The Beauty of Flavonoids

References

Nature produces a wondrous array of colors. These varied and diverse hues have fascinated and inspired humans throughout history and play an important role in maintaining and promoting life on Earth. Naturally-occurring pigments coloring fruits and flowers serve to attract animals and insects that are important to plants’ reproductive cycles, among other functions. Flavonoids are one group of water-soluble plant pigments that have also attracted the attention of many scientists and consumers for their potential health benefits.

Nobel Prize-winning Hungarian scientist Albert Szent-Gyorgi discovered flavonoids in 1936. Using evidence from his own experiments, he theorized that a new vitamin—vitamin P—worked synergistically with vitamin C in a citrus extract to strengthen capillaries. Although the description of flavonoids as vitamins was eventually found to be inaccurate, research into their potential as agents of health and wellbeing has continued.

More than 4,000 different flavonoids have been identified to date, making them the largest group of polyphenols (plant chemicals). The basic molecular structure of flavonoids consists of two aromatic rings connected by a three-carbon “bridge.” At least one hydroxyl group is attached to each ring, and different combinations of hydroxyls and other groups around this basic structure distinguish the major classes of flavonoids, which include flavonols, flavones, catechins, flavanones, anthocyanidins and isoflavones. In addition to acting as pigments, flavonoids perform several important functions in plants, including absorption of ultraviolet (UV) radiation, protection from pathogens and activation of growth and differentiation factors. Flavonoids are also thought to engage in healing and antioxidant activities in plant leaves.¹

In the last few years, scientific studies have generated a growing interest in the potentially important role that flavonoids may play in maintaining human health. Since they are not manufactured in the body, humans must rely exclusively on secondary sources to provide them with flavonoids. Many fruits and vegetables, established bastions of health, are some of these sources, but flavonoids also can be found in abundance in some surprising places such as wine, chocolate and tea. The U.S. Department of Agriculture (USDA) recently developed the USDA Database for the Flavonoid Content of Selected Foods—2003 (www.nal.usda.gov/fnic/foodcomp/Data/Flav/flav.html). It lists the flavonoid content of many foods and beverages, although isoflavones and proanthocyanidins are not included.

Protection from oxidative damage is paramount in the body’s constant struggle to ward off sickness and disease. Free radicals are continuously being formed as a result of internal reactions in the body as well as from external sources such as environmental pollutants. Studies have shown flavonoids have the capacity to act as powerful antioxidants by scavenging free radicals and terminating oxidative reactions. Flavonoids are also able to chelate metal ions, preventing the metals from engaging in harmful reactions.² There is also speculation that flavonoids may function in other ways, such as modulating cellular function, providing a protective influence throughout the body.³

In addition to many flavonoids’ inherent antioxidant abilities, some also work in conjunction with other antioxidants to enhance and supplement this ability—just as Szent-Gyorgi observed in his initial experiments with citrus extract and vitamin C. In a review of research on French maritime pine bark extract, as Horphag Research’s Pycnogenol®, distributed in North America by Natural Health Science, the flavonoids contained in the extract were shown to regenerate and protect vitamins C and E.⁴ Other research has shown the flavonoids quercetin and (-)-epicatechin can work together with vitamin E in chain-breaking antioxidant activity.⁵ This study also demonstrated the ability of quercetin and (+)-catechin to regenerate vitamin E, thus producing a co-antioxidant effect.

Since flavonoids are water-soluble, they cannot be stored in the body for long periods of time. Although there is little data documenting the digestion and absorption of flavonoids in humans, the small intestine and colon are thought to be major sites of flavonoid metabolism.⁶ One study suggests red blood cells are responsible for the distribution of quercetin around the body.⁷ There is also uncertainty surrounding the bioavailability of flavonoids, which may be intimately linked with individual chemical structure. A French study measuring plasma concentration and percentage excreted in urine of a variety of flavonoids showed individual flavonoids had vastly different measurements of these markers of bioavailability.⁸ In another instance, quercetin in apples was shown to be only one-third as bioavailable as quercetin from onions.⁹

Those who strive to maintain a healthy heart know there are many factors that may impact this effort. The American Heart Association identifies the three main risk factors for heart attack as high blood cholesterol, high blood pressure and excess body weight. It is known that a healthy diet, plenty of exercise and certain lifestyle modifications can help in the battle against heart disease. There is also mounting evidence supporting a positive correlation between flavonoid intake and cardiovascular wellness. In a recent meta-analysis of prospective cohort studies investigating the link between flavanol consumption and heart disease, researchers concluded a high dietary intake of flavanols from fruits, vegetables, tea and red wine may result in decreased mortality from heart disease.¹⁰

The so-called “French Paradox,” first described in the late 1980s, aroused the interest of the public and the scientific community alike. This term refers to the proclivity of the French to consume foods high in saturated fat, yet remain relatively free of coronary heart disease compared to other populations.

Speculation on the contributing factors to this phenomenon led scientists to focus on red wine, which is quite prevalent in the French diet. Initially, the alcohol content itself was credited with this apparent cardio-protective capability. However, later studies pointed to the abundance of flavonoids contained in red wine as being the major contributor.

There are multiple mechanisms by which these flavonoids have been shown to aid in heart health. Researchers at the National Institute of Nutrition in Rome investigated the effects of ingesting alcohol-free red wine, and found subjects exhibited a considerable increase in plasma antioxidant capacity as compared to control groups.¹¹ In addition to general oxidative damage in the body, the oxidation of low-density lipoprotein (LDL) in particular has been implicated in initiating atherosclerosis. In a study involving subjects with established coronary artery disease, ingestion of purple grape juice was shown to improve endothelial function and reduce LDL oxidation.¹²

Proanthocyanidins and other flavonoids, including catechins, can also be found in the extract of French maritime pine bark, Pycnogenol. This extract has shown the ability to combat heart problems as well. “Pycnogenol’s notable health benefits are supported by extensive research for men and women specifically in relation to cardiovascular health, cholesterol reduction, improved circulation ... and aided in chronic venous insufficiency,” said Victor Ferrari, Horphag’s chief operating officer and executive vice president. In a recent study, hypertensive patients who were given Pycnogenol over the course of 12 weeks were able to significantly decrease the dosage of their existing blood pressure medication.¹³ Pycnogenol also has been proven effective in inhibiting platelet aggregation in smokers at a much lower dose than the dose of aspirin that would be required for a similar level of inhibition.¹⁴

To the delight of many consumers, a major component of chocolate—cocoa—contains flavonoids called procyanidins that are beneficial to heart health. A review of studies on cocoa indicates that procyanidins in cocoa offer antioxidant protection and help to stabilize the vascular system.¹⁵ Additionally, researchers from the University of Texas Southwestern Medical Center in Dallas have shown cocoa products have the ability to decrease LDL’s susceptibility to oxidation.¹⁶

Cocoa may also inhibit platelet activity in healthy subjects, thereby offering a potential mechanism of protection against thrombosis.¹⁷ All chocolate products are not equal in terms of flavonoid content; however, generally speaking, darker chocolate contains more cocoa and, as a result, more flavonoids. One study showed 100 g each of white and milk chocolate given to healthy subjects had no effect on platelet activity, but 100 g of dark chocolate inhibited platelet aggregation.¹⁸

As the second most popular beverage in the world behind water, tea has long been thought of as a natural guardian of health. The green and black teas consumed by many societies for thousands of years have indeed shown powerful antioxidant potential, thus helping to keep the heart strong. Recently, a buzz has been generated concerning white tea as well. “The uniqueness of white tea, which is the least processed tea product (the less amount of processing, the more antioxidant potential), has made it a hot new product,” said Ginny Bank, technical director at Blauvelt, N.Y.-based RFI Ingredients.

The flavonoids in tea, including quercetin, theaflavin and catechins, have been studied in particular for their impact on cardiovascular health. In a longitudinal analysis of data obtained from the Rotterdam Study, researchers found that tea drinkers were less likely to have a myocardial infarction.¹⁹

The same study also found a significant inverse association between flavonoid intake and fatal myocardial infarction events. The Zutphen Elderly Study produced similar results, showing an inverse association between flavonoid intake (mainly from tea) and coronary heart disease.²⁰

Tea flavonoids have also shown promise in the lab. In a study of hypertensive rats, green and black tea flavonoids helped lower blood pressure.²¹ Additionally, green tea catechins and (-)- epigallocatechin gallate have been observed to prevent death caused by thrombosis in mice due to their antiplatelet activities.²²

According to the American Cancer Society, a diet that includes a wide range of plant foods such as fruits and vegetables can reduce cancer risk. While this effect is probably the result of the broad range of vitamins, minerals and phytochemicals that exert a collective influence on health maintenance, there is evidence that flavonoids may be potent cancer fighters in their own right.

As with the French Paradox, population studies were an initial focal point that helped clue scientists in to the potential of flavonoids to prevent cancer. The relatively low cancer rates in Asian countries such as Japan and China as compared to the Western world led scientists to investigate the dietary habits of people in these areas. They discovered certain dietary mainstays such as soy and tea, and their accompanying flavonoids, might be key in explaining this phenomenon.

Soy products contain genistein, an isoflavone that has been studied extensively for its potential in preventing and possibly treating breast cancer and prostate cancer. Isoflavones are phytoestrogens, plant chemicals that exert an estrogen-like effect in the body, albeit much weaker than the real thing. Genistein has been shown to inhibit the growth and proliferation of breast cancer cells, and also to induce apoptosis in these cells.23 Another study demonstrated the combination of soy and green tea has the ability to shrink breast cancer tumors and inhibit tumor angiogenesis in mice.²⁴ Similarly, researchers have found genistein has antiproliferative effects on prostate cancer cells and can even decrease the secretion of prostate specific antigen, a biological marker of prostate cancer, in the absence of male sex hormones.²⁵

The versatile flavonoids found in grapes and some berries may also be important in the fight against cancer. Resveratrol, found abundantly in the skin of certain grapes, has been the subject of several in vitro experiments involving various forms of cancer. In one such study, resveratrol inhibited cell growth in human breast, colon and prostate cancer cells, and also showed the ability to prevent oxidative damage to DNA, thus displaying its preventive and therapeutic potential.²⁶ In a review of its ability to inhibit growth of leukemia cells, it is suggested that resveratrol’s potential mechanisms of action include apoptosis, differentiation of leukemia cells, inhibition of DNA synthesis and ending the cancerous cell cycle at S-phase, a phase that indicates cells are actively dividing.²⁷

Grapeseed proanthocyanidins also seem to possess chemoprotective qualities. Researchers at Creighton University investigated the effects of a grapeseed extract (ActiVin®, from San Joaquin Valley Concentrates) on several lines of cultured cancer cells, including breast, lung, gastric and leukemia.²⁸ Results from this study showed the grapeseed extract was toxic to breast, lung and gastric adenocarcinoma cells, but actually encouraged growth in noncancerous cells. The same grapeseed extract has also been studied as an agent to alleviate some of the toxic effects that cancer drugs can have on normal cells, and has shown promise in this respect as well.²⁹

Researchers interested in the role of proanthocyanidins from grapeseeds in protecting skin from solar ultraviolet (UV) radiation found that mice supplemented with proanthocyanidins were protected from photocarcinogenesis with regard to tumor incidence, size and multiplicity.³⁰ This study associated the protective effects of the extract with a reduction in oxidative damage and the inhibition of lipid peroxidation.

In addition to grapes, there are many varieties of berries that may be useful in combating various forms of cancer. Blackberries, cranberries, blueberries, raspberries and others contain flavonoids called anthocyanins that have been studied for their apparent anticarcinogenic traits. In one such study, a blend of edible berry extracts (as OptiBerry™ from Benicia, Calif.-based InterHealth Nutraceuticals Inc.) was shown to impair angiogenesis and decrease tumor growth.³¹ According to Allondra Stevens, marketing services manager at InterHealth, “OptiBerry is the result of extensive scientific research, which methodically evaluated key functional parameters, including ORAC (antioxidant activity), VEGF (antiangiogenic activity), bioavailability and safety of numerous individual berry extracts.”

Cocoa and its procyanidins can also be added to the list of cancer fighters. Known to have tumor-suppressive properties, a recent in vitro study with human aortic endothelial cells revealed that procyanidins can act as an inhibitor of ErbB2 expression, which plays a regulatory role in angiogenesis associated with tumor formation.³² A study from the University of California, Davis, showed that flavanols and procyanidins derived from cocoa can influence the production and level of signaling molecules that affect immune function, including tumor necrosis factoralpha (TNF-alpha), which may guard against tumorigenesis.³³

Aside from cardiovascular disease and cancer, research has been done concerning the impact of flavonoids on other specific conditions. Some recent studies have shown that flavonoids may be useful in preventing damage to nerves, which is prominent in many diseases such as diabetes and Parkinson’s. One study showed several flavonoids, including quercetin, were able to inhibit damage to myelin in nerves, suggesting potential application in combating multiple sclerosis.³⁴ Quercetin has also showed neuroprotective capacity by guarding against brain cell death.³⁵

Flavonoids have also been studied for their apparent antimicrobial properties. Canadian researchers found catechins from green tea were able to fight adenovirus infection, which is responsible for the common cold.³⁶ However, the study noted the levels of catechins needed to achieve this effect were higher than those likely to be found in the bodies of tea drinkers. Furthermore, certain flavonoids have demonstrated inhibitory effects against poliovirus by preventing synthesis of its RNA.³⁷

The implications of the growing body of research on flavonoids and their potential uses in supporting general health as well as specific diseases and conditions have generated interest from consumers and manufacturers alike. As they attract more attention, flavonoids are becoming very sought-after ingredients and are branching out into other categories. “The demand has increased dramatically, predominantly in the diet category as well as in the functional beverage and food area,” according to Ron Martin, vice president of sales and marketing at Madera, Calif.-based Polyphenolics (a division of Constellation Wines - U.S.), suppliers of MegaNatural® Gold grapeseed extract.

Although much of the media buzz surrounding flavonoids has focused on chocolate, wine and tea, many consumers might wish to avoid high intakes of the accompanying calories, alcohol and caffeine. There is also much to learn about the details of how flavonoids work in the body and specifically how they can be used to optimize health benefits. All of these are important factors that must be considered when dealing with flavonoid supplementation.

There is even work to be done in the identification and isolation of flavonoids and their natural sources. In terms of formulating supplementary flavonoids, Mandy Kraynik, director of scientific research at Green Bay, Wis.-based EuroPharma said broader is better. “Especially because we still have not even scratched the surface of all the identifiable flavonoids found in different food sources, it is definitely preferable to supplement with a broad spectrum (or full spectrum) of flavonoids,” she said.

This approach is also advocated by Ellen Kamhi, Ph.D., author of The Natural Medicine Chest and professional herbalist for Hauppauge, N.Y.- based Nature’s Answer. “Flavonoids most often appear as complexes in nature, rather than as isolated constituents,” she said. “In keeping with the idea of holistic balance, it is always best to mirror nature and use flavonoids as complex groups.”

Whether in a cup of tea, a glass of wine, a chocolate bar or a dietary supplement, consumers will continue to seek out flavonoids in one form or another as science provides them with numerous and convincing reasons to do so. Researchers can be counted on to discover more about the enormous potential and the ways in which these wonders of nature can help consumers stay healthy.

June 2004 Health Supplement Retailer
"The Beauty of Flavonoids" References

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