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If you’ve ever had a hangover, you know how bad acetaldehyde’s effects can feel. The chemical, produced when the body breaks down drinking alcohol (ethanol), can make people nauseous and cause their mouths to dry and heads to ache. But most people get off comparatively lightly. Others have a mutation in the gene for the enzyme that normally cleans up acetaldehyde, and when they drink heavily they get more than hung over: They are over 80 times more likely to get mouth, throat and esophageal cancers than people with the normal gene and enzyme.
Now Stanford University researchers have found a novel way to pair two small chemicals to reduce this risk. But one of them, unfortunately, is toxic and also can be used to make the illegal and dangerous drug, ecstasy. So scientists are searching for a safe substitute that can take advantage of this powerful pairing approach, they report today in Proceedings of the National Academy of Sciences.
Usually an enzyme called ALDH2 limits the harm acetaldehyde causes by quickly converting it to acetic acid, vinegar’s key ingredient. About 560 million Asians have a mutation in the gene for ALDH2, however, and this mutated enzyme does not work. So acetaldehyde builds up. The result is that such people get more intoxicated and their faces flush strongly when drinking. Acetaldehyde is also ranked as a group 1 carcinogen by the International Agency for Research on Cancer and when it stays in the body longer it raises the cancer risk for these people. “I carry this mutation,” says Stanford University molecular biologist Che-Hong Chen. “So do many of my friends.” Last week, he noted that “now it’s Chinese New Year and everybody’s drinking. If you go to Taiwan you see a lot of red faces, and they continue to drink a lot. That’s actually very dangerous.”
Chen is part the Stanford team, led by Daria Mochly-Rosen, which found that a chemical called safrole can recruit a completely different enzyme to the breakdown task, replacing the ineffective mutant. Chen compares acetaldehyde with a foot, and enzymes to shoes. Normal ALDH2 is a well-fitting shoe but mutant ALDH2 is a broken shoe that cannot fit the acetaldehyde foot at all. The body does make a related shoe, an enzyme known as ALDH3A1, but it is normally much too large to hold acetaldehyde within it. Adding safrole, however, is like stuffing the toe of this new enzyme shoe with paper. This keeps acetaldehyde snugly inside ALDH3A1, giving the enzyme time to break down the alcohol product and move it to its vinegary destiny.
Chen and Mochly-Rosen tested safrole alongside another compound called Alda1, which makes ALDH2 work twice as fast. They gave them to “wild-type” mice with fully working ALDH2 and to mutant mice with a defective version of the enzyme. Some mice got one or other of the two compounds, some received the combo and some were given nothing. The scientists then gave the wild-type animals alcohol equivalent to a human binge-drinking session and the mutants about two thirds as much.
Over the two hours after taking the double-compound “anti-cocktail” wild-type mice behaved almost as if sober. Levels of acetaldehyde and ethanol in the blood dropped. The mutant mice, as expected, were still lethargic several hours after drinking. They did, however, sober up more quickly with the double anti-cocktail than if they were given safrole or Alda1 separately, or nothing at all. Safrole appears to sit in the part of ALDH3A1 that normally acts as a dock for larger molecules, filling the space so the enzyme fits more snugly around acetaldehyde.
This is the first time a problem caused by one broken enzyme has been solved by a molecule working on a different one, notes Thomas Hurley, a biochemist at Indiana University School of Medicine and a specialist in enzyme structure. He says that figuring out that such substitutions can remove harmful compounds is “a critical observation”. As well as reducing cancer risk in Asians with the mutant enzyme, Mochly-Rosen’s team suggests the approach could be used to sober up people who end up in hospital after drinking too much.
They are quick to caution: Safrole cannot be used in people, in part because it is toxic and carcinogenic. Its sale is also restricted because a few chemical changes can turn it into MDMA, the active compound in ecstasy. Chen doubts MDMA itself would work, in case anyone is foolish enough to try it “The requirements for the fit are very specific,” Chen says. “It would also be very dangerous.” (Ten students and two visitors at Wesleyan University in Connecticut were hospitalized this past weekend, two of them in critical condition, after taking a version of MDMA.)
Mochly-Rosen’s lab is working to find other molecules that fit into ALD3A1’s dock, to produce the same acetaldehyde-reducing effect. Chen also underlines that the approach opens up a new general approach to resolve genetic problems. “There are so many other human enzyme or receptor systems where there is a similar situation," he says.