NIH. US: An experimental compound empowers an enzyme to help process
acetaldehyde, a toxic metabolite of alcohol, according to new research
supported by the National Institute on Alcohol Abuse and Alcoholism
(NIAAA). The findings, now online in the Proceedings of the National
Academy of Sciences (PNAS), might lead to new treatments to help people
with impaired ability to metabolize acetaldehyde and other toxic
substances. NIAAA is part of the National Institutes of Health.
"This intriguing finding could have important
implications," said NIAAA Director George F. Koob, Ph.D. "Developing
pharmacologic agents that alter an enzyme’s substrate specificity is a
unique approach that may have wide clinical application in treating
patients with impaired ability to detoxify toxic substances. We look
forward to further research aimed at translating these laboratory
discoveries into possible treatments for people."
After alcohol is consumed, it is first metabolized into
acetaldehyde, a toxic chemical that can cause DNA damage and cancer.
In the liver, aldehyde dehydrogenase 2 (ALDH2) is the main enzyme
responsible for breaking down acetaldehyde into acetate, a nontoxic
metabolite. It also removes other toxic aldehydes that can accumulate
in the body. An estimated 560 million people in East Asia, and many
people of East Asian descent, carry a genetic mutation that produces an
inactive form of ALDH2. When individuals with the ALDH2 mutation drink
alcohol, acetaldehyde accumulates in the body, resulting in facial
flushing, nausea, and rapid heartbeat. People with the ALDH2 mutation
are also at increased risk for cancers of the mouth, esophagus, and
other areas of the upper aerodigestive tract.
Researchers led by Daria Mochly-Rosen, Ph.D., a
professor in the Department of Chemical and Systems Biology at Stanford
University, Stanford, California, have developed a number of small
molecules called aldehyde dehydrogenase activators, or Aldas, that in
previous studies have been found to increase the activity of the ALDH2
enzyme.
In the current study, they tested a new compound,
Alda-89, which they found could provide another aldehyde dehydrogenase
enzyme – ALDH3A1 -- with accelerated acetaldehyde-metabolizing powers
that it ordinarily does not possess.
“We targeted the ALDH3A1 enzyme because it metabolizes
acetaldehyde poorly and is highly expressed in the upper airway,
stomach and gut, all tissues that are prone to cancer development in
people who drink alcohol in excess,” said Dr. Mochly-Rosen. “By
recruiting ALDH3A1 to metabolize acetaldehyde we could perhaps
accelerate the elimination of acetaldehyde from tissues that are more
vulnerable to its carcinogenic effects.”
Dr. Mochly-Rosen and her colleagues showed that Alda-89
increased acetaldehyde metabolism both in normal mice and in mice
carrying the ALDH2 mutation found in the East Asian population. The
researchers also showed that, in test tube analyses, acetaldehyde
removal was faster when they combined Alda-89 with Alda-1, a compound
previously shown to activate ALDH2, compared with activating each ALDH
alone. They also showed in animal studies that mice treated with the
combination of Alda-89 and Alda-1 exhibit accelerated recovery from
alcohol intoxication.
The National Institute on Alcohol Abuse and
Alcoholism, part of the National Institutes of Health, is the primary
U.S. agency for conducting and supporting research on the causes,
consequences, prevention, and treatment of alcohol abuse, alcoholism,
and alcohol problems. NIAAA also disseminates research findings to
general, professional, and academic audiences. Additional alcohol
research information and publications are available at http://www.niaaa.nih.gov.
About the National Institutes of Health (NIH):
NIH, the nation's medical research agency, includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and Human
Services. NIH is the primary federal agency conducting and supporting
basic, clinical, and translational medical research, and is
investigating the causes, treatments, and cures for both common and rare
diseases. For more information about NIH and its programs, visit www.nih.gov.