Role in Metabolism of Alcohol
In the liver, the enzyme alcohol dehydrogenase oxidizes ethanol into acetaldehyde, which is then further converted into the harmless acetic acid (vinegar) by acetaldehyde dehydrogenase. Acetaldehyde is more toxic than alcohol and is responsible for many hangover symptoms. N-acetylcysteine (NAC) is known to assist in processing acetaldehyde in the body and therefore can help to relieve hangover symptoms.
Some persons of far-Eastern descent have a dominant mutation in their acetaldehyde dehydrogenase gene, making this enzyme less effective. A similar mutation is found in about 5-10% of blond-haired blue-eyed people of Northern European descent. In these people, acetaldehyde accumulates after drinking alcohol, leading to symptoms of acetaldehyde poisoning, including the characteristic flushing of the skin and increased heart and respiration rates. Other symptoms can include severe abdominal and urinary tract cramping, hot and cold flashes, profuse sweating, and profound malaise. 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.
ALDH2, which has a lower KM for acetaldhehydes than ALDH1 and acts predominantly in the mitochondrial matrix, is the main enzyme in acetaldehyde metabolism and has three genotypes. 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. ALDH2K has an increased KM for NAD+, rendering it virtually inactive at cellular concentrations of NAD+. Since ALDH2 is a randomized tetramer, the hetero-mutated genotype is reduced to only 6% activity compared to wild type, while homo-mutated genotypes have virtually zero enzyme activity. The ALDH2-deficient subunit is dominant in hybridization with a wild type subunit, resulting in inactivation of the isozyme by interfering with catalytic activity and increasing turnover. 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.
The drug disulfiram (Antabuse) prevents the oxidation of acetaldehyde to acetic acid and is used in the treatment of alcoholism. ALDH1 is strongly inhibited by disulfiram, while ALDH2 is resistant to its effect. The cysteine residue at 302 in ALDH1 and 200 in ALDH2 is implicated as a disulfiram binding site on the enzyme and serves as a disfulfiram sensitive thiol site. 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. Activity can be recovered by treatment with 2-mercaptoethanol, although not with glutathione.
Metronidazole (Flagyl), which is used to treat certain parasitic infections as well as pseudomembranous colitis, causes similar effects to disulfiram. Coprine (which is an amino acid found in certain coprinoid mushrooms) metabolizes in vivo to 1-aminocyclopropanol which causes similar effects as well.
Read more about this topic: Acetaldehyde Dehydrogenase
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