Higher Flavonoid Intake Research Articles

Effect of Dark Chocolate on Arterial Function in Healthy Individuals

Epidemiologic studies suggest that high flavonoid intake confers a benefit on cardiovascular outcome. Endothelial function, arterial stiffness, and wave reflections are important determinants of cardiovascular performance and are predictors of cardiovascular risk. The effect of flavonoid-rich dark chocolate (100 g) on endothelial function, aortic stiffness, wave reflections, and oxidant status were studied for 3 h in 17 young healthy volunteers according to a randomized, single-blind, sham procedure-controlled, cross-over protocol. Flow-mediated dilation (FMD) of the brachial artery, aortic augmentation index (AIx), and carotid-femoral pulse wave velocity (PWV) were used as measures of endothelial function, wave reflections, and aortic stiffness, respectively. Plasma oxidant status was evaluated with measurement of plasma malondialdehyde (MDA) and total antioxidant capacity (TAC). Chocolate led to a significant increase in resting and hyperemic brachial artery diameter throughout the study (maximum increase by 0.15 mm and 0.18 mm, respectively, P < .001 for both). The FMD increased significantly at 60 min (absolute increase 1.43%, P < .05). The AIx was significantly decreased with chocolate throughout the study (maximum absolute decrease 7.8%, P < .001), indicating a decrease in wave reflections, whereas PWV did not change to a significant extent. Plasma MDA and TAC did not change after chocolate, indicating no alterations in plasma oxidant status. Our study shows for the first time that consumption of dark chocolate acutely decreases wave reflections, that it does not affect aortic stiffness, and that it may exert a beneficial effect on endothelial function in healthy adults. Chocolate consumption may exert a protective effect on the cardiovascular system; further studies are warranted to assess any long-term effects.

Nuclear Magnetic Resonance Spectroscopic Based Studies of the Metabolism of Black Tea Polyphenols in Humans

Epidemiological studies indicate that a high intake of flavonoids is associated with an improved health status. Tea is one of the most abundant sources of flavonoids in the human diet. The bioavailability and biotransformation of tea flavonoids are, however, not clearly understood. The aim of the present study was to investigate the metabolism of black tea via a nonspecific screening method. (1)H nuclear magnetic resonance (NMR) spectroscopy was used to obtain nonselective profiles of urine samples collected from three human volunteers before and after a single dose of black tea. The complex spectroscopic profiles were interpreted with the use of pattern recognition techniques. Hippuric acid was confirmed as the major urinary black tea metabolite. One previously unknown metabolite was detected and identified as 1,3-dihydroxyphenyl-2-O-sulfate (sulfate conjugate of pyrogallol) using HPLC directly coupled to mass spectrometry and (1)H NMR spectroscopy. This study shows that NMR-pattern recognition studies can be used for the discovery of unknown flavonoid metabolites in humans.

QTc Prolongation by Grapefruit Juice and Its Potential Pharmacological Basis

A high intake of dietary flavonoids, which are abundant in fruits, vegetables, tea, and wine, is known to reduce cardiovascular mortality. The effects of flavonoids on cardiac electrophysiology, which theoretically may have both antiarrhythmic and proarrhythmic consequences, have not been studied systematically to date. We screened a broad spectrum of flavonoids for their inhibitory activity on HERG channels by using heterologous expression in Xenopus oocytes. At a concentration of 1 mmol/L, 10 compounds caused a significant inhibition of HERG currents, whereas 11 other flavonoids had no effect. The IC50 value for HERG block by naringenin, the most potent inhibitor, was 102.3 micromol/L in Xenopus oocytes and 36.5 micromol/L in HEK cells. To demonstrate the physiological relevance of these findings, we studied the effects of pink grapefruit juice, which contains large amounts of naringenin glycosides (>1000 micromol/L), in human volunteers. In 10 persons, we observed a peak QTc prolongation of 12.5+/-4.2 ms 5 hours after oral ingestion of 1 L of grapefruit juice. This effect was significant (P=0.02). We found a significant QTc prolongation by grapefruit juice in healthy volunteers, probably caused by block of HERG channels by flavonoids. These findings reveal new perspectives on the potential for dietary modification of cardiac electrophysiology.

The Antioxidant Properties of Greek Foods and the Flavonoid Content of the Mediterranean Menu

The Mediterranean diet is currently attracting interest because of its health benefits that may be due, in part, to the high content of this diet in antioxidant phytochemicals. The variety and amount of phytochemicals taken with the consumption of primary and composite foods of the Mediterranean diet may provide better antiatherogenic properties than single phytochemicals. Flavonoids are the most important group of plant antioxidants. The Mediterranean diet is characterized by high intake of olive oil, fruit, vegetables, cereals, and legumes, some of which are good sources of flavonoids. Flavonoids consist of six principal classes: flavones, flavonols, flavan-3-ols, flavanones, anthocyanidins and isoflavones. The flavonoid intake from a traditional Greek plant-based weekly menu was calculated and the daily average flavonoid intake was found 118.6 mg / d, of which flavanones contribute 32% (38.5 mg / d), catechins (the most important group of flavan-3-ols) contribute 28% (32.7 mg / d), flavonols 22% (26.4 mg / d), anthocyanidins 9% (11 mg / d), flavones 8% (8.7 mg / d) and isoflavones contribute 1% (1.3 mg / d). Herbs and spices, which are commonly used in the traditional Greek cuisine, although added in small quantities, significantly contribute to the flavonol and flavone intake due to frequent consumption. The Greek version of the Mediterranean diet with its high consumption of fruit and vegetables is characterized by high intake of flavonoids in comparison to diets in northern European countries.

Antioxidant status and mineral contents in tissues of rutin and baicalin fed rats

The versatile benefit effects of flavonoids lead some nutritionists to believe that they are micronutrients. However, excess intake of flavonoids may cause side effects. In this paper, the effects produced by a higher intake of rutin and baicalin on antioxidant status as well as trace minerals such as iron, copper and zinc in rat tissues were studied. When rats were fed a rutin or baicalin containing diet (1%) for 20 days, the body weight gain was lower than that of the control group. Both rutin and baicalin caused significant a decrease of catalase activity and a moderate increase of total superoxide dismutase activity in the liver. The total antioxidant status of flavonoid fed rats was increased in the liver but decreased in the serum. In comparison to the control group, the lipid peroxidation level in the liver of the rutin fed group was significantly decreased; however, there was no statistical significance in the liver of the baicalin fed group and the brain of both flavonoids groups. The liver homogenates of both flavonoid fed rats significantly inhibited alkyl radical-induced lipid peroxidation. The iron contents in the liver of flavonoid fed rats were significantly decreased; rutin also caused zinc and copper decrease in the liver. These results indicated that high flavonoid intake can improve rat antioxidant systems in the liver; while it can also cause a trace mineral decrease and, in turn, reduce the activities of some metal-containing enzymes and may cause harmful effects on health.

Flavonoids and thyroid disease.

The most potent natural plant-derived compounds that can affect thyroid function, thyroid hormone secretion and availability to tissues is the group of flavonoids, i.e. plant pigments. They are present in our daily food, such as vegetables, fruits, grains, nuts, wine, and tea. Epidemiological studies suggest beneficial effects on health of flavonoids, which are commonly attributed to their activity as antioxidants. Experimental studies in vitro, however, showed inhibition of organification in thyroid cells and follicles by several flavonoids. Studies in vivo and vitro with synthetic and natural flavonoids showed displacement of T4 from transthyretin leading to disturbances in thyroid hormone availability in tissues. Radioactive labeled flavonoids appeared to be eliminated rapidly from the body mainly through excretion in the feces. In pregnant rats synthetic flavonoids cross the placenta and accumulate in the fetal compartment, including the fetal brain. Therefore, a high intake of flavonoids is contraindicated. flavonoids show strong interference with many aspects of thyroid hormone synthesis and availability.

Increasing antioxidant levels in tomatoes through modification of the flavonoid biosynthetic pathway.

Flavonoids are a diverse group of phenolic secondary metabolites that occur naturally in plants and therefore form an integral component of the human diet. Many of the compounds belonging to this group are potent antioxidants in vitro and epidemiological studies suggest a direct correlation between high flavonoid intake and decreased risk of cardiovascular disease, cancer and other age-related diseases. Enhancing flavonoid biosynthesis in chosen crops may provide new raw materials that have the potential to be used in foods designed for specific benefits to human health. Using genetic modification, it was possible to generate several tomato lines with significantly altered flavonoid content and to probe the role and importance of several key enzymatic steps in the tomato flavonoid biosynthetic pathway. Most notably an up to 78-fold increase in total fruit flavonols was achieved through ectopic expression of a single biosynthetic enzyme, chalcone isomerase. In addition, chalcone synthase and flavonol synthase transgenes were found to act synergistically to up-regulate flavonol biosynthesis significantly in tomato flesh tissues.

Improving the nutritional content of tomatoes through reprogramming their flavonoid biosynthetic pathway

Flavonoids are a diverse group of phenolic secondary metabolites that occur naturally in plants and therefore form an integral component of the human diet. Many of the compounds belonging to this group are potent antioxidants in vitro and epidemiological studies suggest a direct correlation between high flavonoid intake and decreased risk of cardiovascular disease, cancer and other age-related diseases. Modifying flavonoid biosynthesis in chosen crops may provide new raw materials that have the potential to be used in foods designed for specific benefits to human health. We report that flavonoid biosynthesis in tomato fruit is subject to tissue specific and developmental regulation. Using transgenic modification, we have investigated the role of several of the enzymatic steps of tomato flavonol biosynthesis. Furthermore, we have generated several tomato lines with significantly altered flavonoid content. Most notably achieving an up to 78-fold increase in total fruit flavonols through ectopic expression of the biosynthetic enzyme, chalcone isomerase. This increase results principally from the accumulation of quercetin-glycosides in peel tissue. In addition, we report that chalcone synthase and flavonol synthase transgenes act synergistically to significantly up-regulate flavonol biosynthesis in tomato flesh tissues. A review of this work is presented in this paper.

Overexpression of petunia chalcone isomerase in tomato results in fruit containing increased levels of flavonols

Tomatoes are an excellent source of the carotenoid lycopene, a compound that is thought to be protective against prostate cancer. They also contain small amounts of flavonoids in their peel ( approximately 5-10 mg/kg fresh weight), mainly naringenin chalcone and the flavonol rutin, a quercetin glycoside. Flavonols are very potent antioxidants, and an increasing body of epidemiological data suggests that high flavonoid intake is correlated with a decreased risk for cardiovascular disease. We have upregulated flavonol biosynthesis in the tomato in order to generate fruit with increased antioxidant capacity and a wider range of potential health benefit properties. This involved transformation of tomato with the Petunia chi-a gene encoding chalcone isomerase. Resulting transgenic tomato lines produced an increase of up to 78 fold in fruit peel flavonols, mainly due to an accumulation of rutin. No gross phenotypical differences were observed between high-flavonol transgenic and control lines. The phenotype segregated with the transgene and demonstrated a stable inheritance pattern over four subsequent generations tested thus far. Whole-fruit flavonol levels in the best of these lines are similar to those found in onions, a crop with naturally high levels of flavonol compounds. Processing of high-flavonol tomatoes demonstrated that 65% of flavonols present in the fresh fruit were retained in the processed paste, supporting their potential as raw materials for tomato-based functional food products.

High Intake of Specific Carotenoids and Flavonoids Does Not Reduce the Risk of Bladder Cancer

An analysis of a previously completed Spanish multicentric case-control study of bladder cancer was carried out using new available data on the contents in foods of specific carotenoids (α-carotene, β-carotene, lutein, and lycopene) and flavonoids (quercetin, kaempferol, myricetin, and luteolin) to investigate the relationship of these phyto-chemicals with bladder cancer. The study included 497 cases first diagnosed with bladder cancer, 547 neighborhood controls, and 566 hospitals controls, matched by gender, age, area of residence, and hospital. Usual food intake was estimated using a dietary history questionnaire administered by trained interviewers. None of the specific carotenoids and none of the specific flavonoids have been found to be significantly associated with bladder cancer risk in this analy-sis. The adjusted odds ratios for subjects in the highest quartile of intake with respect to subjects in the lowest quartile were 1.36 (95% confidence interval = 0.94-1.95) for total carotenoid intake and 1.23 (95% confidence interval = 0.85-1.79) for total flavonoid intake. The result of this study does not support the hypothesis that intake of specific carotenoids and flavonoids is protective against bladder cancer risk.

Dietary flavonoids and cancer risk in the Zutphen Elderly Study.

Flavonoids are polyphenolic antioxidants naturally present in vegetable foods. Some flavonoids, such as quercetin, inhibit carcinogenesis in rodents, but their effect in humans is unknown. We measured the flavonoids quercetin, kaempferol, myricetin, apigenin, and luteolin in foods and assessed flavonoid intake in 1985 by dietary history in 738 men aged 65-84 years without a history of cancer, who were then followed for five years. Mean flavonoid intake was 25.9 mg/day. The major sources of flavonoid intake were tea at 61% and vegetables and fruits (mainly onions, kale, endive, and apples) at 38%. Between 1985 and 1990, 75 men developed cancer (all sites) and 34 men died from cancer. Flavonoid intake in 1985 was not associated with incidence of all-cause cancer (p for trend = 0.54) or with mortality from all-cause cancer (p for trend = 0.51). Flavonoid intake was also not associated with risk of cancers of the alimentary and respiratory tract (p for trend = 0.92). Adjustment for age, body mass index, smoking, physical activity, and vitamin C, vitamin E, beta-carotene, and dietary fiber intake did not change the relative risks. A high intake of flavonoids from vegetables and fruits only was inversely associated with risk of cancer of the alimentary and respiratory tract (relative risk of highest vs. lowest tertile = 0.51, 95% confidence interval 0.25-1.05); these results suggest the presence of other nonvitamin components with anticarcinogenic potential in these foods. We conclude that intake of flavonoids, mainly from tea, apples, and onions, does not predict a reduced risk of all-cause cancer or of cancer of the alimentary and respiratory tract in elderly men. The effect of flavonoids on risk of cancer at specific sites needs further investigation in prospective cohort studies.

The Effect of Flavonoids on Allergic Diseases

The prevalence of allergic diseases has increased worldwide during the last two decades. Dietary change is thought to be one of the environmental factors that cause the increase and worsen allergic symptoms. If this is the case, an appropriate intake of foods may substantially prevent the onset of allergic diseases and ameliorate allergic symptoms. Flavonoids, which are plant secondary metabolites and ubiquitously present in vegetables, fruits and teas, possess antioxidant and immune-modulating as well as anti-allergic traits. Flavonoids inhibit the release of chemical mediators, synthesis of Th2 type cytokines such as interleukin (IL)-4 and IL-13, and CD40 ligand expression by mast cells or basophils. Luteolin, apigenin and fisetin are the strongest inhibitors of IL-4 production by basophils with an IC50 value of 2-6 µM while quercetin and kaempferol also have a substantial inhibitory effect with an IC50 value of 15-19 µM. One cohort epidemiological study in Finland found a significantly low incidence of asthma in a population with a high intake of flavonoids. Moreover, intervention studies of flavonoids in various allergic models demonstrated their beneficial effects. Finally, clinical trials of one flavonoid, enzymatically modified isoquercitrin, showed its ameliorative effect on symptoms related to Japanese cedar pollinosis. Although further studies are required, it is expected that an appropriate intake of flavonoids may constitute a dietary menu effective as a complementary and alternative medicine and a preventative strategy for allergic diseases.