New research suggests that there could be
health hazards associated with consuming excessive amounts of beta-carotene.
This
antioxidant is a naturally occurring pigment that gives color to foods such as
carrots, sweet
potatoes and certain greens. It also converts to vitamin A, and foods
and supplements are the only sources for this essential nutrient.
But
scientists at Ohio State University have found that certain molecules that
derive from beta-carotene have an opposite effect in the body: They actually
block some actions of vitamin A, which is critical to human vision, bone and
skin health, metabolism and immune function.
Because
these molecules derive from beta-carotene, researchers predict that a large
amount of this antioxidant is accompanied by a larger amount of these
anti-vitamin-A molecules, as well.
Vitamin
A provides its health benefits by activating hundreds of genes. This means that
if compounds contained in a typical source of the vitamin are actually lowering
its activity instead of promoting its benefits, too much beta-carotene could
paradoxically result in too little vitamin A.
The
findings also might explain why, in a decades-old clinical trial, more people
who were heavily supplemented with beta-carotene ended up with lung cancer than
did research participants who took no beta-carotene at all. The trial was ended
early because of that unexpected outcome.
The
scientists aren't recommending against eating foods high in beta-carotene, and
they are continuing their studies to determine what environmental and
biological conditions are most likely to lead to these molecules' production.
"We
determined that these compounds are in foods, they're present under normal
circumstances, and they're pretty routinely found in blood in humans, and
therefore they may represent a dark side of beta-carotene," said Earl
Harrison, Dean's Distinguished Professor of Human Nutrition at
Ohio State and lead author of the study. "These materials definitely have
anti-vitamin-A properties, and they could basically disrupt or at least affect
the whole body metabolism and action of vitamin A. But we have to study them
further to know for sure."
The
study is scheduled for publication in the May 4, 2012, issue of the Journal
of Biological Chemistry.
Previous
research has already established that when beta-carotene is metabolized, it is
broken in half by an enzyme, which produces two vitamin A molecules.
In this
new study, the Ohio State researchers showed that some of these molecules are
produced when beta-carotene is broken in a different place by processes that
are not yet fully understood and act to antagonize vitamin A.
Harrison
is an expert in the study of antioxidants called carotenoids, which give
certain fruits and vegetables their distinctive colors. Carotenoids'
antioxidant properties are associated with protecting cells and regulating cell
growth and death, all of which play a role in multiple disease processes.
For
this work, he joined forces with co-authors Robert Curley, professor of
medicinal chemistry and pharmacognosy, and Steven Schwartz, professor of food
science and technology, both at Ohio State.
Curley
specializes in producing synthetic molecules in the pursuit of drug
development, and Schwartz is an expert at carotenoid analysis.
Curley
manufactured a series of beta-carotene-derived molecules in the lab that match
those that exist in nature. The researchers then exposed these molecules to
conditions mimicking their metabolism and action in the body.
Of the
11 synthetic molecules produced, five appeared to function as inhibitors of
vitamin A action based on how they interacted with receptors that would
normally launch the function of vitamin A molecules.
"The
original idea was that maybe these compounds work the way vitamin A works, by
activating what are called retinoic acid receptors. What we found was they
don't activate those receptors. Instead, they inhibit activation of the
receptor by retinoic acid," Curley said. "From a drug point of view,
vitamin A would be called an agonist that activates a particular pathway, and
these are antagonists. They compete for the site where the agonist binds, but
they don't activate the site. They inhibit the activation that would normally
be expected to occur."
Once
that role was defined, the researchers sought to determine how prevalent these
molecular components might be in the human body. Analyzing blood samples
obtained from six healthy human volunteers, the scientists in the Schwartz lab
found that some of these anti-vitamin-A molecules were present in every sample
studied, suggesting that they are a common product of beta-carotene metabolism.
The
compounds also have been found previously in cantaloupe and other
orange-fleshed melons, suggesting humans might even absorb these molecules
directly from their diet.
Harrison
noted that the findings might explain the outcome of a well-known clinical
trial that has left scientists puzzled for years.
In that
trial, people at high risk for lung cancer -
smokers and asbestos workers - were given massive doses of beta-carotene over a
long period of time in an attempt to lower that risk. The trial ended early
because more supplemented participants developed cancer than did those who
received no beta-carotene. This outcome was reinforced by results of a
follow-up animal study.
"Those
trials are still sending shockwaves 20 years later to the scientific
community," said Harrison, also an investigator in Ohio State's
Comprehensive Cancer Center. "What we found provides a plausible
explanation of why larger amounts of beta-carotene might have led to unexpected
effects in these trials."
The
research also has implications for efforts to bio-engineer staple crops in
developing countries so they contain excess beta-carotene, which is considered
a sustainable way to provide these populations with pro-vitamin A. Existing
projects include production of golden rice in Asia, golden maize in South
America and cassava in Africa.
"A
concern is that if you engineer these crops to have unusually high levels of
beta-carotene, they might also have high levels of these compounds,"
Harrison said.
The
researchers are continuing to study these compounds, including whether food
processing or specific biological processes affect their prevalence. Previous
studies have suggested that oxidative stress, which can result from smoking and
air pollution exposure, can lead to higher production of these anti-vitamin-A
molecules, Harrison noted.
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