Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.1.1.1 (alcohol dehydrogenase)
 9,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pharmacogenetic differences among individuals in their capacity to metabolize ingested alcohol are possibly responsible for the large inter-individual and inter-ethnic variations observed in the outcome of alcohol use and misuse. Based on results of adoption, twin, and family studies it is now widely accepted that the vulnerability to alcoholism is determined by genetic factors as well as by environment. There is a constant search for biological markers and specific genes which could identify individuals genetically predisposed to alcohol abuse and alcoholism. Numerous 'candidate genes' for alcoholism have been suggested including the alcohol metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Both ADH and ALDH exhibit genetic heterogeneity. An atypical form of ADH (ADH2), which contains a variant beta 2 subunit instead of the usual beta 1 subunit, differs substantially from the usual form in its kinetic properties and is found more frequently among the Japanese, Chinese and other Mongoloid populations than in Caucasoids and Negroids. A widely prevalent genetic polymorphism has been observed for ALDH; about 50% of Japanese and Chinese livers possess an inactive ALDH (ALDH2 isozyme) whereas none of the Caucasian or Negroid populations show this isozyme abnormality. These metabolic polymorphisms seem to contribute to differences in the in vivo elimination rate of ethanol and acetaldehyde, and may explain differences in alcohol-related behaviour and its disease outcome. Taken together, Orientals who possess an atypical ALDH2 gene are more sensitive to acute responses to alcohol, tend to be discouraged from drinking alcohol, and consequently are at lower risk of developing alcohol-related disorders. However, more work is needed to support these findings. Recent advances in molecular genetics have made it possible to analyze directly the human genome. This may help in a better understanding of the complex genetic and environmental factors in alcohol abuse by providing prospects for identification of gene loci which may be responsible for predisposition to, and protection from, alcoholism.
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PMID:Pharmacogenetics of alcohol metabolism and alcoholism. 130 43

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.
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PMID:Distribution of ADH2 and ALDH2 genotypes in different populations. 173 36

Little is known about factors determining individual susceptibility to the physical complications of alcohol abuse but genetically determined differences in ethanol metabolism may be important. The oxidative metabolism of alcohol is catalyzed by alcohol and aldehyde dehydrogenase. Polymorphisms have been observed at two of the five loci encoding alcohol dehydrogenase subunits: ADH2 (producing three beta subunits) and ADH3 (producing two tau subunits) and also at the locus encoding the metabolically important form of aldehyde dehydrogenase, ALDH2. We have compared ADH2, ADH3 and ALDH2 allele frequencies in patients with alcohol-related cirrhosis (n = 59) and chronic pancreatitis (n = 13) with 79 local healthy control subjects. The different alleles were detected with allele-specific oligonucleotide probes after amplification of leukocyte DNA by the polymerase chain reaction. All patients and all but one control subject were homozygous ADH2*1, encoding the beta 1 subunit. No ADH2*3 alleles were detected. All 34 patients and 39 control subjects tested were homozygous ALDH2*1 encoding the active enzyme. ADH3 allele frequencies were different in patients and control subjects. ADH3*1 frequency: control subjects, 55.1%; cirrhotic patients, 62.7%; chronic pancreatitis patients, 65.4%. The difference between the patient groups combined and the control subjects was significant (p less than 0.05; G-test of Sokal and Rohlf) if it was assumed that the allele frequency in our control population was a reasonable estimate of our local population allele frequency. These results suggest that genetically determined differences in alcohol metabolism may, in part, explain predisposition to alcohol-related end-organ damage.
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PMID:Investigation of the role of polymorphisms at the alcohol and aldehyde dehydrogenase loci in genetic predisposition to alcohol-related end-organ damage. 193 84

The liver enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are responsible for the oxidative metabolism of ethanol, are polymorphic in humans. An allele encoding an inactive form of the mitochondrial ALDH2 is known to reduce the likelihood of alcoholism in Japanese. We hypothesized that the polymorphisms of both ALDH and ADH modify the predisposition to development of alcoholism. Therefore, we determined the genotypes of the ADH2, ADH3, and ALDH2 loci of alcoholic and nonalcoholic Chinese men living in Taiwan, using leukocyte DNA amplified by the PCR and allele-specific oligonucleotides. The alcoholics had significantly lower frequencies of the ADH2*2, ADH3*1, and ALDH2*2 alleles than did the nonalcoholics, suggesting that genetic variation in both ADH and ALDH, by modulating the rate of metabolism of ethanol and acetaldehyde, influences drinking behavior and the risk of developing alcoholism.
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PMID:Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. 201 95

The effect of different amounts of orally ingested ethanol on plasma alcohol dehydrogenase (ADH) and erythrocyte aldehyde dehydrogenase (ALDH), as well as on the blood ethanol and acetaldehyde levels, was examined in healthy nonalcoholic subjects. The genotypes at ADH2 and ALDH2 locus were identified in enzymatically amplified blood DNA by hybridization with allele-specific oligonucleotides. While the Japanese subject was found to be genotypically heterozygous for both ADH2 and ALDH2, the Caucasian subjects were genotypically homozygous normal for these alleles. A faster ethanol elimination associated with a higher blood acetaldehyde level was observed in the Japanese subject as compared to Caucasian subjects. However, no significant change in ADH and ALDH enzyme activities was detected as the result of acute ethanol intake.
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PMID:Effect of acute ethanol drinking on alcohol metabolism in subjects with different ADH and ALDH genotypes. 222 44

Research into the causes of alcoholism is a relatively recent scientific endeavor. One area of study which could lead to better understanding of the disease is the possibility of a genetic predisposition to alcoholism. Recent work has demonstrated that people have varying complements of enzymes to metabolize alcohol. Current knowledge is examined about the influence of various ethanol metabolizing enzymes on alcohol consumption by Asians and members of other ethnic groups. The two principal enzymes involved in ethanol oxidative metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). ADH is responsible for the metabolism of ethanol to acetaldehyde. ALDH catalyzes the conversion of acetaldehyde to acetate. The different isozymes account for the diversity of alcohol metabolism among individuals. An isozyme of ADH (beta 2 beta 2) is found more frequently in Asians than in whites, and an ALDH isozyme (ALDH2), although present in Asians, often is in an inactive form. The presence of an inactive form of ALDH2 is thought to be responsible for an increase in acetaldehyde levels in the body. Acetaldehyde is considered responsible for the facial flushing reaction often observed among Asians who have consumed alcohol. A dysphoric reaction to alcohol, producing uncomfortable sensations, is believed to be a response to deter further consumption. Although the presence of an inactive ALDH2 isozyme may serve as a deterrent to alcohol consumption, its presence does not fully explain the levels of alcohol consumption by those with the inactive isozyme. Other conditions, such as social pressure, and yet undetermined biological factors, may play a significant role in alcohol consumption.
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PMID:Research on alcohol metabolism among Asians and its implications for understanding causes of alcoholism. 251 95

A much higher incidence of alcohol flushing among Orientals in comparison to Caucasians, i.e., greater than 50% vs 5%-10%, has been attributed to racial differences in alcohol-metabolizing enzymes. A large majority of Orientals are "atypical" in alcohol dehydrogenase-2 locus (ADH2), and their livers exhibit significantly higher ADH activity than the livers of most Caucasians. Approximately 50% of Orientals lack the mitochondrial aldehyde dehydrogenase (ALDH2) activity, and elimination of acetaldehyde might be disturbed. We determined by means of hybridization of genomic DNA samples with allele specific oligonucleotide probes, genotypes of the ADH2 and ALDH2 loci in Japanese alcohol flushers and nonflushers. We found that all individuals with homozygous atypical ALDH2(2)/ALDH2(2) and most of those with heterozygous atypical ALDH1(2)/ALDH2(2) were alcohol flushers, while all subjects with homozygous usual ALDH1(2)/ALDH1(2) were nonflushers. Frequency of the atypical ADH2(2) was found to be higher in alcohol flushers than in nonflushers, but the statistical significance was not established in the sample size examined.
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PMID:Genotype of alcohol dehydrogenase and aldehyde dehydrogenase loci in Japanese alcohol flushers and nonflushers. 271 75

Differences in the pharmacokinetics of alcohol absorption and elimination are, in part, genetically determined. There are polymorphic variants of the two main enzymes responsible for ethanol oxidation in liver, alcohol dehydrogenase and aldehyde dehydrogenase. The frequency of occurrence of these variants, which have been shown to display strikingly different catalytic properties, differs among different racial populations. Since the activity of alcohol dehydrogenase in liver is a rate-limiting factor for ethanol metabolism in experimental animals, it is likely that the type and content of the polymorphic isoenzyme subunit encoded at ADH2, beta-subunit, and at ADH3, the gamma-subunit, are contributing factors to the genetic variability in ethanol elimination rate. The recent development of methods for genotyping individuals at these loci using white cell DNA will allow us to test this hypothesis as well as any relationship between ADH genotype and the susceptibility to alcoholism or alcohol-related pathology. A polymorphic variant of human liver mitochondrial aldehyde dehydrogenase, ADLH2, which has little or no acetaldehyde oxidizing activity has been identified. Individuals with the deficient ALDH2 phenotype do not have altered ethanol elimination rates but they do exhibit high blood acetaldehyde levels and dysphoric symptoms such as facial flushing, nausea and tachycardia, after drinking alcohol. Because acetaldehyde is so reactive, it binds to free amino groups of proteins including a 37 kilodalton hepatic protein-acetaldehyde adduct and may elicit an antibody response. We would predict that individuals who have low ALDH2 activity because of liver disease or because they have the inactive ALDH2 variant isoenzyme might form more protein-acetaldehyde adducts and elicit a greater immune response. These adducts may represent good biological markers of alcohol abuse and may also play a role in liver injury due to chronic alcohol consumption.
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PMID:Genetic polymorphism of enzymes of alcohol metabolism and susceptibility to alcoholic liver disease. 306 25

Genetic polymorphisms of two major alcohol-metabolizing enzymes-i.e., one of the class I alcohol dehydrogenase isozymes (ADH2) and the mitochondrial aldehyde dehydrogenase (ALDH2)-exist in Japanese and other Orientals but not in Caucasians. Liver ADH activity of about 90% of Orientals is much higher than that of most Caucasians, while approximately 50% of Orientals lack the ALDH2 activity. The genetic differences have been implicated in the high incidence of alcohol sensitivity observed in Orientals. We determined, by means of hybridization of genomic DNA samples with allele-specific synthetic oligonucleotide probes, genotypes of the ADH2 and the ALDH2 loci of Japanese with alcoholic liver diseases and of control subjects. No significant difference between the patient and control groups was found in the ADH2 genotypes. A remarkable genetic difference between the two groups was found in the ALDH2 locus. The frequency of the typical (Caucasian-type) ALDH1(2) gene was found to be .65 and that of the atypical (Oriental type) ALDH2(2) gene was .35 in the controls, while these were .93 and .07, respectively, in the patients. Thus, most (20 of 23) of the Japanese patients were homozygous Caucasian type ALDH1(2)/ALDH1(2), only three were heterozygous ALDH1(2)/ALDH2(2), and none of the patients were homozygous Oriental type ALDH2(2)/ALDH2(2). The results indicate that Japanese with the atypical ALDH2(2) allele are at a much lower risk in developing the alcoholic liver diseases than are those with homozygous, usual (Caucasian-type) ALDH1(2)/ALDH1(2), presumably owing to their sensitivity to alcohol intoxication.
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PMID:Genotypes of alcohol-metabolizing enzymes in Japanese with alcohol liver diseases: a strong association of the usual Caucasian-type aldehyde dehydrogenase gene (ALDH1(2)) with the disease. 318 38

Isozyme phenotypes of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) from human gastroendoscopic as well as surgical gastric biopsies were determined by starch gel electrophoresis and agarose isoelectric focusing. gamma gamma ADH isozymes were expressed predominantly in the mucosal layer of the stomach, whereas beta beta isozymes were in the muscular layer. In the 56 gastroendoscopic mucosal biopsies examined, the homozygous ADH3 1-1 phenotype was found in 75% of the samples, and the heterozygous ADH3 2-1 phenotype in 25%. Accordingly, the gene frequencies of the alleles ADH1/3 and ADH2/3 were calculated to be 0.88 and 0.12, respectively. Using a modified agarose isoelectric focusing procedure, gastric ALDH I, ALDH II, and up to five ALDH III forms could be clearly resolved. The ALDH III isozymes accounted for more than 80% of the total ALDH activities in gastric mucosa and exhibited Km values in the millimolar range for propionaldehyde at pH 9.0. Forty-five percent of the 55 gastroendoscopic biopsies studied lacked ALDH I isozyme. The complex gastric ALDH III isozyme phenotypes seen in these biopsies fall into three patterns. They can be interpreted by a genetic hypothesis, based on a dimeric molecule, in which there are two separate genes, ALDH3a and ALDH3b, with the ALDH3b locus exhibiting polymorphism. The homozygous phenotypes ALDH3b 1-1 and ALDH3b 2-2 were found to be 4 and 76%, respectively, and the heterozygous ALDH3b 2-1 phenotype 20%, of the total. Therefore, the allele frequencies for ALDH1/3b and ALDH2/3b were calculated to be 0.14 and 0.86, respectively. Several lines of biochemical evidence consistent with this genetic model are discussed.
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PMID:Human stomach alcohol and aldehyde dehydrogenases (ALDH): a genetic model proposed for ALDH III isozymes. 321 14


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