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)

Public health guidelines aim to limit the consumption of alcoholic beverages worldwide and the subsequent health burden. In particular, alcohol consumption is an avoidable risk factor for cancer. In human beings, ethanol in alcoholic drinks is mainly oxidised in the liver by alcohol dehydrogenases to acetaldehyde, and is further detoxified to acetate by aldehyde dehydrogenases. Functional variants in genes involved in alcohol metabolism result in differences between individuals in exposure to carcinogenic acetaldehyde, suggesting a possible interaction of genetic susceptibility and alcohol exposure in cancer. We reviewed available studies of the combined effects of alcohol drinking and genetic polymorphisms on alcohol-related cancer risk. Most available data were for polymorphisms in alcohol and folate metabolism. We give an overview of published studies on the combined effects of alcohol drinking and polymorphisms in genes for alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), cytochrome P450 2E1, and methylene-tetrahydrofolate reductase on the risk of alcohol-related cancer. Current data lend support to a role of polymorphisms ADH1B and ALDH2 combined with alcohol consumption in cancer. Other available data are insufficient or inconclusive, highlighting the need for additional studies.
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PMID:Alcohol and genetic polymorphisms: effect on risk of alcohol-related cancer. 1918 35

Liver alcohol dehydrogenase oxidizes ethanol to acetaldehyde, which is further oxidized to acetate by aldehyde dehydrogenase-2 (ALDH2*1). Individuals who carry a low-activity ALDH2 (ALDH2*2) display high blood acetaldehyde levels after ethanol consumption, which leads to dysphoric effects, such as facial flushing, nausea, dizziness, and headache ("Asian alcohol phenotype"), which result in an aversion to alcohol and protection against alcohol abuse and alcoholism. Mimicking this phenotype may reduce alcohol consumption in alcoholics. RNA interference (RNAi) is a cell process in which a short interfering RNA (siRNA) of 21-25 bp guides the degradation of a complementary target mRNA. Thus, siRNAs may be useful in mimicking the Asian phenotype by inhibiting ALDH2 gene expression. We determined the inhibitory effect of three chemically synthesized siRNAs targeted against rat ALDH2 mRNA in human embryonic kidney cells (HEK-293 cell lines) transfected with a plasmid carrying the rat ALDH2 cDNA. Two of the three siRNAs were active, yielding a 65-75% reduction of ALDH2 activity. Based on the most promising siRNA sequence, three short hairpin RNA (shRNA) genes driven by the human U6 RNA promoter were designed and cloned in a plasmid. After transfection of HEK-293 cells, one of the genes was shown to be active, yielding a 50% reduction of ALDH2 activity. This effect is consistent with a 50% reduction in ALDH2 mRNA, whereas neither beta-actin mRNA nor the interferon-inducible transmembrane protein-1 mRNA levels were affected. This study describes chemically synthesized siRNAs and an endogenously synthesized shRNA, which reduce ALDH2 activity and constitute tools that should be of value for further alcohol research.
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PMID:RNA interference against aldehyde dehydrogenase-2: development of tools for alcohol research. 1925 Nov 11

The key issue in cancer prevention is the identification of specific aetiologic factors. Acetaldehyde, the first metabolite of ethanol oxidation, is carcinogenic in animals. ADH and ALDH2 gene mutations provide an exceptional human model to estimate the long-term effects of acetaldehyde exposure in man. These models provide strong evidence for the local carcinogenic potential of acetaldehyde also in humans. Ethanol is metabolized to acetaldehyde by both mucosal and microbial enzymes. Many microbes produce acetaldehyde from ethanol, but their capacity to eliminate acetaldehyde is low, which leads to the accumulation of acetaldehyde in saliva during an alcohol challenge. Acetaldehyde is the most abundant carcinogen in tobacco smoke, and it readily dissolves into saliva during smoking. Fermented food and many alcoholic beverages can also contain significant amounts of acetaldehyde. Thus acetaldehyde, derived from mucosal or microbial oxidation of ethanol, tobacco smoke, and/or diet, appears to act as a cumulative carcinogen in the upper digestive tract of humans. The evidence strongly suggests the importance of world-wide screening of acetaldehyde and ethanol levels in many beverages and foodstuffs, as well as an urgent need for regulatory measures and consumer guidance. Screening of the risk groups with enhanced acetaldehyde exposure, e.g. people with ADH and ALDH2 gene polymorphisms and hypochlorhydric atrophic gastritis, should also be seriously considered. Most importantly, the GRAS (generally regarded as safe) status of acetaldehyde, which allows it to be used as a food additive, should be re-evaluated, and the classification of acetaldehyde as a carcinogen should be upgraded.
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PMID:Acetaldehyde as a common denominator and cumulative carcinogen in digestive tract cancers. 1939 61

Human class I ADH is a dimmer formed by the random association of three types of subunits (alpha, beta and gamma) encoded by ADH1A, ADH1B, and ADH1C, respectively. Different kinetic properties were reported due to polymorphisms of ADH1B Arg47His and ADHIC Ile349Val. Besides these polymorphisms in the coding region, various mutations in the promoter region and 3' untranslated (UTR) region, which possibly affect expression and degradation rate, were recently reported. In this study, to asses the involvement of each genotype in alcohol metabolism in humans, our previously collected data set of blood EtOH and AcH changes were reanalyzed with regard to the ALDH2 Glu487Lys genotype. The effects of genotypes and haplo-types on transcriptional activity were also examined by a luciferase reporter assay by cloning the promoter region and 3' UTR corresponding to each polymorphism and transfecting into HepG2 cells. Among the nine polymorphisms, including ADH1B Arg47His and ADH1C Ile349Val, blood EtOH levels were significantly affected by polymorphisms ADH1B -451G>T, ADH1B +52A>G, ADH1B +531G>A, ADH1B +1176AG>del. and ADH1A -55C>T in ALDH2 Glu/Glu subjects. In the ALDH2 Glu/Lys genotype background, only ADH1C -254G>C and ADH1B His47Arg showed significant effects on blood EtOH. These five loci (and the two loci which had significant effect on blood EtOH in ALDH2 Glu/Glu and Glu/Lys subjects) also showed strong linkage disequilibrium. In comparison to the in vivo study on alcohol metabolism, significantly higher transcriptional activities in ADH1B -451T (rather than C) promoter and ADH1C-254 G (rather than C) promoter were observed in a luciferase assay in HepG2 cells. In conclusion, polymorphisms in the untranslated regions of ADH class I genes were demonstrated to clearly affect individual differences in alcohol metabolism. Especially, ADH1B -451G>T, ADH1C-254G>C polymorphisms were suggested to have functional significance with regard to transcriptional activity to the linkage equilibrium of polymorphisms ADH1B His47Arg and ADH1C Ile349Val.
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PMID:Effects of polymorphisms in untranslated regions of the class I alcohol dehydrogenase (ADH) genes on alcohol metabolism in Japanese subjects and transcriptional activity in HepG2 cells. 1961 39

Chronic ethanol consumption is a strong risk factor for the development of certain types of cancer including those of the upper aerodigestive tract, the liver, the large intestine and the female breast. Multiple mechanisms are involved in alcohol-mediated carcinogenesis. Among those the action of acetaldehyde (AA), the first metabolite of ethanol oxidation is of particular interest. AA is toxic, mutagenic and carcinogenic in animal experiments. AA binds to DNA and forms carcinogenic adducts. Direct evidence of the role of AA in alcohol-associated carcinogenesis derived from genetic linkage studies in alcoholics. Polymorphisms or mutations of genes coding for AA generation or detoxifying enzymes resulting in elevated AA concentrations are associated with increased cancer risk. Approximately 40% of Japanese, Koreans or Chinese carry the AA dehydrogenase 2*2 (ALDH2*2) allele in its heterozygous form. This allele codes for an ALDH2 enzyme with little activity leading to high AA concentrations after the consumption of even small amounts of alcohol. When individuals with this allele consume ethanol chronically, a significant increased risk for upper alimentary tract and colorectal cancer is noted. In Caucasians, alcohol dehydrogenase 1C*1 (ADH1C*1) allele encodes for an ADH isoenzyme which produces 2.5 times more AA than the corresponding allele ADH1C*2. In studies with moderate to high alcohol intake, ADH1C*1 allele frequency and rate of homozygosity was found to be significantly associated with an increased risk for cancer of the upper aerodigestive tract, the liver, the colon and the female breast. These studies underline the important role of acetaldehyde in ethanol-mediated carcinogenesis.
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PMID:Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism. 1984 67

The association between two functional polymorphisms in alcohol dehydrogenase (ADH2/ADH1B) and aldehyde dehydrogenase (ALDH2) genes and alcohol dependence was examined in 182 Chinese and Indian patients undergoing treatment for alcohol dependence and 184 screened control subjects from Singapore. All subjects were screened by the Alcohol Use Disorders Identification Test (AUDIT). Patients were also administered the Severity of Alcohol Dependence Questionnaire (SADQ). Polymorphisms were genotyped by allele-specific polymerase chain reaction and selected genotypes confirmed by DNA sequencing or restriction fragment length polymorphism. Our results showed that frequencies of ADH1B*2 and ALDH2*2 were higher in controls compared to alcohol-dependent subjects for both Chinese and Indians. Frequencies of these two alleles were also higher in the 104 Chinese controls compared to the 80 Indian controls. None of the eight Chinese who were homozygous for both protective alleles was alcohol dependent. The higher frequencies of the protective alleles could explain the lower rate of alcohol dependence in Chinese.
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PMID:Alcohol and aldehyde dehydrogenase polymorphisms in Chinese and Indian populations. 2002 35

Novel molecular genetic approaches, at genome-scale in different species allowed characterizing genes that have undergone recent selection. The interest in this research field is not limited to the natural curiosity about our evolutionary past, but it is also to identify novel susceptibility genes for neuropsychiatic disorders by pointing specific human traits, such as behavioral and cognitive abilities. Hypotheses have been proposed to relate specific psychiatric disorders to the origin of modern humans, as evidenced by the theory of Crow about schizophrenia. In the present review, we will focus on genes that underwent positive selection in humans or displayed a human specific evolutionary pattern and which were reported as associated with psychiatric disorders. This will include the (1) DRD4 gene associated with attentiondeficit/ hyperactivity disorder, located in a locus that underwent a positive selection; the (2) GABRB2 gene, a gene associated with schizophrenia and recently reported as the target of a positive selection; (3) MARK1, a candidate gene for autism that was reported as displaying a signature of adaptative evolution in the human lineage, and (4) the ADH and ALDH2 genes which are associated with alcoholism, and for which evidence of positive selection was identified in the human lineage since the divergence between humans and chimpanzees. Identification of novel candidate genes based on recent evolution selection, coupled to genome-wide strategies designed to detect rare structural variants, could lead to a better knowledge of the molecular mechanisms of neurodevelopmental disorders and might therefore help to develop new medical chemistry.
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PMID:Primate-accelerated evolutionary genes: novel routes to drug discovery in psychiatric disorders. 2016 40

Epidemiological studies have shown that excessive alcohol consumption is a potent risk factor to develop suicidal behavior. Genetic factors for suicidal behavior have been observed in family, twin, and adoption studies. Because alcohol dehydrogenase (ADH1B) His47Arg and mitochondrial aldehyde dehydrogenase (ALDH2) Glu487Lys single nucleotide polymorphisms (SNPs), which affect alcohol metabolism, have been reported to exert significant impacts on alcohol consumption and on the risk for alcoholism in East Asia populations, we explored associations of the two functional SNPs with suicide using a case-control study of 283 completed suicides and 319 control subjects in the Japanese population. We found that the inactive ALDH2 allele (487Lys) was significantly less frequent in the completed suicides (19.3%) than in the controls (29.3%), especially in males, whereas this was not the case in females. The males bearing alcoholism-susceptible homozygotes at both loci (inactive ADH1B Arg/Arg and active ALDH2 Glu/Glu genotypes) have a 10 times greater risk for suicide compared with the males bearing alcoholism-protective homozygotes at both loci. Our data show the genetic impact of the two polymorphisms on suicidal behavior in the Japanese population, especially in males. Because we did not verify the daily alcohol consumption, the association of these SNPs with suicide might be due to alcoholism itself. Further studies using case-control subjects, which verifies the details of current and past alcohol consumption and diagnosis for alcoholism, are required to confirm these findings.
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PMID:Alcohol and aldehyde dehydrogenase polymorphisms and risk for suicide: a preliminary observation in the Japanese male population. 2018 Aug 59

The most well-known metabolic pathways from ethanol to acetaldehyde include alcohol dehydrogenase (ADH) and the microsomal ethanol oxidizing system that involves cytochrome P450 2E1 (CYP2E1). Acetaldehyde is further oxidized to acetate by aldehyde dehydrogenase (ALDH). The genetic variation of ADH1B, ALDH2, and CYP2E1 is different among racial populations and cause difference in elimination rates of alcohol. The aim of this study was to determine the polymorphisms of ADH1B (rs1229984; Arg47His), ALDH2 (rs671; Glu487Lys), CYP2E1*6 (rs6413432; T7632A), and CYP2E1*7B (rs6413420; G-71T) in unrelated healthy Turkish population and compare it with other populations. ADH1B and ALDH2 polymorphisms were analyzed with an allele-specific polymerase chain reaction (PCR) assay, and CYP2E1*6 and CYP2E1*7B polymorphisms were genotyped by PCR-restriction fragment length polymorphism method. ADH1B polymorphism analysis yielded the genotype distribution as 83.9% ADH1B*1/1 and 16.1% ADH1B*1/2, and no individuals with ALDH2*1/2 and ALDH2*2/2 genotypes were found in Turkish population. The genotype frequencies for CYP2E1*6 polymorphism were found as 85.3% for homozygote common, 14.1% for heterozygote, and 0.6% for homozygote uncommon. For CYP2E1*7B polymorphism, the genotype frequencies were determined to be 86.5% G/G, 13.5% for G/T; however, no individuals with homozygote uncommon genotype were detected. According to our study results, the genotype distributions of ADH1B, ALDH2, CYP2E1*6, and CYP2E1*7B in Turkish population were similar compared with Caucasian and some European populations, whereas differed significantly from East Asian populations. This study may be useful in epidemiological studies of the influence of ADH1B, ALDH2, CYP2E1*6, and CYP2E1*7B polymorphisms on diseases, including several types of cancer related to alcohol consumption and alcohol dependence.
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PMID:Distribution of ADH1B, ALDH2, CYP2E1 *6, and CYP2E1 *7B genotypes in Turkish population. 2059 84

The ethanol in alcoholic beverages and the acetaldehyde associated with alcohol consumption are Group 1 human carcinogens (WHO, International Agency for Research on Cancer). The combination of alcohol consumption, tobacco smoking, the inactive heterozygous aldehyde dehydrogenase-2 genotype (ALDH2*1/*2) and the less-active homozygous alcohol dehydrogenase-1B genotype (ADH1B*1/*1) increases the risk of squamous cell carcinoma (SCC) in the upper aerodigestive tract (UADT) in a multiplicative fashion in East Asians. In addition to being exposed to locally high levels of ethanol, the UADT is exposed to a very high concentration of acetaldehyde from a variety of sources, including that as an ingredient of alcoholic beverages per se and that found in tobacco smoke; acetaldehyde is also produced by salivary microorganisms and mucosal enzymes and is present as blood acetaldehyde. The inefficient degradation of acetaldehyde by weakly expressed ALDH2 in the UADT may be cri! tical to the local accumulation of acetaldehyde, especially in ALDH2*1/*2 carriers. ADH1B*1/*1 carriers tend to experience less intense alcohol flushing and are highly susceptible to heavy drinking and alcoholism. Heavy drinking by persons with the less-active ADH1B*1/*1 leads to longer exposure of the UADT to salivary ethanol and acetaldehyde. The ALDH2*1/*2 genotype is a very strong predictor of synchronous and metachronous multiple SCCs in the UADT. High red cell mean corpuscular volume (MCV), esophageal dysplasia, and melanosis in the UADT, all of which are frequently found in ALDH2*1/*2 drinkers, are useful for identifying high-risk individuals. We invented a simple flushing questionnaire that enables prediction of the ALDH2 phenotype. New health appraisal models that include ALDH2 genotype, the simple flushing questionnaire, or MCV are powerful tools for devising a new strategy for prevention and screening for UADT cancer in East Asians.
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PMID:Alcohol and aldehyde dehydrogenase polymorphisms and a new strategy for prevention and screening for cancer in the upper aerodigestive tract in East Asians. 2118 98


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