Researchers Find Potential ‘Dark Side’ to Diets High in Beta-Carotene

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.

Professor Earl Harrison

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 ofHuman 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 theJournal 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.

This research was supported by the National Institutes of Health and the Ohio Agricultural Research and Development Center.

Additional co-authors include Abdulkerim Eroglu, Carlo dela Sena and Sureshbabu Narayanasamy of the Department of Human Nutrition; Damian Hruszkewycz of the College of Pharmacy; and Ken Riedl and Rachel Kopec of the Department of Food Science and Technology, all at Ohio State. Harrison, Curley, Eroglu and dela Sena also are affiliated with Ohio State’s Biochemistry Program.

 

Scientists Discover New Role For Vitamin C In The Eye — And The Brain

In a surprising finding, vitamin C is found to prolong proper functioning of retinal cells:

Portland, Ore. — Nerve cells in the eye require vitamin C in order to function properly — a surprising discovery that may mean vitamin C is required elsewhere in the brain for its proper functioning, according to a study by scientists at Oregon Health & Science University recently published in the Journal of Neuroscience.

“We found that cells in the retina need to be ‘bathed’ in relatively high doses of vitamin C, inside and out, to function properly,” said Henrique von Gersdorff, Ph.D., a senior scientist at OHSU’s Vollum Institute and a co-author of the study. “Because the retina is part of the central nervous system, this suggests there’s likely an important role for vitamin C throughout our brains, to a degree we had not realized before.”

The brain has special receptors, called GABA-type receptors, that help modulate the rapid communication between cells in the brain. GABA receptors in the brain act as an inhibitory “brake” on excitatory neurons in the brain. The OHSU researchers found that these GABA-type receptors in the retinal cells stopped functioning properly when vitamin C was removed.

Because retinal cells are a kind of very accessible brain cell, it’s likely that GABA receptors elsewhere in the brain also require vitamin C to function properly, von Gersdorff said. And because vitamin C is a major natural antioxidant, it may be that it essentially ‘preserves’ the receptors and cells from premature breakdown, von Gersdorff said.

The function of vitamin C in the brain is not well understood. In fact, when the human body is deprived of vitamin C, the vitamin stays in the brain longer than anyplace else in the body. “Perhaps the brain is the last place you want to lose vitamin C,” von Gersdorff said. The findings also may offer a clue as to why scurvy — which results from a severe lack of vitamin C — acts the way it does, von Gersdorff said. One of the common symptoms of scurvy is depression, and that may come from the lack of vitamin C in the brain.

The findings could have implications for other diseases, like glaucoma and epilepsy. Both conditions are caused by the dysfunction of nerve cells in the retina and brain that become over excited in part because GABA receptors may not be functioning properly.

“For example, maybe a vitamin C-rich diet could be neuroprotective for the retina — for people who are especially prone to glaucoma,” von Gersdorff said. “This is speculative and there is much to learn. But this research provides some important insights and will lead to the generation of new hypotheses and potential treatment strategies.”

Scientists and students in von Gerdorff’s lab in OHSU’s Vollum Institute are dedicated to basic neuroscience research. The vitamin C research work was done using goldfish retinas, which have the same overall biological structure as human retinas.

 

Reference

Calero CI, Vickers E, Moraga Cid G, Aguayo LG, von Gersdorff H, Calvo DJ.  Allosteric Modulation of Retinal GABA Receptors by Ascorbic Acid. J Neurosci 2011;31 (26): 9672-82.