ALDH2

Aldehyde Dehydrogenase 2 (ALDH2) is an enzyme that plays a crucial role in alcohol metabolism, specifically in the oxidation of ethanol to acetic acid. It is encoded by the ALDH2 gene located on chromosome 12 in humans. This enzyme is part of the aldehyde dehydrogenase family, which is responsible for the detoxification of aldehydes produced during alcohol metabolism and lipid peroxidation.

Function

ALDH2 is primarily found in the liver and is involved in the mitochondrial pathway of ethanol metabolism. After alcohol dehydrogenase (ADH) converts ethanol to acetaldehyde, ALDH2 further metabolizes acetaldehyde to acetic acid, which is then converted to carbon dioxide and water, or used in metabolic pathways to produce energy. This process significantly reduces the toxic effects of acetaldehyde, a compound that is more toxic than ethanol and is associated with the hangover symptoms and other health issues related to alcohol consumption.

Genetic Variants

There are several known genetic variants of the ALDH2 gene, leading to differences in enzyme activity among individuals. The most studied variant is ALDH2*2, a single nucleotide polymorphism that results in a glutamate to lysine substitution at position 487 (Glu487Lys), significantly reducing the enzyme's activity. This variant is prevalent in East Asian populations and is associated with a higher sensitivity to alcohol, characterized by flushing, nausea, and an increased heart rate after consuming alcohol. Individuals with this variant have a reduced risk of developing alcoholism due to the adverse effects experienced upon alcohol consumption, but they have a higher risk of developing alcohol-related diseases, such as alcoholic liver disease and esophageal cancer, if they consume alcohol.

Clinical Significance

The activity of ALDH2 not only influences alcohol metabolism but also has implications for cardiovascular health, cancer risk, and the metabolism of certain drugs. Reduced ALDH2 activity has been linked to an increased risk of coronary artery disease and myocardial infarction in some populations. Furthermore, ALDH2 plays a role in the detoxification of other aldehydes, including those derived from lipid peroxidation, suggesting its involvement in the pathogenesis of various diseases related to oxidative stress.

Pharmacological Inhibition

Inhibitors of ALDH2 have been studied for their potential therapeutic applications, including the treatment of alcohol dependence and the mitigation of the cardioprotective effects of ethanol. Disulfiram, a drug used in the treatment of alcohol dependence, inhibits ALDH2, leading to the accumulation of acetaldehyde upon alcohol consumption, which produces unpleasant effects and discourages alcohol intake.

Conclusion

ALDH2 is a vital enzyme in the metabolism of ethanol and other aldehydes, with significant implications for human health and disease. Genetic variations in the ALDH2 gene influence individual responses to alcohol and susceptibility to alcohol-related diseases. Understanding the role of ALDH2 in alcohol metabolism and its broader implications in health and disease continues to be an important area of research.