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PubMed1999

Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism.

The genes that encode the major enzymes of alcohol metabolism, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), exhibit functional polymorphism. The variant alleles ADH2*2 and ADH3*1, which encode high-activity ADH isoforms, and the ALDH2*2 allele, which encodes the low-activity form of ALDH2, protect against alcoholism in East Asians. To investigate possible interactions among these protective genes, we genotyped 340 alcoholic and 545 control Han Chinese living in Taiwan at the ADH2, ADH3, and ALDH2 loci. After the influence of ALDH2*2 was controlled for, multiple logistic regression analysis indicated that allelic variation at ADH3 exerts no significant effect on the risk of alcoholism. This can be accounted for by linkage disequlibrium between ADH3*1 and ADH2*2 ALDH2*2 homozygosity, regardless of the ADH2 genotypes, was fully protective against alcoholism; no individual showing such homozygosity was found among the alcoholics. Logistic regression analyses of the remaining six combinatorial genotypes of the polymorphic ADH2 and ALDH2 loci indicated that individuals carrying one or two copies of ADH2*2 and a single copy of ALDH2*2 had the lowest risk (ORs 0.04-0.05) for alcoholism, as compared with the ADH2*1/*1 and ALDH2*1/*1 genotype. The disease risk associated with the ADH2*2/*2-ALDH2*1/*1 genotype appeared to be about half of that associated with the ADH2*1/*2-ALDH2*1/*1 genotype. The results suggest that protection afforded by the ADH2*2 allele may be independent of that afforded by ALDH2*2.

Adult↗
PubMed2005

Aldehyde dehydrogenase 2 activity affects symptoms produced by an intraperitoneal acetaldehyde injection, but not acetaldehyde lethality.

Aldehyde dehydrogenase 2 (ALDH2) is an important enzyme that oxidizes acetaldehyde. Approximately 45% of Chinese and Japanese individuals are inactive ALDH2 phenotype; acute acetaldehyde toxicity has not been evaluated in these populations. We compared the acute acetaldehyde toxicity between wild-type (Aldh2+/+) and Aldh2-inactive transgenic (Aldh2-/-) mice who were administered an intraperitoneal (ip) injection of a single dose of acetaldehyde. This comparison was made based on the LD(50) values of acetaldehyde and the symptoms following the ip injection. Blood acetaldehyde level was measured in the 400 mg/kg dose group. Immediately after administration of acetaldehyde, the mice exhibited hypoactivity and staggering gait. Subsequently, symptoms such as pale skin, prone position, coma, and abnormal deep respiration were observed. In cases of death, dyspnea, wheezing, and hypothermia were observed from 15 to 30 min after the administration. In cases of survival, crouching, bradypnea, flushing and piloerection were observed. Significant latency of symptom recovery was found in the Aldh2+/- mice as compared with the Aldh2+/+ mice; however, no statistical difference was observed in the acetaldehyde LD(50) values. This might be attributable to the absence of a significant difference in the blood acetaldehyde concentrations in both mice during the first 0-15 min following administration; however, acetaldehyde elimination delay was observed in the Aldh2-/- mice as compared with the Aldh2+/+ mice. Acetaldehyde toxicity difference was observed between the Aldh2+/+ and Aldh2-/- mice; however, no difference in acetaldehyde lethality was observed by administration of a single dose of an ip acetaldehyde injection.

Acetaldehyde↗
PubMed1993

Genetic polymorphism of alcohol and aldehyde dehydrogenase and the effects on alcohol metabolism.

Influence of genetic polymorphism at the alcohol dehydrogenase2 (ADH2) and aldehyde dehydrogenase2 (ALDH2) loci on ethanol elimination and blood acetaldehyde level was studied in healthy subjects. Polymorphic regions of the ADH2 and ALDH2 genes were amplified for genomic DNA by using the technique of polymerase chain reaction. The ADH2 genotype was determined by digestion with the restriction enzyme MaeIII and the ALDH2 genotype was defined by hybridization with sequence specific oligonucleotide probes. Both loci were typed for unrelated 58 individuals by using the above methods. The gene frequencies of each locus were estimated as follows; 0.31 and 0.69 for ADH2*1 and ADH2*2, respectively, and 0.73 and 0.27 for ALDH2*1 and ALDH2*2, respectively. These values were consistent with the Hardy-Weinberg equilibrium. Pedigree analysis of 6 families with 46 subjects on both loci confirmed Mendelian inheritance. In order to investigate differences in ethanol elimination among ADH2 and ALDH2 genotype groups, 0.4 g/kg body weight of ethanol was administered to 93 subjects whose genotypes of both loci were determined by the above methods and blood ethanol and acetaldehyde levels were measured. None of the subjects homozygous for the ALDH2*1 allele showed facial flushing and any increase in blood acetaldehyde level. All the homozygotes and heterozygotes with the ALDH2*2 allele exhibited facial flushing, and the former showed a marked increase in blood acetaldehyde level and the latter did a mild increase. On the other hand, the influence of the ADH2 genotype on blood acetaldehyde level was not significant. The values of Widmark's beta 60 (mg/ml/hr) and ethanol elimination rate (mg/kg/hr) showed significant differences among the three groups of the ALDH2 genotypes in each group of the three ADH2 genotypes, and in decreasing order of both the values were ALDH 2*1/*1, ALDH2*1/*2, ALDH2*/*2, However, there were no significant differences in the values among the ADH2 genotypes.

Acetaldehyde↗
PubMed2000

Deficiency in mitochondrial aldehyde dehydrogenase increases the risk for late-onset Alzheimer's disease in the Japanese population.

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) deficiency is caused by a mutant allele in the Mongoloids. To examine whether genetic constitutions affecting aldehyde metabolism influence the risk for late-onset Alzheimer's disease (LOAD), we performed a case-control study in the Japanese population on the deficiency in ALDH2 caused by the dominant-negative mutant allele of the ALDH2 gene (ALDH2*2). In a comparison of 447 patients with sex, age, and region matched nondemented controls, the genotype frequency carrying the ALDH2*2 allele was significantly higher in the patients than in the controls (48.1% vs 37.4%, P = 0.001). Logistic regression analysis indicates that carriage of the ALDH2*2 allele is an independent risk for LOAD of the epsilon4 allele of the apolipoprotein E gene (APOE-epsilon4) (P = 0.002). Moreover, the odds ratio for LOAD in carriers of the ALDH2*2 allele was almost twice that in noncarriers, irrespective of status with regard to the APOE-epsilon4 allele. Among patients homozygous for the APOE-epsilon4 allele, age at onset of LOAD was significantly lower in those with than without the ALDH2*2 allele. In addition, dosage of the ALDH2*2 allele significantly affected age at onset of patients homozygous for the APOE-epsilon4 allele. These results indicate that the ALDH2 deficiency is a risk for LOAD, synergistically acting with the APOE-epsilon4 allele.

Age of Onset↗
PubMed2005

Inhibition of mitochondrial aldehyde dehydrogenase by nitric oxide-mediated S-nitrosylation.

Mitochondrial aldehyde dehydrogenase (ALDH2) is responsible for the metabolism of acetaldehyde and other toxic lipid aldehydes. Despite many reports about the inhibition of ALDH2 by toxic chemicals, it is unknown whether nitric oxide (NO) can alter the ALDH2 activity in intact cells or in vivo animals. The aim of this study was to investigate the effects of NO on ALDH2 activity in H4IIE-C3 rat hepatoma cells. NO donors such as S-nitrosoglutathione (GSNO), S-nitroso-N-acetylpenicillamine, and 3-morpholinosydnonimine significantly increased the nitrite concentration while they inhibited the ALDH2 activity. Addition of GSH-ethylester (GSH-EE) completely blocked the GSNO-mediated ALDH2 inhibition and increased nitrite concentration. To directly demonstrate the NO-mediated S-nitrosylation and inactivation, ALDH2 was immunopurified from control or GSNO-treated cells and subjected to immunoblot analysis. The anti-nitrosocysteine antibody recognized the immunopurified ALDH2 only from the GSNO-treated samples. All these results indicate that S-nitrosylation of ALDH2 in intact cells leads to reversible inhibition of ALDH2 activity.

Aldehyde Dehydrogenase↗
PubMed1997

Structure of mitochondrial aldehyde dehydrogenase: the genetic component of ethanol aversion.

BACKGROUND: The single genetic factor most strongly correlated with reduced alcohol consumption and incidence of alcoholism is a naturally occurring variant of mitochondrial aldehyde dehydrogenase (ALDH2). This variant contains a glutamate to lysine substitution at position 487 (E487K). The E487K variant of ALDH2 is found in approximately 50% of the Asian population, and is associated with a phenotypic loss of ALDH2 activity in both heterozygotes and homozygotes. ALDH2-deficient individuals exhibit an averse response to ethanol consumption, which is probably caused by elevated levels of blood acetaldehyde. The structure of ALDH2 is important for the elucidation of its catalytic mechanism, to gain a clear understanding of the contribution of ALDH2 to the genetic component of alcoholism and for the development of specific ALDH2 inhibitors as potential drugs for use in the treatment of alcoholism. RESULTS: The X-ray structure of bovine ALDH2 has been solved to 2.65 A in its free form and to 2.75 A in a complex with NAD+. The enzyme structure contains three domains; two dinucleotide-binding domains and a small three-stranded beta-sheet domain, which is involved in subunit interactions in this tetrameric enzyme. The E487K mutation occurs in this small oligomerization domain and is located at a key interface between subunits immediately below the active site of another monomer. The active site of ALDH2 is divided into two halves by the nicotinamide ring of NAD+. Adjacent to the A-side (Pro-R) of the nicotinamide ring is a cluster of three cysteines (Cys301, Cys302 and Cys303) and adjacent to the B-side (Pro-S) are Thr244, Glu268, Glu476 and an ordered water molecule bound to Thr244 and Glu476. CONCLUSIONS: Although there is a recognizable Rossmann-type fold, the coenzyme-binding region of ALDH2 binds NAD+ in a manner not seen in other NAD+-binding enzymes. The positions of the residues near the nicotinamide ring of NAD+ suggest a chemical mechanism whereby Glu268 functions as a general base through a bound water molecule. The sidechain amide nitrogen of Asn169 and the peptide nitrogen of Cys302 are in position to stabilize the oxyanion present in the tetrahedral transition state prior to hydride transfer. The functional importance of residue Glu487 now appears to be due to indirect interactions of this residue with the substrate-binding site via Arg264 and Arg475.

Alcohol Drinking↗
PubMed2002

Diminished alcohol preference in transgenic mice lacking aldehyde dehydrogenase activity.

Aldehyde dehydrogenase (ALDH) 2 plays a major role in the detoxification of aldehyde and is known to be responsible for alcohol preference. A diminished enzyme activity due to mutation of the Aldh2 gene is associated with high alcohol sensitivity and a low alcohol tolerance in humans. The genomic background distinguishing an alcohol preference and avoidance in various inbred mouse strains is not clear. We created Aldh2-negative mice by transgenic knockout of the Aldh2 gene into the high alcohol preference C57BL/6 background. The Aldh2 gene targeting (Aldh-/-) mice exhibited an alcohol avoidance characteristic. After free-choice ethanol and water drinking, brain and liver acetaldehyde concentrations of Aldh2-/- mice were almost equal to those of wild-type (Aldh2+/+) mice although the Aldh2-/- mice drank less ethanol than the Aldh2+/+ mice. This result indicates that a direct effect of the Aldh2 genotype plays an important role on alcohol preference and acetaldehyde concentration in the brain is correlated with alcohol avoidance. This highlights the potential benefits of alcoholism and alcohol-related disease research in the animal model of ALDH2 alleles.

Acetaldehyde↗
PubMed2005

Epidemiological evidence that acetaldehyde plays a significant role in the development of decreased serum folate concentration and elevated mean corpuscular volume in alcohol drinkers.

BACKGROUND: Elevated mean corpuscular volume (MCV) is a traditional biological marker for alcohol abuse and alcoholism, but the underlying mechanism is unclear. Three recent epidemiologic studies consistently showed that MCV was elevated by alcohol drinking more markedly among individuals with genetically inactive aldehyde dehydrogenase-2 (ALDH2) (encoded by ALDH2*2 mutant allele) than those with active ALDH2 (encoded by ALDH2*1/2*1 genotype), suggesting that the elevated MCV was etiologically linked to acetaldehyde exposure. The purpose of the present study was to clarify further this relationship by examining the status of folate and vitamin B12. METHODS: The study participants were 159 men who were aged 40 to 69 years and randomly selected from a Japanese rural population. The genetic polymorphism of ALDH2 was determined by PCR-restriction fragment length polymorphism method; data on alcohol drinking and other lifestyles were collected using a structured questionnaire; serum concentrations of folate and vitamin B12 were measured using the protein competitive reaction method, and blood cell counts were measured by routine methods. A multiple linear regression model was used to analyze the data. RESULTS: : The relationship between alcohol drinking and serum folate concentration was significantly different between ALDH2 genotypes, indicating that the reduction of serum folate by alcohol drinking was more marked in men with ALDH2*1/2*2 than those with ALDH2*1/2*1. The relationship between alcohol drinking and elevated MCV was significantly stronger in men with ALDH2*1/2*2 than those with ALDH2*1/2*1 even after adjustment for serum folate and vitamin B12 concentrations. CONCLUSIONS: These findings indicate that acetaldehyde plays a significant role in the development of decreased serum folate concentration and elevated MCV by alcohol drinking.

Acetaldehyde↗
PubMed2005

Inactive aldehyde dehydrogenase-2 increased the risk of pancreatic cancer among smokers in a Japanese male population.

OBJECTIVES: Most of the acetaldehyde, a recognized animal carcinogen, generated during alcohol metabolism is eliminated by liver mitochondrial aldehyde dehydrogenase 2 (ALDH2). More than 40% of Japanese have the inactive form of ALDH2, and inactive ALDH2 is a risk factor for multiple cancers of the esophagus as well as head and neck cancer. Possible associations between pancreatic cancer and ALDH2 gene polymorphism, in conjunction with smoking and/or drinking habits, were examined in a Japanese population. METHODS: We investigated 114 patients (70 male and 44 female) with pancreatic cancer and compared them with 2070 control subjects (1050 male and 1020 female). The drinking (5 g ethanol consumption/d) and/or smoking habits as well as ALDH2 gene polymorphism were examined. RESULTS: In male subjects, the frequency of the active form of ALDH2 (2*1/2*1) was lower in pancreatic cancer patients than in control subjects (P = 0.018). The frequency of subjects with both smoking and drinking habits was significantly higher in pancreatic cancer patients than in control subjects having ALDH2*1/2*1 and ALDH2*1/2*2. The frequency of smoking habit alone was significantly higher in pancreatic cancer patients compared with control subjects having inactive ALDH2. Drinking habit had no relation to pancreatic cancer. In female subjects, neither habit had a relation to pancreatic cancer. CONCLUSIONS: Smoking habit did increase the risk of pancreatic cancer, and this risk was further enhanced in subjects with inactive ALDH2 in a male population but not in a female population. There was no relationship between drinking habit and pancreatic cancer in either sex population.

Adult↗
PubMed2003

[Gene-environmental interactions in alcohol-related health problems--contributions of molecular biology to behavior modifications].

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.

Alcohol Dehydrogenase↗
PubMed1983

Isolation and characterization of aldehyde dehydrogenase isozymes from usual and atypical human livers.

Usual human livers contain two major aldehyde dehydrogenase isozymes, cytosolic ALDH1 component and mitochondrial ALDH2 component, while human livers with "atypical" phenotype have only ALDH1 isozyme and are missing ALDH2 isozyme. Approximately 50% of orientals are atypical in respect to ALDH isozymes. We previously demonstrated an existence of enzymatically inactive but immunologically cross-reactive material (CRM) in atypical oriental livers. ALDH1 and ALDH2 isozymes were purified to homogeneity from usual livers, and ALDH1 and CRM were purified from atypical oriental livers. Amino acid compositions of ALDH1 and ALDH2 were similar to, but not identical with, each other. Amino acid compositions of ALDH2 and CRM were identical within analytical errors. Subunit molecular size of ALDH1 estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis was 56,200 daltons, and that of ALDH2 was 52,600 daltons. The two isozymes did not contain a common subunit. Subunit molecular weight of CRM was identical with that of ALDH2. Double immunodiffusion precipitation revealed that ALDH1 and ALDH2 were immunologically analogous but not identical, and that CRM and ALDH2 were immunologically indistinguishable. These results support the genetic model that CRM is an abnormal defective protein resulting from a mutation of the ALDH2 locus.

Aldehyde Dehydrogenase↗
PubMed1997

Elevated levels of hemoglobin-associated acetaldehyde related to alcohol drinking in the atypical genotype of low Km aldehyde dehydrogenase.

Acetaldehyde is suspected to be the ultimate carcinogen in alcohol-related carcinogenesis. The atypical genotypes of low Km aldehyde dehydrogenase (ALDH2) have higher blood concentrations of free acetaldehyde after drinking alcohol. We measured levels of acetaldehyde reversibly bound to hemoglobin (HbAA) after drinking 0.4 ml/kg ethanol using fluorigenic high performance liquid chromatography method in volunteers with the two major ALDH2 genotypes. In the ALDH2*1/*1 genotype with high ALDH2 activity, the increase of HbAA was small. By contrast, in the ALDH2*1/*2 genotype with low ALDH2 activity, HbAA increased considerably at 1-6 h after the drink, and the elevated levels persisted up to 48 h. We also measured HbAA in 81 male workers. Although HbAA levels were significantly correlated with alcohol consumption levels in both of the ALDH2 genotypes, the slope was significantly steeper in the ALDH2*1/*2 genotype than in the ALDH2*1/*1 genotype. In summary, we demonstrated for the first time a significant difference in the increase of HbAA levels after drinking alcohol, depending on the ALDH2 genotype. The HbAA levels are not only a good biomarker for increased internal exposure levels to acetaldehyde but may also be a predictive biomarker for acetaldehyde-mediated carcinogenesis.

Acetaldehyde↗
PubMed2006

Acetaldehyde involvement in positive and negative alcohol expectancies in han Chinese persons with alcoholism.

CONTEXT: The ALDH2*2 allele has been shown to be a protective factor against alcoholism in a normal population owing in part to the elevated blood level of acetaldehyde and its accompanying physiological discomforts after drinking alcohol. Despite the well-established link between the ALDH2*2 allele and the physiological discomforts after drinking, very little is known regarding the psychological expectancies of drinking among persons with alcoholism with different ALDH genotypes. OBJECTIVES: To determine whether there are differences in craving, alcohol consumption, and alcohol outcome expectancies between persons with alcoholism who have the ALDH2*1/*2 genotype and persons with alcoholism who have the ALDH2*1/*1 genotype. DESIGN: Cross-sectional survey. SETTING: Six outpatient alcohol treatment facilities in Taiwan. PARTICIPANTS: Ninety-eight persons with alcoholism who met the DSM-IV criteria for current alcohol dependence. MAIN OUTCOME MEASURES: Alcohol Craving Scale, Form 90, and Alcohol Expectancies Scale scores. RESULTS: Overall, the ALDH2*1/*2 group had lower negative alcohol outcome expectancies (F(4,93) = 2.43, P < or = .05, eta(p)2 = 0.10). Specifically, they had fewer expected negative outcomes in the social or interpersonal domain (P < .05) and the emotional and physical domain (P < or = .005) than did the ALDH2*1/*1 group. Moreover, the ALDH2*1/*2 group had higher positive alcohol outcome expectancies (F(7,90) = 2.36, P < .05, eta(p)2 = 0.16), and they had more expected positive outcomes in the relaxation and tension reduction domain (P < .05). The 2 groups did not differ in alcohol craving (P = .61) or consumption (P = .11). CONCLUSIONS: Although the ALDH2*2 allele has been associated with negative physiological responses in normal samples in past research, the psychological expectancies of drinking are more positive and less negative for persons with alcoholism who have the ALDH2*1/*2 genotype. A role of acetaldehyde is implied in these effects, which seem to override the usual discomfort effects associated with protection against alcohol drinking. Future studies are needed to assess alcohol outcome expectancies at different phases of alcohol dependence and to evaluate the concurrent relationships of blood levels of acetaldehyde with physiological and psychological outcomes among persons with alcoholism who have different ALDH genotypes.

Acetaldehyde↗
PubMed1998

Glutathione carbamoylation with S-methyl N,N-diethylthiolcarbamate sulfoxide and sulfone. Mitochondrial low Km aldehyde dehydrogenase inhibition and implications for its alcohol-deterrent action.

S-Methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO) and sulfone (DETC-MeSO2) both inhibit rat liver low Km aldehyde dehydrogenase (ALDH2) in vitro and in vivo (Nagendra et al., Biochem Pharmacol 47: 1465-1467, 1994). DETC-MeSO has been shown to be a metabolite of disulfiram, but DETC-MeSO2 has not. Studies were carried out to further investigate the inhibition of ALDH2 by DETC-MeSO and DETC-MeSO2. In an in vitro system containing hydrogen peroxide and horseradish peroxidase, the rate of DETC-MeSO oxidation corresponded to the rate of DETC-MeSO2 formation. Carbamoylation of GSH by both DETC-MeSO and DETC-MeSO2 was observed in a rat liver S9 fraction. Carbamoylation of GSH was not observed in the presence of N-methylmaleimide. In in vitro studies, DETC-MeSO and DETC-MeSO2 were equipotent ALDH2 inhibitors when solubilized mitochondria were used, but DETC-MeSO was approximately four times more potent than DETC-MeSO2 in intact mitochondria. In studies with rats, the dose (i.p. or oral) required to inhibit 50% ALDH2 (ED50) was 3.5 mg/kg for DETC-MeSO and approximately 35 mg/kg for DETC-MeSO2, approximately a 10-fold difference. Furthermore, maximum ALDH2 inhibition occurred 1 hr after DET(-MeSO administration, whereas maximal ALDH2 inhibition occurred 8 hr after DETC-MeSO2 dosing. DETC-MeSO is, therefore, not only a more potent ALDH2 inhibitor than DETC-MeSO2 in vivo, but also in vitro when intact mitochondria are utilized. The in vitro results thus support the in vivo findings. Since oxidation of DETC-MeSO can occur both enzymatically and non-enzymatically, it is possible that DETC-MeSO2 is formed in vivo. DETC-MeSO2, however, is not as effective as DETC-MeSO in inhibiting ALDH2, probably because it has difficulty penetrating the mitochondrial membrane. Thus, even if DETC-MeSO2 is formed in vivo from DETC-MeSO, it is the metabolite DETC-MeSO that is most likely responsible for the inhibition of ALDH2 after disulfiram administration.

Aldehyde Dehydrogenase↗
PubMed2003

Aldehyde dehydrogenase 2 and beta3-adrenergic receptor gene polymorphisms: their association with elevated liver enzymes and metabolic syndrome.

Recent studies indicate that some patients with nonalcoholic fatty liver have ongoing liver injury that may progress from steatosis to steatohepatitis or fibrosis. The present study was designed to clarify the clinical features of liver dysfunction observed in the course of workplace physical check-ups in relation to multiple risk factor syndrome including obesity, hyperlipidemia, hypertension, and impaired glucose tolerance, and to clarify the involvement of aldehyde dehydrogenase 2 (ALDH2) and beta(3)-adrenergic receptor (beta3-AR) gene polymorphisms in elevation of liver enzymes. One hundred forty-eight male workers 35 years of age were enrolled. They were requested to answer questionnaires about drinking and smoking habits, and underwent urinalysis, physical and peripheral blood examinations, blood chemistry, electrocardiogram and chest x-rays. The genotypes of ALDH2 and beta3-AR were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The subjects were divided into active ALDH2 or inactive ALDH2 groups. They were also divided into 2 groups according to the beta3-AR genotype. The relationships between ALDH2 and beta3-AR gene polymorphism and the results of the physical examination including liver function tests were analyzed. The subjects were also divided according to the number of components of metabolic syndrome. The prevalence of elevated alanine aminotransferase (ALT) level increased with the accumulation of components of metabolic syndrome. Active ALDH2 was associated with elevated ALT level to a greater degree than beta3-AR polymorphism. Among those with normal body mass index (BMI), the genotypes of ALDH2 and beta3-AR were strongly associated with elevated ALT level. Logistic regression analysis revealed that BMI, triglyceride level, and ALDH2 genotype were associated with ALT elevation. In conclusion, evaluating the genotype of ALDH2 and beta3-AR may assist in predicting and preventing the development of fatty liver which may be related to multiple risk factor syndrome.

Adult↗
PubMed2001

Screening for acetaldehyde dehydrogenase 2 genotype in alcohol-induced asthma by using the ethanol patch test.

BACKGROUND: We have previously reported that alcohol-induced asthma in Japanese patients is caused by increased blood acetaldehyde concentration resulting from abnormalities of acetaldehyde dehydrogenase 2 (ALDH2) enzyme activity on the basis of ALDH2 genotype differences. OBJECTIVES: The purpose of the present study was to determine whether the ethanol patch test could predict the ALDH2 genotype in Japanese asthmatic subjects. METHODS: An ethanol patch test on the upper arm and a questionnaire survey addressing the past history of alcohol-induced asthma were administered to 148 adult Japanese asthmatic subjects. The ALDH2 genotypes in these 148 subjects were also determined by means of PCR. RESULTS: The genotype distribution of ALDH2 determined by PCR in 68 subjects with positive ethanol patch test results was 4 (5.9%), 56 (82.4%), and 8 (11.8%) for genotypes NN (normal homozygote), NM (mutant heterozygote), and MM (mutant homozygote). The ALDH2 genotype in 80 subjects with a negative test result was only NN. The distribution of ALDH2 genotype in 78 (52.7%) subjects who had experienced alcohol-induced asthma symptoms on the basis of the questionnaire was 27 (34.6%), 44 (56.4%), and 7 (9.0%) for genotypes NN, NM, and MM, respectively. On the other hand, 70 subjects had never experienced alcohol-induced asthma symptoms. In these subjects the ALDH2 genotype was NN in 51 (72.9%), NM in 18 (25.7%), and MM in 1 (1.4%). CONCLUSIONS: Our results indicate that the results of ethanol patch testing correlate well with ALDH2 genotype, as determined by means of PCR, suggesting that the ethanol patch test is useful for the screening of alcohol-induced asthma.

Adult↗
PubMed1985

Cloning of cDNAs for human aldehyde dehydrogenases 1 and 2.

Partial cDNA clones encoding human cytosolic aldehyde dehydrogenase (ALDH1) and mitochondrial aldehyde dehydrogenase (ALDH2) were isolated from a human liver cDNA library constructed in phage lambda gt11. The expression library was screened by using rabbit antibodies against ALDH1 and ALDH2. Positive clones thus obtained were subsequently screened with mixed synthetic oligonucleotides compatible with peptide sequences of ALDH1 and ALDH2. One of the positive clones for ALDH1 contained an insertion of 1.6 kilobase pairs (kbp). The insert encoded 340 amino acid residues and had a 3' noncoding region of 538 bp and a poly(A) segment. The amino acid sequence deduced from the cDNA sequence coincided with the reported amino acid sequence of human ALDH1 [Hempel, J., von Bahr-Lindström, H. & Jörnvall, H. (1984) Eur. J. Biochem. 141, 21-35], except that valine at position 161 in the previous amino acid sequence study was found to be isoleucine in the deduced sequence. Since the amino acid sequence of ALDH2 was unknown, 33 tryptic peptides of human ALDH2 were isolated and sequenced. Based on the amino acid sequence data thus obtained, a mixed oligonucleotide probe was prepared. Two positive clones, lambda ALDH2-21 and lambda ALDH2-36, contained the same insert of 1.2 kbp. Another clone, lambda ALDH2-22, contained an insert of 1.3 kbp. These two inserts contained an overlap region of 0.9 kbp. The combined cDNA contained a sequence that encodes 399 amino acid residues, a chain-termination codon, a 3' untranslated region of 403 bp, and a poly(A) segment. The deduced amino acid sequence was compatible with the amino acid sequences of the tryptic peptides. The degree of homology between human ALDH1 and ALDH2 is 66% for the coding regions of their cDNAs and 69% at the protein level. No significant homology was found in their 3' untranslated regions.

Aldehyde Dehydrogenase↗
PubMed2006

Esophageal squamous cell carcinoma and aldehyde dehydrogenase-2 genotypes in Japanese females.

BACKGROUND: Aldehyde dehydrogenase-2 (ALDH2) is the key enzyme for elimination of acetaldehyde, an established animal carcinogen produced after drinking. In persons with inactive ALDH2, the body fails to metabolize acetaldehyde rapidly, leading to excessive accumulation of acetaldehyde. Inactive heterozygous ALDH2 enhances the risk of esophageal squamous cell carcinoma (SCC) in Japanese male drinkers. METHODS: We studied whether this is the case for women. The risk factors of esophageal SCC were examined in 52 Japanese women with esophageal SCC and 412 cancer-free Japanese women. RESULTS: The increasing trend in cancer risk according to the quantity of alcohol consumption was significantly steeper in women with inactive heterozygous ALDH2 than in those with active ALDH2 [adjusted odds ratios (ORs) (95% confidence intervals (CIs)) per +7 U/wk increment of alcohol drinking were 3.91 (2.09-7.31) and 1.39 (0.92-2.09), respectively; p = 0.006 for difference in OR; 1 Ut = 22 g of ethanol]. The results obtained using an alcohol-flushing questionnaire were essentially comparable with those obtained by ALDH2 genotyping [adjusted ORs (95% CIs) per +7 U/wk increment of alcohol drinking were 3.94 (1.87-8.31) and 1.46 (0.96-2.23) in those with and without flushing, respectively; p = 0.021 for difference in OR]. The risk of esophageal cancer was markedly higher in heavy drinkers with ALDH2*1/*2 than in never/rare drinkers with ALDH2*1/*1 [adjusted OR (95% CI) = 59.1 (4.65-750)]. Other independent significant risk factors of esophageal SCC were smoking, a preference for hot food or drinks, and lower intake of green and yellow vegetables. CONCLUSIONS: Japanese men and women shared several common risk factors of esophageal SCC, including drinking with inactive heterozygous ALDH2.

Adult↗