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PubMed1996

[The ethanol elimination pharmacokinetics--the effects of genotypes of ALDH2 and CYP2E1 on the ethanol metabolism].

The effects of the genotypes of CYP2E1, ALDH2, ADH upon the blood ethanol and acetaldehyde levels were investigated. The predicting 95% confidence bounds determined on regression analysis of the data suggested that after venous injection of ethanol, the blood ethanol and acetaldehyde concentrations in a volunteer normal homozygous for ALDH2 (ALDH2*1/1) were significantly lower than that heterozygous (ALDH2*1/2). And the blood ethanol and acetaldehyde concentrations in a volunteer with C2 allele (C1/C2) were significantly lower than that in (C1/1). However, there were no significant differences in the blood ethanol and acetaldehyde concentrations between volunteers with ADH2*1/1 and ALDH2*1/2. It is possible that the ALDH2*1 and C2 alleles may correspond to the lower blood ethanol and acetaldehyde concentrations after intravenous administrations of 0.2 g /kg of ethanol.

Adult↗
PubMed1998

Simultaneous genotyping of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) loci by amplified product length polymorphism (APLP) analysis.

Genotyping of the alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) loci is important in alcohol studies. We describe a method for simultaneous genotyping of ADH2 and ALDH2 based on amplified product length polymorphism (APLP) analysis. Two polymerase chain reaction (PCR) fragments for ADH2 (57 bp, 53 bp) and two for ALDH2 (78 bp, 73 bp) are simultaneously amplified. Nine banding patterns reflecting the genotypes of the ADH2 and ALDH2 loci are clearly and unambiguously distinguished. The APLP method seems to be particularly suited for large-scale population studies of ADH2 and ALDH2 loci because it is simple and rapid.

Alcohol Dehydrogenase↗
PubMedDate not supplied

ALDH2 polymorphism and biological monitoring of toluene.

In this study, we evaluated the effects of the genetic polymorphism of ALDH2 (low Km aldehyde dehydrogenase) on toluene metabolism and determined biological exposure indices (BEIs) of the genotypes of ALDH2. The study subjects included 45 toluene workers and 122 nonexposed students. The genotype of ALDH2 was classified into the homozygous genotype of normal ALDH2 (NN), the homozygous genotype of an inactive one (DD), and the heterozygous genotype of normal and inactive ones (ND) by means of artificial-RFLP. The personal exposure levels to toluene were monitored, using diffusion type samplers and urinary hippuric acid (HA) and creatine concentrations were determined. The urinary HA levels of the three genotypes of ALDH2 of nonexposed students did not differ. In the toluene workers, positive correlations between the personal exposure to toluene and urinary HA levels were observed in the NN, ND, and DD groups. The urinary HA level of the DD group was significantly lower than that of the NN or ND group. Regression lines were used to estimate the BEIs of the NN, ND, and DD groups, which were approximately 2.9 g/g creatinine, 3.3 g/g creatinine, and 1.9 g/g creatinine, respectively.

Adult↗
PubMed2000

The effects of the ALDH2*1/2, CYP2E1 C1/C2 and C/D genotypes on blood ethanol elimination.

The effects of CYP2E1 genotypes on the blood ethanol and acetaldehyde levels were investigated in a pair of Japanese volunteers whose ADH2, ADH3 and ALDH2 genotypes were identical but whose CYP2E1 genotypes were different. In the same way, the effects of ALDH2 and ADH2 on the ethanol elimination kinetics were also studied. The predicting 95% confidence bounds determined on regression analysis of the data suggested that after venous injection of ethanol, the blood ethanol and acetaldehyde concentrations in a volunteer normal homozygous for ALDH2 (ALDH2*1/1) were lower than in a heterozygous one (ALDH2*1/2). Also, the blood ethanol and acetaldehyde concentrations in a volunteer with the c2 and C alleles of CYP2E1 (c1/c2 and C/D) were lower than in one without the c2 and C alleles (c1/c1 and D/D). However, there were no significant differences in the blood ethanol and acetaldehyde concentrations between volunteers with ADH2*1 (ADH2*1/1) and without ADH2*1 (ADH2*1/2).

Acetaldehyde↗
PubMed2006

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.

Adolescent↗
PubMed2005

Alcohol, ALDH2, and esophageal cancer: a meta-analysis which illustrates the potentials and limitations of a Mendelian randomization approach.

Mendelian randomization, the use of common polymorphisms as surrogates for measuring exposure levels in epidemiologic studies, provides one method of assessing the causal nature of some environmental exposures. This can be illustrated by looking at the association between the ALDH2 polymorphism and esophageal cancer. Alcohol drinking is considered a risk factor for esophageal cancer, and exposure to high levels of acetaldehyde, the principal metabolite of alcohol, may be responsible for the increased cancer risk. The ability to metabolize acetaldehyde is encoded by the ALDH2 gene, which is polymorphic in some populations. The ALDH2*2 allele produces an inactive protein subunit, which is unable to metabolize acetaldehyde. An individual's genotype at this locus may influence their esophageal cancer risk through two mechanisms, first through influencing alcohol intake and second through influencing acetaldehyde levels. We have carried out a meta-analysis of studies looking at the ALDH2 genotype and esophageal cancer and found that risk was reduced among *2*2 homozygotes [odds ratio (OR), 0.36; 95% confidence interval (95% CI), 0.16-0.80] and increased among heterozygotes (OR, 3.19; 95% CI, 1.86-5.47) relative to *1*1 homozygotes. This provides strong evidence that alcohol intake increases the risk of esophageal cancer and individuals whose genotype results in markedly lower intake, because they have an adverse reaction to alcohol are thus protected. This meta-analysis also provides evidence that acetaldehyde plays a carcinogenic role in esophageal cancer. The two different processes operating as a result of the ALDH2 genotype have implications for the interpretation of studies using the Mendelian randomization paradigm.

Acetaldehyde↗
PubMed1996

Low Km aldehyde dehydrogenase (ALDH2) polymorphism, alcohol-drinking behavior, and chromosome alterations in peripheral lymphocytes.

Excessive drinking of alcohol is now widely known to be one of the major lifestyle choices that ca effect health. Among the various effects of alcohol drinking, cytogenetic and other genotoxic effects are of major concern from the viewpoint of prevention of alcohol-related diseases. Alcohol is first metabolized to acetaldehyde, which directly causes various types of chromosomal DNA lesions and alcohol-related diseases, and is then further detoxified to the much less toxic metabolite acetate. About 50% of Oriental people are deficient in the aldehyde-dehydrogenase 2 isozyme (ALDH2) that can most efficiently detoxify acetaldehyde. We have performed a series of experiments to investigate how the genetic deficiency in ALDH2 affects the behavioral pattern for alcohol drinking and the sensitivity of peripheral lymphocytes to the induction of chromosome alterations by exposure to alcohol and alcohol-related chemicals. We found great effects of the ALDH2 genotypes on alcohol sensitivity and alcohol-drinking behavior. We also show that lymphocytes from habitual drinkers with the deficient ALDH2 enzyme had significantly higher frequencies of sister chromatid exchanges than those from ALDH2-proficient individuals.

Adult↗
PubMed2006

ALDH2*2 is associated with a decreased likelihood of alcohol-induced blackouts in Asian American college students.

OBJECTIVE: A recent report found the heritability estimate for alcohol-induced blackouts was 53%. The present study was designed to determine whether possession of two specific genetic variations, an aldehyde dehydrogenase ALDH2*2 allele and an alcohol dehydrogenase ADHIB*2 allele, were associated with lower rates of lifetime blackouts. METHOD: Asian American college students (N=403) of Chinese and Korean descent were genotyped at the ALDH2 and ADHIB loci and assessed for lifetime alcohol-induced blackouts and the maximum number of drinks ever consumed in a 24-hour period. RESULTS: Participants who had an ALDH2*2 allele had approximately one third the risk of having a lifetime blackout of participants without this allele. Rates of experiencing a lifetime blackout did not significantly differ by ADHIB*2 status. Possessing an ALDH2*2 allele was associated with decreased risk of lifetime blackouts even after controlling for maximum number of drinks ever consumed in a 24-hour period and ethnicity. CONCLUSIONS: These findings suggest the protective effects of possessing an ALDH2*2 allele include a lowered risk of experiencing alcohol-induced blackouts.

Adult↗
PubMed2000

Relationships between cigarette smoking, alcohol drinking, the ALDH2 genotype and adenomatous types of colorectal polyps in male self-defense force officials.

Alcohol drinking as well as cigarette smoking has been associated with development of colorectal polyps, Asians such, as Japanese, Chinese and Korean have high frequency of genetic polymorphism in low Km aldehyde dehydrogenase (ALDH2) gene which greatly regulates alcohol intake. In the present study, we investigated associations of this polymorphism and lifestyles with colorectal polyps in self-defense forces personnels in Japan. All subjects received colonoscopy at a retirement health examination. The ALDH2 genotype was determined using polymerase chain reaction and restriction fragment length polymorphism method. Frequency of the ALDH2 genotype was not different between those with colorectal polyps (n=69) and those without the polyps (n=131). Smoking was associated with development of colorectal polyps (OR=4.7, 95% confidence interval=1.9-11.5) in the ALDH2 proficient genotype. The association appeared to be enhanced by drinking alcohol since a synergistic effect of smoking and alcohol drinking (> or =60 ml/day) was indicated (OR=9.9, 95% confidence interval=2.9-34.1) by logistic regression analysis. In the ALDH2 deficient genotype, however, we could not evaluate interactions of smoking and alcohol drinking on colorectal polyp development because of the small sample size of heavy alcohol drinkers. The genotype analysis would be useful in evaluating effects of environmental factors on outcomes for each genetically defined subpopulation.

Adenomatous Polyps↗
PubMed1993

[Contribution of the ALDH2 and CYP2E1 genes to flushing response and drinking patterns in Japanese healthy volunteers].

Relationship between genotypes of the loci for ALDH2 and CYP2E1 and the flushing response as well as drinking pattern were investigated among 31 Japanese healthy persons. In 14 persons who showed flushing symptom and whose ALDH2 genotype was heterozygote (ALDH2*1/ALDH2*2), 6 persons whose CYP2E1 genotype was mutant homozygote or heterozygote (C2/C2 or C1/C2), reported to drink more frequently and their alcohol consumption was higher than that of C1/C1 carriers. However, 2 subjects possessing C2 allele in 3 persons carrying ALDH2 homozygous genotype showed very low alcohol consumption. It is concluded that a person heterozygous for ALDH2 and either mutant homozygous or heterozygous for CYP2E1 may become able to drink more alcohol, if his drinking pattern grows more frequent.

Adult↗
PubMed1992

Distribution of ADH2 and ALDH2 genotypes in different populations.

The distribution of the human liver alcohol dehydrogenase, ADH2, and aldehyde dehydrogenase, ALDH2, genotypes in 21 different populations comprising Mongoloids, Caucasoids, and Negroids was determined by hybridization of the amplified genomic DNA with allele-specific oligonucleotide probes. Whereas the frequency of the ADH1(2) allele was found to be relatively high in the Caucasoids, Mexican Mestizos, Brazilian Indios, Swedish Lapps, Papua New Guineans and Negroids, the frequency of the ADH2(2) gene was considerably higher in the Mongoloids and Australian Aborigines. The atypical ALDH2 gene (ALDH2(2)) was found to be extremely rare in Caucasoids, Negroids, Papua New Guineans, Australian Aborigines and Aurocanians (South Chile). In contrast, this mutant gene was found to be widely prevalent among the Mongoloids. Individuals possessing the abnormal ALDH2 gene show alcohol-related sensitivity responses (e.g. facial flushing), have the tendency not to be habitual drinkers, and apparently suffer less from alcoholism and alcohol-related liver disease.

Alcohol Dehydrogenase↗
PubMed1990

Developmental changes of aldehyde dehydrogenase isozymes in human livers: mitochondrial ALDH2 isozyme is expressed in fetal livers.

Previous reports suggested that the major cytosolic aldehyde dehydrogenase (ALDH1) was present in fetal and infant livers, but the major mitochondrial isozyme (ALDH2) was absent or severely diminished. Re-examination by means of starch gel electrophoresis followed by enzyme activity staining, and by means of dot blot immuno-hybridization of liver samples with known genotypes of the ALDH2 locus, indicated that both ALDH1 and ALDH2 genes are expressed in fetal and infant livers. In addition, ALDH4 isozyme was also observed. The results imply that a fetus with the 'usual' homozygous ALDH1(2)/ALDH1(2) genotype, but not one with the atypical ALDH1(2)/ALDH2(2) or ALDH2(2)/ALDH2(2), is capable of detoxifying acetaldehyde transferred from the mother.

Aldehyde Dehydrogenase↗
PubMed2003

XRCC1, CYP2E1 and ALDH2 genetic polymorphisms and sister chromatid exchange frequency alterations amongst vinyl chloride monomer-exposed polyvinyl chloride workers.

Vinyl chloride monomer (VCM) is a known human carcinogen, which may be metabolized by cytochrome P450 2E1 (CYP2E1), aldehyde dehydrogenase 2 (ALDH2), and glutathione S-transferase T1 (GSTT1). A DNA-repair gene, X-ray repair cross-complementing group 1 ( XRCC1, exon 10), may also be implicated in the process of VCM-related carcinogenesis. Thus, VCM-exposed workers with inherited susceptible metabolic and DNA-repair genotypes may experience an increased risk of genotoxiciy. This study was designed to investigate whether metabolic and DNA-repair genotypes affected sister chromatid exchange (SCE) frequency in occupationally VCM-exposed workers from polyvinyl chloride (PVC) manufacturing plants. Study subjects comprised 61 male workers having experienced VCM exposure, and 29 male controls. Questionnaires were administered to obtain detailed histories of cigarette-smoking habits, alcohol consumption behavior, and occupation. The frequency of SCE in peripheral lymphocytes was determined using a standardized method, and genotypes of CYP2E1, ALDH2, GSTT1 and XRCC1 were identified by the polymerase chain reaction (PCR) procedure. Our results demonstrated that smoking, age and VCM exposure and XRCC1 ( P=0.03), CYP2E1 ( P=0.04), and ALDH2 ( P=0.08) were significantly associated with an increased SCE frequency. Further analysis of gene combinations, including CYP2E1, ALDH2 and XRCC1, revealed an increased trend for these genotypes to influence SCE frequencies for the low VCM-exposure group ( P<0.01), but not so for the high VCM-exposure group ( P=0.29) or for controls ( P=0.49). These results suggest that workers with susceptible metabolic and DNA-repair genotypes, may experience an increased risk of DNA damage elicited by VCM exposure.

Adult↗
PubMed2005

ALDH2 and CYP2E1 genotypes, urinary acetaldehyde excretion and the health consequences in moderate alcohol consumers.

Deficiencies in mitochondrial low-Km aldehyde dehydrogenase (ALDH2) activity, and consequently high blood acetaldehyde levels, have been suggested to relate to various diseases in Japanese, including esophageal cancer. In the present study, 200 men aged 35-59 years randomly selected from an occupational population were analyzed for the association of ALDH2 genotypes and cytochrome P450-2E1 (CYP2E1) genotypes with the urinary excretion of acetaldehyde (which is bound to some chemicals in the urine) and with common alcohol-related health consequences. Urinary acetaldehyde excretion was increased, reflecting increased alcohol consumption even in this moderate alcohol-consuming population. Neither the ALDH2 nor the CYP2E1 genotypes showed significant influence on the elevation of urinary acetaldehyde excretion. Neither these genotypes nor urinary acetaldehyde concentration significantly affected blood pressure, serum aspartate aminotransferase and gamma-glutamyl transferase activities, or serum HDL-cholesterol and lipid peroxide concentrations. It was concluded that acetaldehyde accumulates in moderate alcohol consumers irrespective of ALDH2 and CYP2E1 genotype, and that the implications of these genotypes and acetaldehyde accumulation in terms of common alcohol-related health consequences were obscure. The results also suggest that the carcinogenicity of acetaldehyde on esophageal mucosa depends greatly upon repeated exposure to high blood acetaldehyde, even through transient rather than chronic exposure.

Acetaldehyde↗
PubMedDate not supplied

Effects of alcohol on the EEG in Asian men with genetic variations of ALDH2.

Approximately 50% of Asians experience a facial flush following alcohol ingestion. These individuals have an inactive form of mitochondrial aldehyde dehydrogenase (ALDH) encoded by the ALDH2*2 allele. This study matched 15 flushing and 15 nonflushing Asian men on demographics and drinking histories. The 30 subjects were genotyped for ALDH2 and were evaluated both before and following placebo and 0.75 ml/kg alcohol. The two groups did not differ significantly on blood alcohol concentrations after drinking, but did differ in electroencephalographic (EEG) response on the falling phase of the blood alcohol curve. Nonflushing subjects displayed significant increases in slow-alpha EEG activity (7.5-9.0 Hz) at 90 and 150 min post-alcohol consumption, compared to flushing subjects who did not show characteristic increases in this frequency band at these timepoints. These data suggest flushers, those with at least one ALDH2*2 allele, have less of slow-alpha wave EEG response to alcohol than nonflushers with ALDH2*1/2*1 genotype.

Adult↗
PubMed1993

Mitochondrial aldehyde dehydrogenase (ALDH2) polymorphism in AA and ANA rats: lack of genotype and phenotype line differences.

Polymorphism of the gene coding for mitochondrial ALDH2 in humans is known to be associated with differences in alcohol drinking behavior. Recently, two different alleles of the ALDH2 gene, ALDH2R and ALDH2Q, have been found in rats also and a possible relationship between the frequencies of the two alleles and drinking behavior has been proposed. In this study, we examined whether this polymorphism of ALDH2 was the underlying cause for the previously reported acetaldehyde accumulation in the alcohol-avoiding ANA rat line and, thus, could be one of the factors explaining the differences in alcohol drinking behavior between the ANA and the alcohol-preferring AA rat lines. The experimental animals were genotyped and their mitochondrial ALDH activities and blood acetaldehyde concentrations after ethanol injection were measured. The two lines did not differ in their frequencies of ALDH2R and ALDH2Q alleles. Thus, the polymorphism in the ALDH2 gene does not explain the acetaldehyde accumulation in ANA rats and it does not seem to be associated with differences in the alcohol drinking behavior in these rat lines.

Acetaldehyde↗
PubMed2000

Dipole estimation of alpha EEG during alcohol ingestion in males genotypes for ALDH2.

Using a dipole tracing method based on the two-dipole model, the purpose of the present study was to investigate alcohol-induced changes in the alpha band of electroencephalogram (EEG) and its equivalent current dipoles (ECDs) in 12 healthy male volunteers, who were genetically typed for mitochondrial aldehyde dehydrogenase-2 (ALDH2). The alpha power and the mean interval dipolarity, which represents the goodness of fit of alpha EEG with the two-dipole model, increased at 30 min after 0.75 ml/kg of alcohol ingestion, when breath alcohol concentration showed its peak. However, the location of ECDs and distribution of alpha EEG did not change after alcohol ingestion. These findings indicate that alcohol enhances alpha EEG but does not change the location of its electrical sources. Interestingly, the time course of alcohol-induced EEG changes differed significantly according to the aversive flushing reaction after its intake. From 60 to 120 min, the non-flushing group which had homozygous ALDH2* 1 (active type) displayed significant increase not only in the alpha power but also in the interval dipolarity compared to the baseline, whereas the flushing group with heterozygous ALDH2*1/2*2 (inactive type) did not exhibit this significant increase. The difference in the time course was discussed from the viewpoint of the protective effect of ALDH2*2 allele against the risk for alcoholism. These results suggest that the dipole tracing method could provide an alternative neurophysiological marker for the risk for alcoholism.

Adult↗
PubMed2000

Relationship between alcohol drinking, ADH2 and ALDH2 genotypes, and risk for hepatocellular carcinoma in Japanese.

The polymorphism in the ALDH2 gene plays a central role in Asian alcohol hypersensitivity and has been associated with the risk for esophageal cancer. In the present study, we attempted to examine associations between the ADH2 and ALDH2 polymorphisms, alcohol drinking and hepatocellular carcinoma (HCC) development in a case-control study in Japan. One hundred and two patients with HCC (85 males and 17 females) and 125 control subjects (101 males and 24 females) were enrolled in the study. Higher cumulative amounts of alcohol consumption (drink-years of > or = 40 drinks/day x year) showed a significant association with HCC development (odds ratio, OR = 2.7; 95% CI = 1.3-5.5, adjusted for age and smoking). By contrast, we could find no association of the ALDH2 genotypes with HCC development (adjusted OR for ALDH2*1/*2 = 1.1; 95% CI = 0.6-2.1). Likewise, the ADH2 genotypes were not associated with HCC development (adjusted OR for ADH2*2/*2 = 0.8; 95% CI = 0.5-1.5). The present results do not support a contribution of acetaldehyde, an active metabolite of ethanol, to HCC development and rather indicate a direct involvement of ethanol in hepatocarcinogenesis.

Aged↗