The "Comeback" Carotenoids

Thanks to Nutrition Science News for permission to reproduce this article!

By Jack Challem

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Research shows that eating ample amounts of lycopene-rich tomatoes greatly reduces the risk of prostate cancer. Lycopene is the most potent carotenoid antioxidant, followed by beta-carotene, cryptoxanthin, lutein and zeaxanthin.

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Public confidence in beta-carotene, long considered a leading antioxidant, has been shaken during the past few years by negative studies that showed it can increase the risk of lung cancer and coronary heart disease. But a review of published research during this time shows far more positive than negative findings.

Several important themes have emerged. One, natural beta-carotene (from Dunaliella salina algae) is different and apparently better than the synthetic form, which was used in the studies with negative results. Two, related carotenoids, particularly lutein and lycopene, look promising as antioxidants and cancer fighters and should be among the mix of supplemental carotenoids. Three, there is a synergism among carotenoids and other antioxidants, such as vitamins E and C, and the sum effect may be greater than the parts.

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Debunking The Criticism

The beta-carotene controversy began in 1996 after two studies -- the Finnish Alpha-Tocopherol Beta-Carotene (ATBC) and the Beta-Carotene and Retinol Efficacy Trial (CARET) -- unexpectedly determined that supplements of this nutrient increased the risk of lung cancer among people who were either smokers or exposed to asbestos, a known carcinogen. Some researchers, such as Lester Packer, Ph.D., of the University of California, Berkeley, questioned the validity of these studies, in part because they were contradicted by hundreds of others.

When researchers reexamined the data for the ATBC study, they found that beta-carotene supplements did not increase lung cancer risk unless the subjects smoked more than a pack of cigarettes and consumed one or more alcoholic drinks daily. [1] In the CARET study, smokers and heavy drinkers had twice the lung cancer risk if they also took high doses of beta-carotene. But when alcohol consumption was factored out, the increase in lung cancer associated with beta-carotene was not statistically significant among people who smoked less than a pack a day. Furthermore, former smokers had a decreased risk of lung cancer if they took beta-carotene supplements. [2,3] (For more information on these studies, please see NSN, 1(1): 4, 1996; 2(1): 7, 1997; 2(3): 100, 1997.)

Why would beta-carotene increase the risk of lung cancer under any circumstances? It is possible that high doses of beta-carotene or vitamin A (to which some beta-carotene is converted), when combined with tobacco smoke, are susceptible to free radical oxidation. Without other antioxidants to quench beta-carotene or vitamin A free radicals, these free radicals might cause cell damage and lead to cancerous changes. [4]

Indeed, another team of researchers suggested the unexpected increase in lung cancer among smokers taking beta-carotene was related to just that--the lack of other supplemental antioxidants. T. George Truscott, Ph.D., of Keele University, England, reported that antioxidants work together to neutralize free radicals, such as those associated with tobacco smoke.

In experiments, Truscott determined that vitamin E was the first antioxidant to quench free radicals from tobacco smoke. The chemical reaction turned vitamin E into a weak free radical, but beta-carotene recycled this free radical back to vitamin E. In the process, beta-carotene became a free radical, but it could be restored with vitamin C. The bottom line: Smokers need a mix of antioxidants, not just beta-carotene. [5]

In another analysis of the CARET data, John R. Balmes, M.D., of the University of California, San Francisco, looked at the relationship between lung capacity and beta-carotene intake, regardless of whether the nutrient was a synthetic supplement or was obtained from foods. Balmes reported that higher intake of beta-carotene was associated with better lung capacity--in essence, stronger lungs--even if the subjects smoked or were exposed to asbestos. [6] Although increased lung capacity appeared inconsistent with lung cancer, Balmes could not bring himself to recommend beta-carotene supplements to increase lung capacity, because he was afraid the supplements could increase the risk of cancer.

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Natural Vs. Synthetic

It also turned out that the negative studies used synthetic beta-carotene, which is different in chemical structure from natural beta-carotene. Does that mean natural beta-carotene is better? Research has not yet directly compared natural to synthetic beta-carotene on lung cancer risk. However, Ami Ben-Amotz, Ph.D., a carotenoid researcher at the National Institute of Oceanography, Israel, has stressed the differences between natural beta-carotene derived from dunaliella algae and the synthetic version.

Natural beta-carotene consists of two isomers; that is, two different structures of the same molecule. One is the all-trans and the other is the 9-cis; each contains the same atoms but in different arrangements. However, synthetic beta-carotene consists of only the all-trans form. [7] In experiments, Ben-Amotz found that the natural 9-cis is a potent antioxidant that rapidly quenches free radicals. If that's the case, it would give natural beta-carotene a powerful advantage over the synthetic.

Ben-Amotz believes that the all-trans form found in synthetic beta-carotene is not an antioxidant at all and is in fact a "pro-oxidant," which is why it damages cells and leads to cancer.

But there may be different explanations. Part of the beta-carotene we consume is converted to vitamin A. Vitamin A has hormonelike effects that control cell growth and differentiation. The all-trans is converted to vitamin A much more efficiently than the 9-cis form, so it is quite conceivable that all-trans' effects may be related more to its vitamin A activity than to whether it is a pro-oxidant.

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Recent Beta-Carotene Research

Despite the controversy surrounding beta-carotene, research on this nutrient looks exceptionally promising. Highlights of the more recent findings include:

Immune enhancement:   In an article in the Journal of Laboratory and Clinical Medicine, David A. Hughes, Ph.D., and colleagues explained that monocytes, a type of white blood cell, contain surface proteins that distinguish cancer cells from normal ones. When these proteins, called MHC II, identify cancer cells, they signal the immune system to attack them.

Hughes, a researcher at the Institute of Food Research, Norwich, England, found that monocytes don't identify cancer cells if they don't have enough MHC II proteins. After giving 25 apparently healthy men beta-carotene supplements, Hughes found that the number of MHC II proteins on their monocytes increased. The beta-carotene also increased the subjects' production of tumor necrosis factor alpha (TNF-a), which helps kill cancerous and virus-infected cells. [8]

Mental functioning:   Several other recent studies demonstrate beta-carotene's broad roles in maintaining health. In an epidemiological study of 5,182 middle-age and elderly people, Dutch researchers saw a strong correlation between beta-carotene intake and mental functioning. L.J. Launer, Ph.D., of Erasmus University, Netherlands, reported that people who ate less than 0.9 mg of dietary beta-carotene daily were more than twice as likely to suffer from poor memory, difficulty in solving problems and disorientation, compared with people who eat more than 2.1 mg/day of the nutrient. [9]

Arthritis:   Beta-carotene may also slow the progression of rheumatoid arthritis. George W. Comstock, M.D., of the Johns Hopkins University School of Hygiene and Public Health, Baltimore, analyzed levels of beta-carotene, vitamin E and vitamin A from blood samples obtained in 1974. He then studied how levels of these nutrients correlated with illness the blood donors developed in subsequent years.

Comstock found low blood levels of these antioxidant nutrients were associated with the subsequent development of rheumatoid arthritis and lupus erythematosus. However, the only statistically significant relationship was between low beta-carotene and the development of rheumatoid arthritis. People who developed this type of arthritis had blood levels of beta-carotene averaging 29 percent less than those of healthy subjects. [10]

Prostate cancer:   Beta-carotene supplements may also reduce the risk of prostate cancer, according to a study led by Harvard University researcher Meir Stampfer, M.D. In analyzing the risk of prostate cancer among more than 3,000 physicians, Stampfer noted several important trends. One, men who did not eat enough fruits and vegetables and did not take beta-carotene supplements were 36 percent more likely to develop prostate cancer than their counterparts who did. Two, men with diets high in beta-carotene had a 36 percent lower risk of developing prostate cancer. Three, men who ate few fruits and vegetables but took beta-carotene supplements had a similar low risk of prostate cancer--the supplements appeared to compensate for the lack of produce in the diet. Finally, men who ate a lot of fruits and vegetables, and took beta-carotene supplements, had a slight increase in risk, suggesting that there is an optimal range for beta-carotene consumption, whether from diet or supplements. [11]

Skin protection:   In what may be one of the more unusual uses of beta-carotene, a team of German and Israeli researchers discovered that beta-carotene supplements--taken internally--protect against sunburn. In a controlled experiment, researchers asked 20 young women to use either a combination of topical sunscreens and beta-carotene supplements (30 mg daily) or a sunscreen alone for 10 weeks. By measuring skin redness and inflammation, the researchers found that supplementation with beta-carotene before sun exposure, combined with sunscreens, was more protective than sunscreens alone. [12] (For more information on sun protection, see related article, "A Holistic Approach To Skin Protection," on p. 204.)

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Lutein And Lycopene

Many studies have demonstrated a link between low intake of lutein and zeaxanthin--the body converts some lutein to zeaxanthin--and macular degeneration, the leading cause of blindness among the elderly. These two carotenoids filter out harmful blue light and quench free radicals that can damage the macula, the part of the eye responsible for sharp and detailed vision. [13]

By all measures, macular degeneration is not reversible. However, lutein supplements might slow its progression and provide a protective effect. In studies at Florida International University, Miami, John T. Landrum, Ph.D., gave healthy human subjects 30 mg of lutein daily for several months. The macular pigment increased by as much as 39 percent, decreasing by 30 to 40 percent the amount of blue light reaching receptors in the eyes. [14]

Lutein may also play a role in cancer prevention, though research is still at an early stage. In a small study conducted at Washington State University, Pullman, researchers injected laboratory mice with breast cancer cells, leading to solid cancers in 60 to 70 percent of the mice. Some of the mice were also given diets that included various percentages of lutein. Even very small quantities of lutein--about two-thousandths of a percent (0.002) of the diet--decreased the incidence, appearance and growth of tumors. [15] Other research, as yet unpublished, indicates that human breast and cervix cells retain higher levels of lutein than do other tissues. This suggests that lutein plays a normal biological role in these cells.

Two years ago, Edward Giovannucci, M.D., and colleagues at the Harvard University School of Public Health in Boston, reported that high intake of tomatoes, rich in the carotenoid lycopene, reduced the risk of prostate cancer by 45 percent. [16] Two subsequent analyses of other groups of men found the same benefit. It turns out that lycopene is a major antioxidant and may protect against other forms of cancer as well.

Catherine A. Rice-Evans, Ph.D., of Guy's Hospital, London, tested carotenoids for their antioxidant properties and found that lycopene was the most potent, followed by beta-carotene and cryptoxanthin, and then by lutein and zeaxanthin. [17]

Several Japanese cell-culture and animal studies also have revealed that lycopene can inhibit the growth of cancers. It works at least in part by blocking the activity of transforming growth factor alpha (TGF-a), which is known to promote cancer, according to a report by researchers at Japan's Meiji University. [18] The carotenoid also increases the number of immune T4 cells and normalizes the T4:T8 ratio, a sign of improved immune function. [19]

In other cell-culture experiments, Joseph Levy, Ph.D., and his colleagues at the Ben-Gurion University, Israel, found that lycopene inhibited the growth of endometrial, breast and lung cancers. The lycopene inhibited the cancer growth in just 24 hours, and it was substantially more potent than alpha-carotene or beta-carotene. [20]

In an interview, Michael Aviram, D.Sc., a carotenoid researcher currently working at the University of Michigan, Ann Arbor, sized up the carotenoids this way: 9-cis (natural) beta-carotene is better than all-trans (synthetic) beta-carotene--but lycopene is better than either of them.

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Carotenoid Synergism

Not surprisingly, a mix of natural carotenoids, similar to what is in a diet rich in fruits and vegetables, may offer the greatest health benefits. Carotenoids are found in all fruits and vegetables. A well-rounded selection might include broccoli, carrots, citrus fruits, red and yellow peppers, spinach, sweet potatoes and tomatoes. Diversity is really the key here. Unfortunately, most Americans eat few fruits and vegetables, and when they do, the choices are generally very limited.

In one study, Tim R. Kramer, Ph.D., and Betty J. Burri, Ph.D., of the USDA Agricultural Research Service in Washington, D.C., asked nine women to eat a low-carotene diet--few fruits, vegetables and juices--for four months. At first, five of the women took a low-dose beta-carotene supplement for two months, while the remaining four women were given placebos.

By measuring the activity of lymphocytes, such as T4 cells, Kramer and Burri found that a low-carotene diet compromised immune function, and low-dose beta-carotene supplements did not improve lymphocyte activity. However, when they gave the women a mixed-carotenoid supplement--containing higher amounts of beta-carotene as well as alpha-carotene, lutein, cryptoxanthin, zeaxanthin and lycopene--immune function returned to normal. [21]

There's also compelling evidence that the carotenoids work best with other antioxidants, and not just to reduce lung cancer risk. In a study at the University of Nebraska, Lincoln, Judy A. Driskell, Ph.D., fed rabbits a high-cholesterol diet. She gave some of the rabbits beta-carotene, vitamin E, or both. The beta-carotene lowered cholesterol levels, while vitamin E prevented its oxidation--both important steps in lowering cholesterol. [22] Taken together, the combination both lowered cholesterol and prevented its oxidation. Why would beta-carotene lower cholesterol? In a recent paper, Aviram pointed out that the carotenoids and cholesterol share a common metabolic pathway, and high intake of carotenoids blocks cholesterol synthesis. [23]

While most scientific researchers have a "reductionist" view of nutrition, looking for the single effective ingredient, a wholesome diet consists of a multitude of beneficial nutrients that work together and provide collective benefits. Applying the same principle in supplementation--using multiple instead of single nutrients--would appear to be sound. When it comes to carotenoids, a mix of natural beta-carotene and other carotenoids may be the best way to go. NSN

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Jack Challem is based in Aloha, Ore. He has been writing about vitamin research for more than 20 years and publishes The Nutrition Reporter newsletter.

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REFERENCES: 1. Albanes, D., Heinonen, O.P., et al. J Natl Cancer Inst 88: 1560-70, 1996. 2. Omenn, G.S., Goodman, G.E., et al. J Natl Cancer Inst 88: 1550-59, 1996. 3. Challem, J.J. "Beta-carotene and other carotenoids: promises, failures, and a new vision," Orthomolec Med 12: 11-19, 1997. 4. Bland, J. J Appl Nutr 48: 42-5, 1996. 5. Bohm, F., Edge, R., et al. J Am Chem Soc 119: 621-22, 1997. 6. Chuwers, P., Barnhart, S., et al. Am J Resp Crit Care Med, 155: 1066-71, 1997. 7. Challem, J.J. J Natl Cancer Inst, 89: 325, 1997. 8. Hughes, D.A., Wright. A.J.A., et al. J Lab Clin Med, 129; 309-17,1997. 9. Jama JW, Launer, L.J., et al. Amer J Epidem 144: 275-80, 1996. 10. Comstock, G.W., Burke, A.E., et al. Annals Rheum Dis 56: 223-25, 1997. 11. Stampfer, M.J., Cook, N.R., et al. Am Soc Clin Oncol, Denver, May 19, 1997. 12. Gollnick, H.P.M., Hopfenmuller, W., et al. European J of Derm 6: 200-05, 1996. 13. Seddon, J.M., Ajani, U.A., et al. JAMA 272: 1413-20, 1994. 14. Landrum. J.T., Bone, R.A., et al. Exp Eye Res 65: 57-62, 1997. 15. Park, J.S., Chew, B.P., and Wong, T.S.. FASEB J 11: A447, #2586, 1997. 16. Giovannucci, E., Ascherio, A., et al. J Natl Cancer Inst 87: 1767-76, 1995. 17. Miller, N.J., Sampson, J., et al. FEBS Letters 384: 240-42, 1996. 18. Mitamura, T., Tsunoda, S., & Nagasawa, H. Bull Fac Ag, Meiji University, 108: 45-48, 1996. 19. Kobayashi, T., Iijima, K., et al. Anti-Cancer Drugs 7: 195-98, 1996. 20. Levy, J., Bosin, E., et al. Nutr and Cancer 24: 257-66, 1995. 21. Kramer, T.R. & Burri, B.J. Am J Clin Nutr 65:871-75, 1997. 22. Sun, J., Giraud, D.W., Moxley, R.A., et al. Int J Vit Min Res 67: 155-163, 1997. 23. Fuhrman, B., Elis, A., & Aviram, M. Biochem and Biophys Res Comm 233: 658-662, 1997.

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