Quercetin Synergy

By Jacob Schor, ND, FABNO


A quercetin molecule. Image by the Shaddack via Wikipedia.org, used under the Fair Use Doctrine.

Buckminster Fuller invented the term 'synergy' to explain some of his stranger architectural concepts. Although I idealized Fuller in my younger years, I admit that, for the most part, I had no idea what he was talking about. The concept of synergy and geodesic domes are probably the most prominent legacy with which Fuller has left us.

The term synergy in modern medical science is now used to describe the way drugs, nutrients, or toxins interact to enhance each other’s effects, both good and bad. One classic example is codeine mixed with acetaminophen, a combination that enhances the codeine’s pain relieving action.

I am often guilty of overlooking the synergistic actions of the supplements I suggest to patients. I fall into a simplistic worldview in which nutrients isolated from food and plants act singly and alone. This is absurd but easy to do. My only excuse is reading too much peer reviewed medical literature. Interactions between multiple nutrient complexes are difficult to test, and synergistic effects even more difficult. Most of the research related to nutrients is goal oriented, searching to isolate single patentable chemicals for market.

I am lead to these ruminations by a fascinating series of reports published over the past few years describing the effects of quercetin on athletic performance. David Nieman and fellow researchers at Appalachian State University in Boone, North Carolina are behind many of these studies.

Quercetin is found in many kinds of fruits and vegetables. It is well established that people who eat larger that average amounts of fruits and vegetables are protected against many diseases. It was an easy jump for researchers to wonder if these benefits were correlated with greater quercetin intake. Indeed in test tube and animal experiments quercetin appears to exert many powerful chemical effects that appear protective against human disease.

Quercetin should be anti-oxidative, anti-inflammatory, anti-bacterial, immunomodulatory, anti-carcinogenic and cardio-protective. Those who eat the most quercetin have lower rates of cancer (colorectal, kidney, pancreatic, prostate and lung cancer), cardiovascular disease and diabetes.

Food sources of quercetin include elderberries (42 mg/100 gm), red onions (33 mg/100 gm), hot peppers (15 mg/100 gm), apples (4.7 mg/100 gm), kale (7.7 mg/100 gm) etc. Capers actually contain the most quercetin (180 mg/100 gm) of pretty much any food but as few people consume them in quantity are rarely listed.

Athletes are useful test subjects to use in studying certain types of disease. The effects of sustained endurance ‘events’ in many ways mimic the physiologic effects caused by aging, trauma and surgery on blood chemistry. Thus in theory one could test the benefits of quercetin relatively easily.

Prolonged and intensive physical exertion by endurance athletes causes inflammation, oxidative stress and lowers immune protection, leaving them at high risk of upper respiratory tract infection (URTI).

In the first of their quercetin studies, the Nieman and the Boone researchers gave competitive cyclists either 1000 mg/day doses of quercetin or a placebo. After three weeks supplementation, the cyclists were rode very hard (3 hours per day) for three days in a row. They were then tested for multiple measures of inflammation, oxidative stress and immune function along with incidence of URTI. Those who took quercetin increased plasma quercetin levels and had fewer URTIs during the two week period following their 3 day burst of hard riding, but taking the quercetin had no effect on laboratory measurements of immune dysfunction, inflammation or oxidative stress.

The Boone researchers conducted a second similar study but, instead of cyclists, used the ultra-marathon runners who competed in the 160 Kilometer Western States Endurance Run (WSER). Subjects again took 1,000 mg of quercetin or a placebo each day for three weeks and again supplementation had no effect on blood measurements of inflammation, immune dysfunction or oxidative stress triggered by this severe exertion. URTI rates were again lower in those who took quercetin but not statistically significant. Combining URTI data from this WSER study with data from the earlier cyclist study did yield a statistically significant reduction in post exertion illness; URTI rates were a full 2/3 lower in the quercetin group than in the placebo group. Yet the lack of measurable effect on blood chemistry was frustrating.

The Boone researchers looked to knowledge gained in rat studies on the synergistic effect of other nutrients on quercetin.

In an experiment published in July 2009, again cyclists took 1000 mg of quercetin per day this time for only two weeks, but with or without the addition of 120 mg of epicallocatechin 3–gallate (EGCG), 400 mg isoquercetin and 400 mg of EPA-DHA. The EGCG dose is about equivalent to a single cup of green tea. The riders again went through a 3 hour per day, 3 day period of extreme exertion. This trial yielded far different results: the mixture reduced the measurements of inflammation, oxidative stress, and immune disruption significantly. The levels of quercetin in the blood of those who took the mixture of supplements were almost twice as high in those who took only quercetin.

Adding a few other supplements to quercetin worked far better than quercetin alone. What is most surprising about this information, at least in hindsight, is that it took so long to figure it out. Researchers were looking so hard to find the single chemical that would act magically and cause all the positive health changes that they lost sight of the bigger picture.

Single foods provide complex mixtures of nutrients. Diets consist of complex mixtures of foods. Expecting to isolate a single nutrient from a diet that provides all the benefits of the diet seems absurd. We now consider the Mediterranean Diet to be very healthy. Choosing foods like those eaten by Mediterranean cultures certainly provides eaters with a fair amount of quercetin; it also provides omega-3 fats from fish and a decent amount of EGCG. It is this combination of nutrients that together brings some of the benefit.

The easy take home lesson from this research is that we should forget about giving quercetin alone to people. If we want clinical benefit we should always give doses of green tea and fish oil along with quercetin to maximize its benefit.

The more advanced lesson is that we need to look further in the direction of identifying synergistic combinations of nutrients. We can easily list several other major phytonutrients common in the Mediterranean Diet, for example, resveratrol and genestein. It shouldn’t surprise us that resveratrol and EGCG have synergistic action against cancer cells. Or that resveratrol and genestein do as well. A combination of nutrients may work well where a single nutrient fails.

The real lesson though is that we can’t really fully understand the interactions between the countless components found in food within our bodies. At best we can mimic the eating habits of healthy populations and hope to see similar benefit in ourselves. This brings to mind the advice given by my nutrition professor thirty years ago. “Eat a wide variety of healthy foods.”

For those of us who seek health benefits through nutritional supplements, we should be cautious of over idolizing single nutrients and realize nutrients often work far better in combination with others than they do alone.

Note: Much of the information in this article is from a still unpublished review paper written by David Nieman, PhD. It deserves special and particular mention rather than simply to be referenced as a footnote. Dr. Nieman has been the guiding force behind quercetin research that has emerged from the Human Performance Laboratory at Appalachian State University in Boone, North Carolina. The paper is titled, “Quercetin’s bioactive effects in human athletes.” His paper was accepted for publication February 11, 2010 and will appear in Current Topics in Nutraceutical Research, Volume 8, No. 1 later this year. A special thank you to Dr. Nieman both for sharing this paper but for tolerating my many questions.

The 1,000 mg/day dose of quercetin used in these recent trials far exceeds the amount of quercetin that can easily be consumed via diet. Food sources of quercetin include elderberries (42 mg/100 gm), red onions (33 mg/100 gm), hot peppers (15 mg/100 gm), apples (4.7 mg/100 gm), kale (7.7 mg/100 gm) etc. Capers, by the way, actually contain the most quercetin (180 mg/100 gm) of pretty much any food but as few people consume them in quantity, are rarely listed.

References:
Nieman DC. Risk of Upper Respiratory Tract Infection in Athletes: An Epidemiologic and Immunologic Perspective. J Athl Train. 1997 Oct;32(4):344-349

McAnulty SR, McAnulty LS, Nieman DC, Quindry JC, Hosick PA, Hudson MH, Still L, Henson DA, et al. Chronic quercetin ingestion and exercise-induced oxidative damage and inflammation. Appl Physiol Nutr Metab. 2008 Apr;33(2):254-62.

Nieman DC, Henson DA, Davis JM, Dumke CL, Gross SJ, Jenkins DP, et al. Quercetin ingestion does not alter cytokine changes in athletes competing in the Western States Endurance Run. J Interferon Cytokine Res. 2007 Dec;27(12):1003-11.

Moon YJ, Wang L, DiCenzo R, Morris ME. Quercetin pharmacokinetics in humans. Biopharm Drug Dispos. 2008 May;29(4):205-17.

Mostafavi-Pour Z, Zal F, Monabati A, Vessal M. Protective effects of a combination of quercetin and vitamin E against cyclosporine A-induced oxidative stress and hepatotoxicity in rats. Hepatol Res. 2008 Apr;38(4):385-92. Epub 2007 Oct 9.

Zal F, Mostafavi-Pour Z, Vessal M. Comparison of the effects of vitamin E and/or quercetin in attenuating chronic cyclosporine A-induced nephrotoxicity in male rats. Clin Exp Pharmacol Physiol. 2007 Aug;34(8):720-4.

Camuesco D, Comalada M, Concha A, Nieto A, Sierra S, Xaus J, Zarzuelo A, Gálvez J. Intestinal anti-inflammatory activity of combined quercitrin and dietary olive oil supplemented with fish oil, rich in EPA and DHA (n-3) polyunsaturated fatty acids, in rats with DSS-induced colitis. Clin Nutr. 2006 Jun;25(3):466-76.

Nieman DC, Henson DA, Maxwell KR, Williams AS, McAnulty SR, Jin F, et al. Effects of quercetin and EGCG on mitochondrial biogenesis and immunity. Med Sci Sports Exerc. 2009 Jul;41(7):1467-75.

Hsieh TC, Wu JM. Suppression of cell proliferation and gene expression by combinatorial synergy of EGCG, resveratrol and gamma-tocotrienol in estrogen receptor-positive MCF-7 breast cancer cells. Int J Oncol. 2008 Oct;33(4):851-9.

Gynecol Oncol. 2009 Jun;113(3):374-8. Regulation of Vascular Endothelial Growth Factor in endometrial tumour cells by resveratrol and EGCG. Dann JM, Sykes PH, Mason DR, Evans JJ.

Ahmad KA, Harris NH, Johnson AD, Lindvall HC, Wang G, Ahmed K. Protein kinase CK2 modulates apoptosis induced by resveratrol and epigallocatechin-3-gallate in prostate cancer cells. Mol Cancer Ther. 2007 Mar;6(3):1006-12.

Harper CE, Cook LM, Patel BB, Wang J, Eltoum IA, Arabshahi A, Shirai T, Lamartiniere CA. Genistein and resveratrol, alone and in combination, suppress prostate cancer in SV-40 tag rats. Prostate. 2009 Nov 1;69(15):1668-82.