September 11, 2008 - By Erin Digitale
STANFORD, Calif. - Marauding molecules cause the tissue damage that underlies heart attacks, sunburn, Alzheimer's and hangovers. But scientists at the Stanford University School of Medicine say they may have found ways to combat the carnage after discovering an important cog in the body's molecular detoxification machinery.
The culprit molecules are oxygen byproducts called free radicals. These highly unstable molecules start chain reactions of cellular damage - an escalating storm that ravages healthy tissue.
"We've found a totally new pathway for reducing the damage caused by free radicals, such as the damage that happens during a heart attack," said Daria Mochly-Rosen, PhD, professor of chemical and systems biology and the senior author of a study reporting the new findings. The research appears in the Sept. 12 issue of Science.
Before the study, scientists knew that heart muscle could be preconditioned to resist heart attack damage - for instance, moderate drinkers tend to have smaller, less severe heart attacks than teetotalers. But scientists didn't understand how pre-conditioning worked.
To figure out how alcohol protects heart muscle from free-radical damage, Mochly-Rosen's team tested alcohol pretreatment in a rat heart-attack model. They compared the enzymes activated during the attacks to those switched on with no alcohol. Enzymes are the "doers" of the cellular machinery, catalyzing all of the biochemical reactions that form the basis of life.
Surprisingly, the treatment activated aldehyde dehydrogenase 2 (ALDH2), an obscure alcohol-processing enzyme. Alcohol pretreatment increased the enzyme's activity during heart attack by 20 percent, leading to a 27 percent drop in the associated damage.
"Although this enzyme was discovered a long time ago, my research group knew nothing about the enzyme except that it helps remove alcohol when people drink," said Mochly-Rosen, who is also the senior associate dean for research in the School of Medicine and the George D. Smith Professor in Translational Medicine.
ALDH2 wasn't one of the well-studied antioxidant players that the scientists expected to find fighting free-radical damage. The enzyme neutralizes an aldehyde molecule, a toxic byproduct of the ethanol in alcoholic beverages. But aldehydes are also formed in the body when free radicals react with fat molecules.
The body's cells contain a lot of fat, Mochly-Rosen noted. "It's very easy for free radicals to find fat and oxidize it to aldehydes."
Inside cells, the accumulating aldehydes permanently bind and damage cellular machinery and DNA. Such damage occurs in many diseases, from heart attack and Parkinson's to sun-induced aging of the skin.
After learning of ALDH2's novel role in reducing the damage, the researchers searched for a molecule that could make the enzyme function even better. They enlisted the Stanford High Throughput Bioscience Center, directed by David Solow-Cordero, PhD, to find a molecule that heightened the enzyme's activity.
The winner of this contest was a tiny molecule that reduced heart attack damage by 60 percent in the rat model. The molecule, Alda-1, has a surprising mode of action: it protects ALDH2 itself from aldehyde attack. The enzyme, it turns out, was being hobbled by the very chemical it removes.
Because Alda-1 is small, it should be easy to adapt for pharmacological use, Mochly-Rosen said. She expects the new molecule to have many possible drug applications.
"It has a huge potential use," she said. So far, Alda-1 has been tested only in the rat model, but Mochly-Rosen's lab is investigating other possible applications, such as fighting neurodegenerative disease and sun damage on the skin. The team also hopes to interest drug companies in human trials.
In addition to its lofty medical applications, Alda-1 could also have a much lowlier use: fighting hangovers. Many nasty hangover symptoms are due to aldehyde buildup.
The tiny molecule may also improve alcohol tolerance and reduce susceptibility to free-radical diseases in people with a common ALDH2 mutation. The mutation affects 40 percent of people of Asian descent and causes an intolerance for alcohol.
Mochly-Rosen's Stanford team included Che-Hong Chen, PhD, a senior scientist and a key contributor; postdoctoral scholars Grant Budas, PhD, and Eric Churchill, PhD; and senior scientist Marie-Helene Disatnik, PhD. Thomas Hurley of the University of Indiana School of Medicine collaborated with the Stanford scientists.
The research was funded by the National Institute on Alcohol Abuse and Alcoholism and also received support from Stanford's SPARK program, which helps mature nascent medical technologies with the goal of transferring them to commercial entities to benefit society.
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