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.


Study Adds Weight to Link Between Calcium Supplements and Heart Problems

Research: Calcium supplements with or without vitamin D and risk of cardiovascular events: Reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis

Research published in BMJ (British Medical Journal) in April 2011 adds to mounting evidence that calcium supplements increase the risk of cardiovascular events, particularly heart attacks, in older women. The findings suggest that their use in managing osteoporosis should be re-assessed.

Calcium supplements are often prescribed to older (postmenopausal) women to maintain bone health. Sometimes they are combined with vitamin D, but it’s still unclear whether taking calcium supplements, with or without vitamin D, can affect the heart.

The Women’s Health Initiative (WHI) study – a seven-year trial of over 36,000 women – found no cardiovascular effect of taking combined calcium and vitamin D supplements, but the majority of participants were already taking personal calcium supplements, which may have obscured any adverse effects.

So a team of researchers, led by Professor Ian Reid at the University of Auckland, re-analysed the WHI results to provide the best current estimate of the effects of calcium supplements, with or without vitamin D, on the risk of cardiovascular events.

They analysed data from 16,718 women who were not taking personal calcium supplements at the start of the trial and found that those allocated to combined calcium and vitamin D supplements were at an increased risk of cardiovascular events, especially heart attack.

By contrast, in women who were taking personal calcium supplements at the start of the trial, combined calcium and vitamin D supplements did not alter their cardiovascular risk.

The authors suspect that the abrupt change in blood calcium levels after taking a supplement causes the adverse effect, rather than it being related to the total amount of calcium consumed. High blood calcium levels are linked to calcification (hardening) of the arteries, which may also help to explain these results.

Further analyses – adding data from 13 other trials, involving 29,000 people altogether – also found consistent increases in the risk of heart attack and stroke associated with taking calcium supplements, with or without vitamin D, leading the authors to conclude that these data justify a reassessment of the use of calcium supplements in older people.

But in an accompanying editorial, Professors Bo Abrahamsen and Opinder Sahota argue that there is insufficient evidence available to support or refute the association.

Because of study limitations, they say “it is not possible to provide reassurance that calcium supplements given with vitamin D do not cause adverse cardiovascular events or to link them with certainty to increased cardiovascular risk. Clearly further studies are needed and the debate remains ongoing.”


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Medical News: Calcium Builds Bones But May Weaken Heart – in Cardiovascular, Myocardial Infarction from MedPage TodayThe findings suggest the use of these supplements in managing osteoporosis should be re-assessed, researchers reported online today in the BMJ. In the new study, researchers analyzed data from 16,718 women who were not taking personal calcium supplements at the start of the trial and found that those allocated to combined calcium and vitamin D supplements were at an increased risk of cardiovascular events, especially MI.

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No Bones About It: Eating Dried Plums Helps Prevent Fractures And Osteoporosis

When it comes to improving bone health in postmenopausal women — and people of all ages, actually — a Florida State University researcher has found a simple, proactive solution to help prevent fractures and osteoporosis: eating dried plums.

Bahram Arjmandi is Florida State's Margaret A. Sitton Professor and chairman of the Department of Nutrition, Food and Exercise Science. Photo: FSU Photography Services

“Over my career, I have tested numerous fruits, including figs, dates, strawberries and raisins, and none of them come anywhere close to having the effect on bone density that dried plums, or prunes, have,” said Bahram H. Arjmandi, Florida State’s Margaret A. Sitton Professor and chairman of the Department of Nutrition, Food and Exercise Sciences in the College of Human Sciences. “All fruits and vegetables have a positive effect on nutrition, but in terms of bone health, this particular food is exceptional.”

Arjmandi and a group of researchers from Florida State and Oklahoma State University tested two groups of postmenopausal women. Over a 12-month period, the first group, consisting of 55 women, was instructed to consume 100 grams of dried plums (about 10 prunes) each day, while the second — a comparative control group of 45 women — was told to consume 100 grams of dried apples. All of the study’s participants also received daily doses of calcium (500 milligrams) and vitamin D (400 international units).

The group that consumed dried plums had significantly higher bone mineral density in the ulna (one of two long bones in the forearm) and spine, in comparison with the group that ate dried apples. This, according to Arjmandi, was due in part to the ability of dried plums to suppress the rate of bone resorption, or the breakdown of bone, which tends to exceed the rate of new bone growth as people age.

The group’s research, “Comparative Effects of Dried Plum and Dried Apple on Bone in Post Menopausal Women,” was published in the British Journal of Nutrition. Arjmandi conducted the research with his graduate students Shirin Hooshmand, Sheau C. Chai and Raz L. Saadat of the College of Human Sciences; Dr. Kenneth Brummel-Smith, Florida State’s Charlotte Edwards Maguire Professor and chairman of the Department of Geriatrics in the College of Medicine; and Oklahoma State University statistics Professor Mark E. Payton.

In the United States, about 8 million women have osteoporosis because of the sudden cessation of ovarian hormone production at the onset of menopause. What’s more, about 2 million men also have osteoporosis.

“In the first five to seven postmenopausal years, women are at risk of losing bone at a rate of 3 to 5 percent per year,” Arjmandi said. “However, osteoporosis is not exclusive to women and, indeed, around the age of 65, men start losing bone with the same rapidity as women.”

Arjmandi encourages people who are interested in maintaining or improving their bone health to take note of the extraordinarily positive effect that dried plums have on bone density.

“Don’t wait until you get a fracture or you are diagnosed with osteoporosis and have to have prescribed medicine,” Arjmandi said. “Do something meaningful and practical beforehand. People could start eating two to three dried plums per day and increase gradually to perhaps six to 10 per day. Prunes can be eaten in all forms and can be included in a variety of recipes.”


Dietary Calcium Is Better Than Supplements At Protecting Bone Health

Women who get most of their daily calcium from food have healthier bones than women whose calcium comes mainly from supplemental tablets. Surprisingly, this is true even though the supplement takers have higher average calcium intake.

Adequate calcium is important to prevent osteoporosis, which affects an estimated 8 million American women and 2 million American men. Another 34 million Americans have low bone mass, placing them at increased risk for osteoporosis. Calcium consumption can help maintain bone density by preventing the body from stealing the calcium it needs from the bones, say researchers at Washington University School of Medicine in St. Louis. The researchers’ conclusions about calcium intake, published in the American Journal of Clinical Nutrition, came from a study of 183 postmenopausal women. The researchers asked the women to meticulously detail their diet and their calcium supplement intake for a week. “We assumed that this sample represented each woman’s typical diet,” says senior author Reina Armamento-Villareal, M.D., assistant professor of medicine in the Division of Bone and Mineral Diseases and a bone specialist at Barnes-Jewish Hospital. “In addition to analyzing the volunteers’ daily calcium intake, we tested bone mineral density and urinary concentrations of estrogen metabolites.” The researchers found that the women could be divided into three groups: one group, called the “supplement group,” got at least 70 percent of their daily calcium from tablets or pills; another, the “diet group,” got at least 70 percent of their calcium from dairy products and other foods; and a third, the “diet plus supplement group,” consisted of those whose calcium-source percentages fell somewhere in between these ranges. The “diet group” took in the least calcium, an average of 830 milligrams per day. Yet this group had higher bone density in their spines and hipbones than women in the “supplement group,” who consumed about 1,030 milligrams per day. Women in the “diet plus supplement group” tended to have the highest bone mineral density as well as the highest calcium intake at 1,620 milligrams per day. The hormone estrogen is known to maintain bone mineral density. But the standard form of estrogen is broken down or metabolized in the liver to other forms – some active and some inactive. Urinalysis showed that women in the “diet group” and the “diet plus supplement group” had a higher ratio of active to inactive estrogen metabolites than women in the “supplement group.” “This suggests that dietary calcium is associated with a shift in estrogen metabolism that favors production of active forms of estrogen,” says Armamento-Villareal. “Although we’re not yet certain what underlies this effect, it could be that nutrients other than calcium cause this shift. It’s also known that dairy products, which are a major source of calcium, can contain active estrogenic compounds, and these can influence bone density and the amount of estrogenic metabolites in the urine.” Calcium supplements differ in how well their calcium can be absorbed, and this also could play a role in the study’s findings, according to its authors. For example, calcium carbonate tablets need to be taken with a meal so that stomach acid can facilitate absorption, but calcium citrate tablets don’t have this limitation. If the study participants taking calcium carbonate weren’t conscientious about the timing of their supplements, they might not have received the highest benefit from them. “Only about 35 percent of the calcium in most supplements ends up being absorbed by the body,” Armamento-Villareal says. “Calcium from the diet is generally better absorbed, and this could be another reason that women who got a high percentage of calcium in their food had higher bone densities.” Although dairy foods are excellent sources of calcium, Armamento-Villareal suggests that individuals with dairy sensitivities could consume other calcium-rich food sources such as calcium-fortified orange juice. Dark green leafy vegetables also contain calcium, but it is not as readily absorbed as calcium from dairy sources.


Blueberries Help Lab Rats Build Strong Bones

Compounds in blueberries might turn out to have a powerful effect on formation of strong, healthy bones, if results from studies with laboratory rats turn out to hold true for humans. Jin-Ran Chen and his colleagues are exploring this idea in research funded by the US Department of Agriculture at the Arkansas Children’s Nutrition Center in Little Rock.

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