Disease relevance of ALDH2

• Genotyping of ADH2, ADH3, ALDH2, and P4502E1 was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods on peripheral white blood cell DNA from 75 alcoholic cirrhotic patients, 48 acute alcoholic pancreatitis patients, 19 heavy drinkers without liver disease or pancreatitis, and 235 controls [1].
• 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 [2].
• Thus, this association of ALDH2 genotype with DM-Mt3243 provides insight into the etiology of diabetes in the mitochondrial diseases [3].
• Genetic polymorphisms of ADH2, ADH3, CYP4502E1 Dra-I and Pst-I, and ALDH2 in Spanish men: lack of association with alcoholism and alcoholic liver disease [4].
• Co-expression of ALDH2 with ALDH2(2) in the presence of E. coli chaperonins produced a soluble enzyme with a K(m) for acetaldehyde of 8.79 microM, suggesting that the product was a heteromer [5].

Psychiatry related information on ALDH2

• In this study, the relationship of the ALDH2 genotype to alcohol-associated symptoms and drinking behavior was investigated in 524 Japanese workers, using a new, rapid, and nonisotopic polymerase chain reaction (PCR) method [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 [7].
• The relationship of ethnicity to alcohol dependence was mediated by ALDH2 status and conduct disorder, although Chinese ethnicity remained significant [8].
• 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 [9].
• Heterozygous for ALDH2 in alcohol dependence: relationship between the ALDH2 genotype and personality disorder in alcohol-dependent patients with the Flushing syndrome [10].

High impact information on ALDH2

• Administration of ASO-9 (20 mg/kg/day for 4 d) to rats resulted in a 50% reduction in liver ALDH2 mRNA, a 40% inhibition in ALDH2 activity, and a fourfold (P < 0.001) increase in circulating plasma acetaldehyde levels after ethanol (1 g/kg) administration [11].
• Rat hepatoma cells incubated for 24 h with an antisense oligonucleotide (ASO-9) showed reductions in ALDH2 mRNA levels of 85% and ALDH2 (half-life of 22 h) activity of 55% equivalent to a >90% inhibition in ALDH2 synthesis [11].
• Deficiency in mitochondrial aldehyde dehydrogenase (ALDH2), a tetrameric enzyme, results from inheriting one or two ALDH2*2 alleles [12].
• In addition to this effect on the enzyme activity, we now report that ALDH2*2 heterozygotes had lower levels of ALDH2 immunoreactive protein in autopsy liver samples [12].
• The ALDH2*2-encoded subunit (ALDH2K) reduces the activity of ALDH2 enzyme in cell lines expressing the wild-type subunit (ALDH2E) [12].

Chemical compound and disease context of ALDH2

• According to these results, not only ALDH2 gene, often claimed to be responsible for alcohol dependence among Japanese, but also ADH2 gene polymorphism, which modulates the metabolism of ethanol, play important roles in habitual alcohol intake behavior in Japanese patients and in some patients leads to alcoholic liver diseases [13].
• In conclusion, the ALDH2 Lys/Lys genotype is a risk factor for myocardial infarction in Japanese men due to its influence on HDL cholesterol level [14].
• About half of the Japanese population have inactive low Km aldehyde dehydrogenase (ALDH2), which metabolizes acetaldehyde to acetic acid at very low concentrations, leading to severe pharmacological effects of aldehyde when drinking alcohol [15].

Biological context of ALDH2

• Logistic regression analyses of the remaining six combinatorial genotypes of the polymorphic ADH2 and ALDH2 loci indicated that individuals carrying one or two copies of ADH2*2 and a single copy of ALDH2*2 had the lowest risk (ORs 0.04-0.05) for alcoholism, as compared with the ADH2*1/*1 and ALDH2*1/*1 genotype [16].
• It is concluded that a point mutation in the human ALDH2 locus produced the glutamine leads to lysine substitution and enzyme inactivation [17].
• Diplotype trend regression analysis of the ADH gene cluster and the ALDH2 gene: multiple significant associations with alcohol dependence [18].
• Genetic polymorphisms have been reported in ADH2, ADH3, ALDH2, and the 5'-flanking region of P450IIEI [19].
• We developed a new restriction fragment length polymorphism method to genotype the mutant and normal ALDH2 alleles by using polymerase chain reaction-directed mutagenesis, which proved to be simpler and faster than the conventional detection methods that use hybridization with allele-specific oligonucleotide probes [20].

Anatomical context of ALDH2

• 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 [21].
• In addition, the interaction of ALDH1 and ALDH2 may alter the retinoid metabolism in the pancreas, thereby influencing insulin secretion and precipitating diabetes [3].
• Genotoxic effects of alcohol in human peripheral lymphocytes modulated by ADH1B and ALDH2 gene polymorphisms [7].
• Western blot analysis revealed that ALDH2 is highly expressed in the heart, skeletal muscle, and brain with moderate expression in liver, eye, and swim bladder of the zebrafish [22].
• ALDH2 expression and localisation was also determined in human skin, while ethanol oxidation, catalysed by ADH, was investigated in the mouse, guinea-pig and human skin cytosol [23].

Associations of ALDH2 with chemical compounds

• Separation of their digests by high-performance reverse-phase chromatography and by two-dimensional paper chromatography and electrophoresis revealed that ALDH2 contained a peptide sequence of -Glu-Leu-Gly-Glu-Ala-Gly-Leu-Gln-Ala-Asn-Val-Gln-Val-Lys- and that the glutamine adjacent to lysine was substituted by lysine in CRM [17].
• All other tryptic peptides, including eight peptides containing S-carboxymethylcysteine, were common in ALDH2 and CRM [17].
• 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 [2].
• The aim of this study was to evaluate zebrafish (Danio rerio) as a model for ethanol metabolism by cloning, expressing, and characterizing the zebrafish ALDH2 [22].
• Moreover, the ADH1B and ALDH2 genes might be involved in dopamine metabolism [24].
• The impact of ALDH2 Lys+ with ADH2 Arg+ was more evident in low folate consumer (OR = 2.32, 1.19-4.55) than high folate consumer (OR 1.38, 0.80-2.38) [25].

Physical interactions of ALDH2

• Thus, the proximal ALDH2 promoter was bound by NF-Y/CP1 and this transcription factor may be responsible for the basal expression of the gene observed in most tissues [26].
• In vitro phosphorylation of HNF4 by PKA decreased binding to FP330-3'. Fasting reduced the ALDH2 protein level in liver and kidney, two tissues expressing HNF4, but not heart [27].
• In our previous study on grass carp (Ctenopharyngodon idellus) liver ALDH, a significant amount of the ALDH activity did not adsorb on the alpha-cyanocinnamate Sepharose column which binds ALDH2 [28].

Regulatory relationships of ALDH2

• The frequency of the inactive ALDH2 genotype was higher than that in the normal control subjects (P < 0.002) and that in the NIDDM control subjects (P < 0.003) [3].
• However, the ADH2 genotype did not seem to influence drinking frequency or amounts of alcohol intake in each ALDH2 genotype [29].
• The ALDH2 FP330-3' site appears to represent a complex nuclear receptor response element that is activated by RXRs and HNF-4 but repressed by members of the COUP-TF family [30].
• GTN (1 microM) inhibited ALDH2 activity (55 +/- 6% of control) and ablated ALDH3 activity [31].

Other interactions of ALDH2

• Allelic variation at alcohol metabolism genes ( ADH1B, ADH1C, ALDH2) and alcohol dependence in an American Indian population [32].
• The results of this study have identified important novel associations between ADH1B/ALDH2 polymorphisms and genotoxicity in alcohol drinkers [7].
• CYP2E1 and ALDH2 genotypes and alcohol dependence in Japanese [33].
• Therefore, association studies of alcoholism in Chinese Han might be more sensitive if controlled for the genotypes of ADH2,ADH3, and ALDH2, when other loci, such as DRD2, are examined [34].
• Neither MTHFR C677T nor ALDH2 showed a measurable association with colorectal adenoma [35].

Analytical, diagnostic and therapeutic context of ALDH2

• Recombinant zebrafish ALDH2 protein was expressed using the baculovirus expression system and purified to homogeneity by affinity chromatography [22].
• A mutant-type ALDH2 (ALDH2(2)) was developed using site-directed mutagenesis of the ALDH2 cDNA and also cloned [5].
• This study investigated the relationship of functional MTHFR C677T and ALDH2 polymorphisms to colorectal adenomas with reference to alcohol consumption in a case-control study of male officials in the Self-Defense Forces (SDF) who received a preretirement health examination at two SDF hospitals [35].
• Examination of liver extracts by two-dimensional crossed immunoelectrophoresis revealed that an atypical Oriental liver with no ALDH2 isozyme contained an enzymatically inactive but immunologically cross-reactive material corresponding to ALDH2, besides the active ALDH1 isozyme.(ABSTRACT TRUNCATED AT 400 WORDS)[36]
• Fifty-one percent of the specimens studied lacked the ALDH2 activity band on the isoelectric focusing gels [37].

References