[11], The drug disulfiram (Antabuse) prevents the oxidation of acetaldehyde to acetic acid and is used in the treatment of alcoholism. Disulfiram irreversibly inhibits acetaldehyde dehydrogenase and causes acetaldehyde to accumulate following ingestion of alcohol. Two recently identified SNP at the promoter region of the ALDH2 gene (−357 G→A and −361 A→G) seems to be related to the risk of alcoholism (Chou et al., 1999; Harada et al., 1999), but are independent of the risk of ALD (Blasco et al., 2002). [10] ALDH2 genetic variation has been closely correlated with alcohol dependence, with heterozygotes at a reduced risk compared to wild type homozygotes and individual homozygotes for the ALDH2-deficient at a very low risk for alcoholism. We use cookies to help provide and enhance our service and tailor content and ads. [7] Individuals with deficient acetaldehyde dehydrogenase activity are far less likely to become alcoholics, but seem to be at a greater risk of liver damage, alcohol-induced asthma, and contracting cancers of the oro-pharynx and esophagus due to acetaldehyde overexposure.[7]. Acetaldehyde dehydrogenases (EC are dehydrogenase enzymes which catalyze the conversion of acetaldehyde into acetic acid. Acetaldehyde is detoxified by ALDH to acetic acid. The latter are common in Oriental populations. One clinic, where supervised disulfiram was the major plank for the first year of outpatient treatment and was continued by some patients for much longer, reported a 7-year abstinence rate of 50% (Krampe et al 2006). Despite of that many continue to drink with severe consequences especially with respect to cancer development (see below) (Yokoyama et al., 1998, 2002). The alleles with 3.5 and 4 repeats seem to be more active than those with 3, while the activities of the alleles with 2 and 5 repeats are still unclear. ALDH2*1/*1 genotype is common in populations of European and African-American origin. Copyright © 2020 Elsevier B.V. or its licensors or contributors. have shown that ADH is highly expressed in the normal mammary epithelium.28 CYP2E1 is also expressed in normal breast tissues.29 Castro et al. It has been hypothesized that ethanol-induced inhibition of HDACs is due to the depletion of NAD+ caused during its metabolism.92, Mariko Murata MD, PhD, ... Shosuke Kawanishi PhD, in Molecular Aspects of Alcohol and Nutrition, 2016. In Cloninger’s Tridimensional Theory of Personality, the unified neurobiological model of personality was divided into three independent heritable dimensions of temperament—novelty seeking, harm avoidance, and reward dependence—which were proposed in relation to dopamine, serotonin, and norepinephrine, respectively. Tachyarrhythmias, hypotension, collapse and occasional deaths occur if large quantities of alcohol are consumed. In the 1990s, the occurrence of alcoholism among Japanese men with ALDH2*1/*2 genotype has been found to be 75% lower than among men with ALDH2*1/*1 genotype. The ALDH2∗1/∗1-encoded enzyme is active in the metabolism of acetaldehyde, whereas the enzymes encoded by the ALDH2∗1/∗2 and ALDH2∗2/∗2 are partially and totally inactive, respectively. The enzymatic ALDH2 molecule is a tetramer, and tetramers containing one or more ALDH22 chains are catalytically inactive. ", "Associations of ADH and ALDH2 gene variation with self report alcohol reactions, consumption and dependence: an integrated analysis", "The role of aldehyde dehydrogenase-1 (ALDH1A1) polymorphisms in harmful alcohol consumption in a Finnish population", Branched-chain alpha-keto acid dehydrogenase complex, https://en.wikipedia.org/w/index.php?title=Acetaldehyde_dehydrogenase&oldid=988948383, Creative Commons Attribution-ShareAlike License, This page was last edited on 16 November 2020, at 04:56. Coprine (which is an amino acid found in certain coprinoid mushrooms) metabolizes in vivo to 1-aminocyclopropanol which causes similar effects as well. It should be avoided when there is active liver disease (Chick 1999). As mentioned above, acetaldehyde produced by the action of alcohol dehydrogenase when we consume alcohol. The structure of acetaldehyde dehydrogenase 2 (ALDH2) gene is related to strong unpleasant effects of drinking alcohol. Acetaldehyde dehydrogenase (ALDH) deficiency results in acetaldehyde accumulation. The hydrogen which is released when alcohol dehydrogenase turns alcohol into acetaldehyde is bound to a compound called NAD+ (Nicotinamide Adenine Dinucleotide) to form NADH (this is short for Nicotinamide Adenine Dinucleotide plus Hydrogen). Acetaldehyde is metabolized to acetate by aldehyde dehydrogenase and then to carbon dioxide and water. Acetaldehyde is more toxic than alcohol and is responsible for many hangover symptoms. [12] Covalent binding of disulfiram to the thiol blocks the binding of one of the cysteine residues with iodoacetamide, thereby inactivating the enzyme and significantly lowering catalytic activity. Subjects carrying the ALDH22 allele frequently suffer from an unpleasant flushing response after drinking very low doses of ethanol, probably as a consequence of the presence of significant levels of acetaldehyde in their blood (Mizoi et al., 1994; Wall et al., 1997). This gene has a functional SNP in exon 12, resulting in a glutamic acid/lysine exchange at position 487 and shows two variant alleles: ALDH2∗1 and ALDH2∗2. This may exacerbate schizophrenia and may rarely cause psychosis in otherwise healthy individuals. The drug antabuse binds to the enzyme acetaldehyde dehydrogenase and prevents it from breaking down the acetaldehyde produced by the metabolism of alcohol. The ALDH2 gene is mapped to chromosome 12q24. DRD2 density is 30–40% lower in A1 allele carriers than in homozygotic A2 allele carriers. After drinking alcohol, ethanol is metabolized by alcohol dehydrogenase (ADH) to acetaldehyde mainly in the liver. Dermatitis, hepatitis, peripheral neuritis and encephalopathy may also rarely occur. Your liver converts the ethanol to acetaldehyde, a substance that can cause cell damage. A single point mutation (G → A) at exon 12 of the ALDH2 gene causes a replacement of glutamine with lysine at residue 487, resulting in the ALDH2K enzyme. The ALDH2 gene is located in the chromosome 12 (Hsu et al., 1986) and shows two allelic variants. Facial flushing has been found to associate independently with alcohol dependence, after controlling for familial alcohol problems, trait anxiety, antisocial behaviour, social support and stimulation when intoxicated by alcohol (Poikolainen, 2000). ALDH1 is involved in the metabolism of Vitamin A. In this context it is important to note that 40% of Asians have an extremely low ALDH2 activity due to a mutation at the ALDH2 gene. (2008.) Vascular monoamine transporter2 (VMAT2)-positive epithelium and myoepithelium of mammary glands may produce dopamine that reacts with acetaldehyde, resulting in the formation of salsolinol. Since AA is toxic, it has to be rapidly metabolized by AA dehydrogenase (ALDH). Disulfiram can be started when the blood/breath alcohol level is zero. A common genetic vulnerability for the comorbidity has been proposed. Elevated blood acetaldehyde causes facial flushing, severe headache, palpitations, tachycardia, hypertension, respiratory distress, nausea and vomiting. One of these involves sirtuins (SIRTs), NAD+-dependent enzymes that have HDAC activity,90 recognizes histones, and the transcription factor p53 as substrates.91 SIRTs, or Class 3 HDACs, are activated only in the presence of NAD+, which is hydrolyzed into nicotinamide, a potent inhibitor of HDAC activity of SIRTs. This enzyme is encoded by the ALDH2 Gene. Urinary catecholamine levels in daily life are elevated in women at familial risk of breast cancer.32 Dopamine is one of catecholamines and is an important neurotransmitter, originating from the central nervous system. Peripheral dopamine is released from neuronal cells in peripheral tissues, and dopamine released from sympathetic nerves predominantly contributes to plasma dopamine levels.33 Dopamine is accumulated and compartmentalized by the dopamine transporter and the vesicular monoamine transporter 2 (VMAT2)35,36 in the brain. Deficiencies in the performance of these enzymes may protect from alcoholism, and lack of these deficiencies may increase the risk of alcoholism. Acetaldehyde from Alcohol. Malcolm Bruce, Jonathan Chick, in Companion to Psychiatric Studies (Eighth Edition), 2010. ADH helps convert alcohol to acetaldehyde. When they consume alcohol, AA accumulates and results in a flush syndrome (Edenberg). While these genetic deficiencies are more common in Oriental than in European populations, facial flushing and other unpleasant effects are also experienced among a minority of the latter. Among the Han Chinese, the risk for alcoholism has been found to be 99% lower for the ADH2*2/*2-ALDH2*2/*2 individuals than the ADH2*1/*1-ALDH2*1/*1 individuals (Chen et al., 1999). This allele has only been detected in Oriental populations, where it is more prevalent than the ALDH21 allele, and in a lower proportion in Amerindians (Goedde et al., 1992). The residue is alkylated by iodoacetamide in both the cytosolic and mitochondrial isozymes, with modifications to Cys-302 indicative of catalytic activity with other residues.


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