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A Way to Fix Lightweight Drinkers

A compound may repair a defective enzyme in people who metabolize alcohol poorly.
January 11, 2010

An estimated 40 percent of people of East Asian descent carry a defective copy of a gene involved in breaking down alcohol, making them more susceptible to the harmful effects of drinking, such as nausea, facial flushing and rapid heartbeat. The gene codes for an enzyme called aldehyde dehydrogenase 2 (ALDH2), which breaks down a toxic metabolite of alcohol, acetaldehyde, into non-toxic acetate.

Researchers have now identified a molecule, called Alda-1, that appears to restore activity of the defective form of the enzyme. According to a release from the National Institute on Alcohol Abuse and Alcoholism, which funded the research:

The normal, active form of ALDH2 creates a catalytic tunnel, a space within the enzyme in which acetaldehyde is metabolized. In the defective enzyme, the tunnel does not function properly. Alda-1 binds to the defective enzyme in a way that effectively reopens the catalytic tunnel and thus allows the enzyme to metabolize acetaldehyde. Alda-1 binds to the defective enzyme in a way that effectively reopens the catalytic tunnel and thus allows the enzyme to metabolize acetaldehyde.

Research has shown that people with two defective copies of the gene are less susceptible to alcoholism. So why would you need a drug that helped them drink? Because the enzyme is also responsible for breaking down other toxic aldehydes that can accumulate in the body. The defective variation has been linked to an increased risk of cancer, and lack of response to nitroglycerin, a drug used to treat chest pain. According to Thomas Hurley, a biologist at Indiana University School of Medicine in Indianapolis who led the research, it “opens up the possibility of designing new analogs that can selectively affect the metabolism of other molecules that are detoxified by aldehyde dehydrogenase.”

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