Disease relevance of ADH1C

• A rare truncating mutation in ADH1C (G78Stop) shows significant association with Parkinson disease in a large international sample [1].
• We previously demonstrated that a functional polymorphism in alcohol dehydrogenase type 1C (ADH1C, also known as ADH3) modifies the association between moderate alcohol consumption and high-density lipoprotein (HDL) levels and risk of myocardial infarction among older men [2].
• Therefore, the aim of the current study was to investigate possible associations of MCV value with polymorphisms of ADH1C in white patients with alcohol-associated esophageal carcinoma, chronic alcoholic pancreatitis, and alcoholic cirrhosis as well as in heavy drinkers without organ damage [3].
• There was a significant interaction of alcohol use and genotype (P = 0.05), with an estimated oral cancer risk in heavy drinkers of 7.1 (95% CI, 2.3-22.0) for homozygous variants compared with an OR of 2.3 (95% CI, 1.4-3.8) for ADH1C homozygous wild type or heterozygous individuals (controlling for smoking, age, race, and gender) [4].
• The ADH1C polymorphism modifies the risk of squamous cell carcinoma of the head and neck associated with alcohol and tobacco use [4].

Psychiatry related information on ADH1C

• Our results confirm that ADH1C genotype modifies the association between alcohol consumption and HDL levels among men and postmenopausal women not using PMH who drink moderately [2].

High impact information on ADH1C

• RESULTS: At 33 or 500 mmol/L ethanol, pH 7.5, the activities in the ADH3 1-1 phenotypic and mu-ADH-expressing mucosal specimens were significantly greater than that in the ADH3 1-2 phenotypic and mu-ADH absent mucosal specimens, respectively [5].
• 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 [6].
• Since ADH catalyzes the conversion of retinol to retinal, which can be further converted to retinoic acid by aldehyde dehydrogenase, these results suggest that retinoic acid activation of ADH3 constitutes a positive feedback loop regulating retinoic acid synthesis [7].
• Deletion mapping experiments identified a region in the ADH3 promoter located between -328 and -272 bp which confers retinoic acid activation [7].
• Within a 34-bp stretch, the ADH3 retinoic acid response element (RARE) contains two TGACC motifs and one TGAAC motif, both of which exist in RAREs controlling other genes [7].

Chemical compound and disease context of ADH1C

• Kinetic simulations using the experimentally determined Hill constant suggest that gastric ADH3 may highly effectively contribute to the first-pass metabolism at 0.5-3 M ethanol, an attainable range in the gastric lumen during alcohol consumption [8].

Biological context of ADH1C

• Deletion of the conserved HNF1 site in the BAC led to the shutdown of human class I ADH gene expression in the transgenic livers, leaving ADH1C gene expression in the stomach unchanged [9].
• A rare nonsense single-nucleotide polymorphism in ADH1C (G78stop, rs283413) was identified in 3 of these patients but in no controls [1].
• Alcohol consumption and high-density lipoprotein levels: the effect of ADH1C genotype, gender and menopausal status [2].
• Both linkage and association analysis identified several ADH1C alleles and a neighboring microsatellite marker that affected risk of alcohol dependence and were also related to binge drinking [10].
• ADH1C genotyping was performed by PCR-based restriction fragment length polymorphism (PCR-RFLP) analysis from whole blood [3].

Anatomical context of ADH1C

• It was assessed that livers with ADH1B*1 may eliminate approximately 95% or more of single-passed ethanol as inflow sinusoidal alcohol reaches approximately 1 mM and that stomachs with different ADH1C genotypes may remove 20% to 30% of single-passed alcohol at the similar level in mucosal cells [11].
• The 30-fold difference in expression between two cell lines demonstrates that this upstream U3 element, which inserted after the duplications that created the three class I ADH genes, plays an important role in regulating tissue-specificity of ADH1C [12].
• Genotyping of the ADH1C-locus was performed using polymerase chain reaction-based restriction fragment length polymorphism methods on leukocyte DNA [13].
• In day 12.5 and 13.5 embryos, ADH3 transgene expression remained in the neural tube and heart and was also observed in more distal regions of the forelimb and hindlimb buds as well as the kidney [14].
• In this study the GSTmu phenotype and ADH genotype at the ADH3 locus were investigated in a group of 39 alcoholic men with upper respiratory/digestive tract cancer: 21 with oropharyngeal cancer and 18 with laryngeal cancer [15].

Associations of ADH1C with chemical compounds

• ADH1C allozymes were the major contributor at low ethanol (< 2 mM), whereas ADH1B3 the major form at higher levels (> 10 mM) in ADH1B*3 individuals [11].
• A methylated upstream region of ADH1C achieved histone H3 hyperacetylation upon either 5-aza-dC or TSA treatment [16].
• Trichostatin A treatment elevated expression of ADH1C [16].
• Variations in the ADH1B and ADH1C genes may influence the LR to alcohol by increasing levels of acetaldehyde during alcohol metabolism, although most data on this question come from Asian populations [17].
• CONCLUSIONS: Because the ADH1C gene is involved in the metabolic pathways of many alcohols, we propose several hypotheses about the causal pathway, including ethanol oxidation activity and, more probably, retinol oxidation [18].

Regulatory relationships of ADH1C

• This might explain why ADH3 is expressed at lower levels than ADH2 in the liver [19].

Other interactions of ADH1C

• Case-control studies that have investigated the association between alcoholism and alcohol-induced liver damage and the ADH2, ADH3, CYP2E1, and ADLH2 polymorphisms have reported controversial or inconclusive results [20].
• Allelic variation at alcohol metabolism genes ( ADH1B, ADH1C, ALDH2) and alcohol dependence in an American Indian population [10].
• For organisms where multiple species-specific isoenzymes exist within a class, we recommend adding a capital letter after the Arabic number; i.e. ADH1A, ADH1B, and ADH1C for human alpha, beta, and gamma class I ADHs, respectively [21].
• For gastric mucosal-alcohol clearance, the relative contributions of ADH1C allozymes and ADH4 were converse as ethanol concentration increased [11].
• The genotype for the most active alcohol dehydrogenase enzyme ADH1C was associated with a lower risk of alcoholism (P = .026) and was less prevalent in alcoholics with DRD2TaqIA2/A2 (P = .047), GABAA-beta2 1412C/C (P = .01), or EAAT2 603G/A (P = .022) genotypes [22].

Analytical, diagnostic and therapeutic context of ADH1C

• Recent epidemiological studies resulted in contradictory results and therefore we have investigated ADH1C genotypes in heavy alcohol consumers only [23].
• This study sought to determine whether an association exists between ADH (ADH1C previously ADH3, ADH1B*2 previously ADH2*2) genotypes, alcohol dependence, drinking history, and liver function tests in the two major ethnic groups of Trinidad and Tobago (TT) [24].
• We have used directed mutagenesis by the polymerase chain reaction (PCR) to amplify and analyze the genotype of ADH 2 and ADH 3 loci [25].
• METHODS: Twenty-four adults, matched by age, body mass index, nutritional state, and homozygosity at ADH3, were recruited from a population base of 304 men [26].
• 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 [27].

References