Disease relevance of ADH1B

• The inactive ALDH2 encoded by ALDH2*1/*2 and the less-active ADH1B encoded by ADH1B*1/*1 increase the risk of esophageal squamous cell carcinoma in East Asian drinkers [1].
• Alcohol dehydrogenase 1B (ADH1B) genotype, alcohol consumption and breast cancer risk by age 50 years in a German case-control study [2].
• Likewise, the proportion of persons with positive results for ethanol-induced cutaneous erythema differed significantly depending on the ADH2 genotype in both the ALDH2(1)/ALDH2(1) and ALDH2(1)/ALDH2(2) genotypes [3].
• On the other hand, there were significant differences in the ADH2 and ALDH2 polymorphisms between healthy controls and esophageal cancer patients [4].
• Promoter activity of human ADH3, but not ADH1 or ADH2, was shown to be activated by retinoic acid in transient transfection assays of Hep3B human hepatoma cells [5].

Psychiatry related information on ADH1B

• METHODS: We recruited 579 Han Chinese individuals in Taiwan, intending to examine the alcoholism-protection effects of different ADH1B and ALDH2 genotypes with or without antisocial personality disorder [6].
• Alcohol flushing and drinking behavior may partly explain this carcinogenic effect in carriers of less-active ADH2 genotypes [7].
• This study examined aldehyde dehydrogense (ALDH2) gene status, alcohol dehydrogense (ADH2) gene status, conduct disorder, and alcohol dependence in Chinese, Korean, and White American college students [8].

High impact information on ADH1B

• The complete sequence of 340 kb of DNA around the rice Adh1-adh2 region reveals interrupted colinearity with maize chromosome 4 [9].
• In contrast, all of the factors bound to the 5'-flanking region of Adh2 are constitutively present and unchanged by hypoxia [10].
• The transcriptional activation of maize alcohol dehydrogenase-1 (Adh1) and alcohol dehydrogenase-2 (Adh2) is accompanied by changes in the chromatin structure within the 5'-flanking region of each gene [10].
• The ADH1B Arg47His functional polymorphism has the highest F(st) of the 54 SNPs in the ADH cluster, and it is significantly above the mean F(st) of 382 presumably neutral sites tested on the same 42 population samples [11].
• Previous work from our laboratory has shown that the two sites showing the association are in linkage disequilibrium and has identified the ADH1B Arg47His site as causative, with the ADH1C Ile349Val site showing association only because of the disequilibrium [12].

Chemical compound and disease context of ADH1B

• In our previous study, we found that polymorphisms of alcohol and aldehyde dehydrogenase (ADH1B and ALDH2) are important risks for esophageal squamous cell carcinoma in a Taiwanese population [13].
• Clinical evaluations including alcohol consumption, percentage of alcohol drinkers, plasma glucose, HbA1c, insulin, AST, ALT, gamma-GTP, and prevalence of diabetes were compared among the ADH2 genotypes [14].

Biological context of ADH1B

• The genetic polymorphisms of alcohol dehydrogenase-2 (ADH1B) and acetaldehyde dehydrogenase-2 (ALDH2) influence the metabolism of alcohol [15].
• BACKGROUND: suggested that the genetic variation at ADH1B and ALDH2 influences the risk of alcoholism [6].
• The aim of this study was to test the hypothesis that polymorphisms of the ADH1B and ALDH2 genes are significantly associated with genotoxicity induced by alcohol drinking, measured using the cytokinesis-block micronucleus (CBMN) assay, an established biomarker of genome instability, in peripheral blood lymphocytes of 286 healthy Japanese men [15].
• Methylation of the ADH1B proximal promoter in vitro decreased its activity to 54% and inhibited the binding of the upstream stimulatory factor [16].
• Nearly all participants were subsequently genotyped on two polymorphic SNPs in the ADH1B and ADH1C loci known to affect in vitro ADH activity [17].

Anatomical context of ADH1B

• Genotoxic effects of alcohol in human peripheral lymphocytes modulated by ADH1B and ALDH2 gene polymorphisms [15].
• 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 [18].
• ADH2 promoter DNA fragments containing various lengths of 5'-flanking sequences were fused upstream from the gene encoding chloramphenicol acetyltransferase (cat) and transfected into the HepG2 human hepatoma cell line [19].
• While fibroblasts cultured from a skin biopsy from one Japanese individual revealed a heterodimer (ADH2 2-1) of alcohol dehydrogenase, skin extract from another Japanese showed a homodimer (ADH2 2-2) [20].
• The influences of estimated body water, recent drinking history, recent smoking history, polymorphism at the ADH2 and ADH3 loci, family history of alcoholism, and percentage Native American heritage on alcohol elimination rate were determined using multiple regression analyses [21].

Associations of ADH1B with chemical compounds

• H3 histones associated with a methylated upstream region of ADH1B were hyperacetylated in TSA-treated, but not in 5-aza-dC-treated, HepG2 cells [16].
• Moreover, the ADH1B and ALDH2 genes might be involved in dopamine metabolism [22].
• The human ADH1A, ADH1B, and ADH1C genes encode alcohol dehydrogenases (ADHs) that metabolize ethanol [23].
• By these criteria, all-trans-retinol, 4-oxo-retinol, and 4-hydroxy-retinol were successfully docked to both ADH1B and ADH4 [24].
• The crystal structures of human ADH1B and ADH4 provide the opportunity to examine their active sites for potential binding to many diverse retinol structures using molecular docking algorithms [24].

Regulatory relationships of ADH1B

• However, the ADH2 genotype did not seem to influence drinking frequency or amounts of alcohol intake in each ALDH2 genotype [25].
• This might explain why ADH3 is expressed at lower levels than ADH2 in the liver [26].

Other interactions of ADH1B

• Meta-analyses of ALDH2 and ADH1B with alcohol dependence in Asians [27].
• Thus, the previously observed epistatic effect of ADH7 cannot be explained by its linkage disequilibrium with a causative factor in ADH1B [28].
• Polymorphisms of CYP 2E1, GSTT1 and ADH2 may be a major reason of genetic susceptibility in VCM-induced hepatic damage [29].
• Furthermore, docking of all retinols was more favorable in the active site of ADH4 rather than ADH1B as measured by force field and contact scores [24].
• Accordingly, the gene frequencies of the alleles ADH1/3 and ADH2/3 were calculated to be 0.88 and 0.12, respectively [30].

Analytical, diagnostic and therapeutic context of ADH1B

• Self reports of flushing reaction after drinking, cutaneous sensitivity to alcohol (patch test), and genotypic determination of ADH2, ADH3, and ALDH2 were studied in 53 Brazilian volunteers of different ethnic groups [31].
• In this study, we increased the sample size to investigate the modifying effect of lifetime alcohol consumption on the association between ADH1B and ALDH2 genotypes and the risks of esophageal cancer [13].
• STUDY DESIGN: Blood samples from 263 black mother/child pairs (217 mothers and 239 children) were analyzed to determine incidence of the ADH1B allele and the relation of the maternal allele to pregnancy drinking assessed at every prenatal clinic visit [32].
• No significant difference between the patient and control groups was found in the ADH2 genotypes [33].
• Extracts from the primary root or scutellum of induced F2 seedlings from the above crosses were assayed for ADH activity by native polyacrylamide gel electrophoresis (PAGE) and simultaneously scored for survival to determine whether Adh2 and atn were segregating independently [34].

References