Researchers have discovered a compound that can repair a defective alcohol metabolism enzyme, a discovery that could help an estimated 1 billion people worldwide who suffer from a particular type of alcohol intolerance—an inability to safely digest and metabolize alcohol. The findings, published Jan. 10 in the online edition of Nature Structural and Molecular Biology, suggest the possibility of treatment for those affected by the inactive enzyme. The compound may also lead to treatments to reduce the risk of heart disease.
For some people, particularly an estimated 40 percent of people of East Asian descent, a genetic mutation produces an inactive form of the enzyme aldehyde dehydrogenase 2 (ALDH2), which is responsible for breaking down the toxic elements in a molecule of alcohol. When people with the mutation drink beverages like beer or wine, they experience flushed cheeks, nausea and rapid heartbeat. It also increases the risk of cancer.
The researchers, working with the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and led by biochemistry and molecular biology professor Thomas D. Hurley of the Indiana University School of Medicine, have identified a molecule called Alda-1 that activates the defective enzyme when alcohol is present. It helps break down toxic compounds that could otherwise inflict damage on DNA.
Kenneth R. Warren, the NIAAA's acting director, explained in a statement that "this intriguing finding could have broad public-health implications," including treatments to reduce cellular damage during a heart attack.
The research stems from previous studies by Daria Mochly-Rosen, a professor of chemical and systems biology at Stanford University School of Medicine. Knowing that moderate drinking of red wine may reduce the risk of cardiovascular disease, the researchers sought to find just what in alcohol protects cellular tissue from damage during a heart attack. Experimenting on mice, they discovered that alcohol triggers production of the ALDH2 enzyme, and during heart attacks, the enzyme can neutralize toxins and lessen possible damage to heart tissue. They also isolated a compound, Alda-1, which when injected into cells, enhanced ALDH2 activity. It also reactivated the defective enzyme in people with alcohol intolerance.
"We started with the idea of activating the enzyme to protect heart tissue," Dr. Hurley said. "It turns out that it does this, but also we noticed it reactivates the enzyme."
Alda-1 binds to the structure of the inactive ALDH2 enzyme and allows the enzyme to metabolize alcohol as it would in someone who does not have the mutation. If this is developed into a treatment, the person could drink without alcohol intolerance side effects. Alda-1 could also have another use: fighting hangovers, the researchers say. Many hangover symptoms are due to aldehyde build-up, which ALDH2 can reduce.
"We can't deny the fact that if it works the way we think it will, it would eliminate alcohol intolerance [caused by the mutation]," Hurley said. "We want to continue looking for a treatment for heart attack damage. It's a double-edged sword. We could correct the defect but then that increases the risk of other health problems if people are not drinking moderately. If they drink moderately, it's great, but must be tempered with the fact that some people don't."
More research is needed, however. "This is just the starting stages," said Hurley.