1991

Acetaldehyde metabolism in different aldehyde dehydrogenase-2 genotypes.

In order to clarify the relationships between acetaldehyde (Ac-CHO) metabolism and low Km (mitochondrial) aldehyde dehydrogenase (ALDH2) genotypes, hepatic ALDH2 activity was determined and serial changes of blood Ac-CHO levels after ethanol administration were analyzed in the individuals homozygous for the normal ALDH2 genes, heterozygous for the normal and mutant ALDH2 genes, and homozygous for the mutant ALDH2 genes. Genomic DNA was extracted from white blood cells and genotyping of ALDH2 was performed using the polymerase chain reaction technique and slot blot hybridization with synthesized oligonucleotide probes specific to the normal and mutant ALDH2 genes. ALDH2 activity was not detectable in the liver in two cases of the mutant homozygote. In four out of eight cases of the heterozygote, hepatic ALDH2 activity was measurable, although the activity was lower compared with that in the normal homozygote. Blood ethanol levels after alcohol administration were not different among the three different ALDH2 genotypes. Blood Ac-CHO levels after drinking of alcohol were significantly higher in the heterozygotes and the mutant homozygotes than in the normal homozygotes. The levels after a moderate amount of ethanol (0.8 g/kg of body weight) in a case of the mutant homozygote were not different from those of the heterozygotes. However, the levels after a small amount of ethanol (0.1 g/kg of body weight) were significantly higher in the mutant homozygotes than in the heterozygotes. These results indicate that hepatic ALDH2 activity is lacking completely, and metabolism of Ac-CHO in the liver is severely impaired in the homozygotes of the mutant ALDH2 genes.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde↗
PubMed1999

[Genetic factors which regulate alcohol drinking behavior and their effects on health status].

High alcohol sensitivity common among Orientals is mainly due to genetic polymorphism in the low K(m) aldehyde dehydrogenase (ALDH2) gene. The relation of the ALDH2 genotype to alcohol sensitivity and drinking behavior was investigated in a Japanese occupational population. The frequency of alcohol-associated symptoms generally increased in the order of the typical homozygote, heterozygote, and atypical homozygote. Both drinking frequency and amounts of alcohol consumption were also significantly affected by the polymorphism. Polymorphism in the alcohol dehydrogenase beta-subunit (ADH2 gene) appeared to contribute to skin flushing post-alcohol exposure but not to alcohol drinking behavior. Multivariate analysis revealed that high alcohol consumption, the ALDH2*1/*1 genotype, and high daily hassles levels significantly contribute to the prevalence of those with a high problem-drinking score in an occupational population. In the study to assess the effects of the ALDH2 polymorphism and alcohol use on the induction of chromosome alterations in peripheral lymphocytes, we found that lymphocytes from habitual drinkers with the atypical ALDH2 genotypes had significantly higher frequencies of sister-chromatid exchange (SCE) than those from the typical ALDH2 genotype. We also measured acetaldehyde reversibly bound to hemoglobin (HbAA). In volunteers with the ALDH2*1/*2 genotype, the HbAA levels increased immediately after the drink and the elevated levels persisted up to 48 h. Among male workers, HbAA levels were significantly correlated with the recent alcohol consumption levels in both the ALDH2*1/*1 and ALDH2*1/*2 genotypes. However, the slope was much steeper in the ALDH2*1/*2 than in the ALDH2*1/*1. SCE and HbAA may be utilized as a good biomarker for health problems in the atypical ALDH2 genotype. Further extensive studies are required for evaluation of the interactive effects of genetic and environmental factors on alcohol-related health problems.

Alcohol Dehydrogenase↗
PubMed2003

Genetic deficiency of a mitochondrial aldehyde dehydrogenase increases serum lipid peroxides in community-dwelling females.

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) plays a major role in acetaldehyde detoxification. The alcohol sensitivity is associated with a genetic deficiency of ALDH2. We and others have previously reported that such a deficiency influences the risk for late-onset Alzheimer's disease (LOAD), hypertension, and myocardial infarction. Then we tried to find phenotypes to which the ALDH2 polymorphism contributes by conducting several evaluations including biochemical and functional analyses of various tissues in a community-dwelling population. Several serum proteins, lipids, and lipid peroxides (LPO) levels showed differences between the nondefective (ALDH2*1/1) and defective (ALDH2*1/2 and ALDH2*2/2) ALDH2 individuals. However, alcohol-drinking behavior is known to affect these evaluations. Thus, we excluded the effects of alcohol-drinking behavior from the association with the ALDH2-deficient genotype through correction and found that the concentration of LPO was significantly lower in the nondefective ALDH2 females than the defective females. The effect of frequent alcohol-drinking behavior in males seems to override the phenotype of the high serum LPO level. These results indicate that the ALDH2 deficiency may enhance oxidative stress in vivo. Thus, these findings suggest that ALDH2 functions as a protector against oxidative stress and the decrease in protection may influence the onset of AD, hypertension, and myocardial infarction.

Adult↗