Alcohol Could be Toxic and Cause DNA Damage for Some People

NIH, US | JANUARY 25, 2010

After alcohol is consumed, it is first metabolized, or broken down, into acetaldehyde, a toxic chemical that causes DNA damage.

For most of us, an enzyme called aldehyde dehydrogenase 2 (ALDH2) breaks down acetaldehyde into acetate (a nontoxic metabolite) and removes other toxic aldehydes that can accumulate in the body. But not all of us are that lucky.

An estimated 1 billion people worldwide carry a genetic mutation that produces an inactive form of ALDH2. The defective alcohol metabolism enzyme affects about 40 percent of the East Asian population, and many people of East Asian descent throughout the world.

When individuals with the ALDH2 mutation drink alcohol, acetaldehyde accumulates in the body, resulting in facial flushing, nausea, and rapid heartbeat.

The inactive form of ALDH2 is linked to increased cancer risk, and it also reduces the effectiveness of nitroglycerin (a drug to treat angina, chest pain that occurs when the heart doesn't get enough oxygen-rich blood).

"We recently identified a molecule called Alda-1 that activates the defective enzyme, and (...) we determined how this activation is achieved," said Thomas D. Hurley, Ph.D., professor and associate chairman of biochemistry and molecular biology at Indiana University School of Medicine.

In a series of experiments that examined the interaction between Alda-1 and the defective ALDH2 enzyme, Dr. Hurley and his colleagues found that Alda-1 restored the structure of the inactive enzyme.

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.

The findings suggest the possibility of a treatment to reduce the health problems associated with the enzyme defect.

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