Despite alcohol being a common recreational substance we’ve been drinking for at least 12,000 years, it seems we still don’t fully understand just what it does inside our bodies… or brains, for that matter.
A new study in mice and human brain samples has looked at the enzyme called aldehyde dehydrogenase and discovered that it might break down a particular byproduct of alcohol digestion in the brain rather than just in the liver.
We do know that when you drink alcohol, your body jumps into action to begin breaking it down into other compounds. Alcohol breaks down into acetaldehyde, which then breaks down to acetate, which eventually becomes carbon dioxide and water.
It’s this acetaldehyde-to-acetate relationship that the team looked at more closely; the enzyme that controls this process, called aldehyde dehydrogenase, is encoded by a gene called ALDH2.
You may have heard of this gene before. Many people from Asian populations have a genetic variation that causes a flushed face and elevated levels of acetaldehyde when they drink alcohol – due to the molecule being broken down less efficiently.
Acetaldehyde and acetate are both well-known products of alcohol production, and it was thought that the process occurred entirely in the liver before acetate passed through the blood-brain barrier into the nervous system to cause some of the drunken behavior.
“At the behavioral level, much of the research on alcohol intermediate metabolites has focused on acetaldehyde, whose pattern of effects is similar to that of ethanol,” the team writes in their new paper.
“Until recently, acetate had been considered a harmless alcohol by-product, and brain acetate is thought to derive largely from liver alcohol metabolism.”
Using three human brain samples and eleven mice, the team looked at where the gene ALDH2 was being expressed – and turns out it wasn’t just in the liver. Instead, ALDH2 was also being expressed in brain cells in the cerebellum known as astrocytes in two of the four human brain samples the team looked at.
We already knew that the cerebellum is a primary brain region involved in alcohol motor impairment, but it was thought that all the acetate was being trucked into the brain from the liver after acetaldehyde had been broken down there.
But when the researchers bred mice that were ALDH2 deficient in the brain and couldn’t produce aldehyde dehydrogenase in the cerebellum astrocytes, they found something fascinating – alcohol didn’t affect the animals’ motor function as expected, and the levels of acetate in their brains stayed at pre-alcohol levels.
Plus, when the researchers removed ALDH2 from the liver, the levels of acetate in the mouse brains weren’t affected.
Taken together, the researchers think this means some of the acetaldehyde produced by drinking becomes acetate directly in the brain, rather that all being transported from the liver. The brain itself in this case is metabolizing the alcoholic product.
“Thus, astrocytic ALDH2 controls the production, cellular and behavioral effects of alcohol metabolites in a brain-region-specific manner,” the team writes.
“Our data indicate that astrocytic ALDH2 is an important, but previously under-recognized, target in the brain to alter alcohol pharmacokinetics and potentially treat alcohol use disorder.”
There’s a lot more work to do in this space, including confirming that this is also the case in humans, but it’s still an exciting finding. It’s fascinating to think we’re still learning new things all the time – even with a drink that’s arguably older than science itself.
The research has been published in Nature Metabolism.
