Is alcohol the key to the French paradox?

A compound resulting from the normal metabolism of alcohol may explain why having a drink or two each day lowers the risk of heart disease. Researchers now have evidence that the chemical, acetaldehyde, interrupts a harmful cascade of reactions that lead to blood vessel damage.

Yousef Al-Abed of the Picower Institute for Medical Research in Manhasset, N.Y., described the study last week at a meeting of the American Chemical Society in New Orleans.

The observation that moderate alcohol consumption can protect against heart disease is the basis for what is known as the French paradox: Despite a typical diet rich in fat, France doesn't seem to have as high a rate of heart disease as the United States. The difference may be that the French consume more red wine.

Researchers have tried to determine which chemical in wine might be responsible. Some studies single out antioxidants called flavonoids (SN: 10/30/93, p. 278), but others focus on the alcohol, since beer and liquor also appear to reduce heart attack risk (SN: 12/2/95, p. 380).

Al-Abed and his colleagues looked at the effect of alcohol on the Maillard reaction, which occurs in the body when a sugar links up with a protein. These sugar-protein molecules are known as Amadori products. Weeks or months after forming, these molecules break up and rearrange their parts to form a wide variety of compounds called advanced glycation end products, or AGEs.

The compounds go on to cause cardiovascular damage--for example, by cross-linking proteins in arterial walls, making them less elastic. Studies have also implicated AGEs in triggering complications associated with diabetes, such as blood vessel damage in the eyes and kidneys.

Al-Abed notes that scientists have identified at least two dozen AGEs.

In their latest study, the Picower group found that acetaldehyde from alcohol might stop the formation of AGEs. Al-Abed and his colleagues determined that in the test tube, acetaldehyde can react with the Amadori product made when the sugar glucose links to hemoglobin, the iron-carrying protein in red blood cells.

"The Amadori product is a very flexible molecule. It can open or close," explains Al-Abed. "The closed form is not dangerous, but the open form can react. Acetaldehyde stabilizes the unreactive [closed] form of the Amadori product," preventing it from forming AGEs, he says.

By studying rats that had been treated with a drug to make them diabetic, the researchers also found evidence that acetaldehyde helps prevent the formation of AGEs. Diabetic rats fed alcohol produced half as much of the AGEs as rats fed no alcohol.

Acetaldehyde's bad reputation makes it "a provocative answer to the French paradox," notes Raja G. Khalifah of the University of Kansas Medical Center in Kansas City. "Acetaldehyde is a very nasty chemical," he says. "It reacts with many things, not just Amadori products."

Khalifah cautions that acetaldehyde's reactivity makes it difficult to determine whether the compound stops AGE formation in rats by interfering with an Amadori product. "It's possible that ... it may proceed through other mechanisms," he says.

Khalifah cites the example of aminoguanidine, an experimental diabetes drug that researchers thought was blocking AGE production by forming complexes with Amadori products. "Subsequent studies could not show that that's what's actually happening in vivo," says Khalifah.

Now, scientists suspect that aminoguanidine acts on compounds created in the later stages of AGE synthesis, after the Amadori products fragment. The drug is currently being tested on people without much success, says Al-Abed.

He says that his group's research may lead to new compounds that disable Amadori products without the harmful effects of acetaldehyde.