Epidemiological studies have indicated that dietary flavonoids generally, and flavonols specifically, may contribute to cardiovascular health. Tea consumption, which is often the main dietary source of flavonoids and flavonols, is associated with a reduced risk of cardiovascular outcomes. The primary objective of the present study was to explore the association of the habitual intake of flavonols from tea and non-tea sources with the risk of atherosclerotic vascular disease mortality in a population of elderly women. A total of 1063 women, aged over 75 years, were randomly selected from ambulant Caucasian women living in Perth, Western Australia. Flavonoid consumption was assessed using the US Department of Agriculture Flavonoid, Flavone and Proanthocyanidin databases. Atherosclerotic vascular disease mortality was assessed over 5 years of follow-up through the Western Australian Data Linkage System. During the follow-up, sixty-four women died from atherosclerotic vascular disease. Women in the highest compared with the lowest tertile of flavonol intake had a lower risk of atherosclerotic vascular disease death (OR 0·27, 95 % CI 0·13, 0·59; P≤ 0·01 for trend in multivariate-adjusted models). Similar relationships were observed for flavonol intake derived from both tea (OR 0·38, 95 % CI 0·18, 0·79; P< 0·01) and non-tea (OR 0·41, 95 % CI 0·20, 0·85; P= 0·05) sources. Tea was the main contributor to flavonol intake (65 %), and the intakes of flavonols from tea and non-tea sources were not significantly correlated. In conclusion, increased consumption of flavonols was independently associated with a lower risk of atherosclerotic vascular disease mortality. Both tea and non-tea sources of flavonols were independently associated with this benefit.

Quercetin, a flavonol in fruits and vegetables, has been demonstrated to have antioxidant, anti-inflammatory and immunomodulating influences. The purpose of the present study was to determine if quercetin, vitamin C and niacin supplements (Q-500 = 500 mg/d of quercetin, 125 mg/d of vitamin C and 5 mg/d of niacin; Q-1000 = 1000 mg/d of quercetin, 250 mg/d of vitamin C and 10 mg/d of niacin) would alter small-molecule metabolite profiles and serum quercetin conjugate levels in adults. Healthy adults (fifty-eight women and forty-two men; aged 40–83 years) were assigned using a randomised double-blinded placebo-controlled trial to one of three supplement groups (Q-1000, Q-500 or placebo). Overnight fasted blood samples were collected at 0, 1 and 3 months. Quercetin conjugate concentrations were measured using ultra-performance liquid chromatography (UPLC)-MS/MS, and metabolite profiles were measured using two MS platforms (UPLC-quadrupole time-of-flight MS (TOFMS) and GC-TOFMS). Statistical procedures included partial least square discriminant analysis (PLS-DA) and linear mixed model analysis with repeated measures. After accounting for age, sex and BMI, quercetin supplementation was associated with significant shifts in 163 metabolites/quercetin conjugates (false discovery rate, P< 0·05). The top five metabolite shifts were an increase in serum guaiacol, 2-oxo-4-methylthiobutanoic acid, allocystathionine and two bile acids. Inflammatory and oxidative stress metabolites were not affected. PLS-DA revealed a clear separation only between the 1000 mg/d and placebo groups (Q2Y= 0·763). The quercetin conjugate, isorhamnetin-3-glucuronide, had the highest concentration at 3 months followed by quercetin-3-glucuronide, quercetin-3-sulphate and quercetin diglucuronide. In human subjects, long-term quercetin supplementation exerts disparate and wide-ranging metabolic effects and changes in quercetin conjugate concentrations. Metabolic shifts were apparent at the 1000 mg/d dose; further research is required to understand the health implications of these shifts.

Flavonols, flavanones and flavones (FLAV) are sub-classes of flavonoids that exert cardioprotective and anti-carcinogenic properties in vitro and in vivo. We aimed to estimate the FLAV dietary intake, their food sources and associated lifestyle factors in ten European countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. FLAV intake and their food sources for 36 037 subjects, aged between 35 and 74 years, in twenty-seven study centres were obtained using standardised 24 h dietary recall software (EPIC-SOFT). An ad hoc food composition database on FLAV was compiled using data from US Department of Agriculture and Phenol-Explorer databases and was expanded using recipes, estimations and flavonoid retention factors in order to increase its correspondence with the 24 h dietary recall. Our results showed that the highest FLAV-consuming centre was the UK health-conscious group, with 130·9 and 97·0 mg/d for men and women, respectively. The lowest FLAV intakes were 36·8 mg/d in men from Umeå and 37·2 mg/d in women from Malmö (Sweden). The flavanone sub-class was the main contributor to the total FLAV intake ranging from 46·6 to 52·9 % depending on the region. Flavonols ranged from 38·5 to 47·3 % and flavones from 5·8 to 8·6 %. FLAV intake was higher in women, non-smokers, increased with level of education and physical activity. The major food sources were citrus fruits and citrus-based juices (especially for flavanones), tea, wine, other fruits and some vegetables. We concluded that the present study shows heterogeneity in intake of these three sub-classes of flavonoids across European regions and highlights differences by sex and other sociodemographic and lifestyle factors.

This study hypothesized that ginger (Zingiber officinale) and cranberry (Vaccinium macrocarpon) extracts would alter the physiological response to exercise as well as markers of muscle damage, and mRNA expression for the inflammatory cytokines tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and interleukin-6 (IL-6) after an exhaustive bout of exercise in horses. Nine unfit Standardbred mares (age 10 ± 4 years, ~450 kg) completed three graded exercise tests (GXTs) in a crossover design, where they were assigned to the initial order of treatment in a randomized fashion. The GXTs were conducted between 07.00 and 12.00 hours, 7 days apart. Mares received either water (2 l), cranberry (~30 g in 2 l of water) or ginger (~30 g in 2 l of water) extract 1 h prior to testing. Blood samples were taken prior to dosing (pre-exercise), at the end of each step of the GXT, at the end of the exercise and at 2, 5 and 30 min, 1, 2, 4 and 24 h post-GXT. Plasma total protein (TP) concentration and haematocrit (HCT) were analysed immediately following the tests. Analysis of creatine kinase (CK) and aspartate aminotransferase (AST) was done commercially. There was no effect of treatment (P>0.05) on VO2max, run-time to fatigue, core temperature, TP or HCT. CK was substantially elevated (P < 0.05) in the ginger group at 4 h post-GXT. All CK levels returned to baseline 24 h post-GXT. No change (P>0.05) was noted in AST. A slight increase (P < 0.05) in CK was seen in all groups at 2 h post-GXT. The cranberry group had significantly lower TNF-α mRNA expression than the control and ginger groups. Ginger appeared to influence (P < 0.05) the upregulation and expression of IFN-γ mRNA at 30 min post-GXT, but, more strikingly, significantly decreased recovery time defined as the time for VO2 to recover from the peak observed at fatigue to a post-exercise plateau (ginger = 101 ± 3 s, water = 130 ± 14 s, cranberry = 131 ± 16 s). No effect of treatment or exercise (P>0.05) was seen on IL-6 mRNA expression. Results suggest that cranberry extract blunts the upregulation and expression of TNF-α mRNA, while ginger extract reduces cardiovascular recovery time in horses completing a short, exhaustive bout of exercise.

Epidemiological studies suggest that a diet high in flavonoids protects against chronic diseases such as CVD and cancer. The objective of the present study was to evaluate the relationship between the intake of quercetin, kaempferol, isorhamnetin, apigenin and luteolin and their corresponding plasma concentrations, and further to explore whether these flavonoids can serve as biomarkers of their intake. Flavonoid intake and their plasma concentrations were analysed in ninety-two subjects consuming their habitual diet. Flavonoid intake was estimated with 7-d dietary records using available data on the flavonoid content of food. Plasma flavonoid concentrations were quantified by HPLC. In addition, we undertook a dietary intervention study to investigate plasma apigenin concentration after the consumption of celery leaf. The mean intake estimates of quercetin, kaempferol, isorhamnetin, apigenin and luteolin amounted to 13·58, 14·97, 12·31, 4·23 and 8·08 mg/d, respectively. The corresponding mean plasma concentrations were 80·23, 57·86, 39·94, 10·62 and 99·90 nmol/l. The mean 7 d intake of five flavonoids was positively correlated to their corresponding plasma concentrations, with correlation coefficients ranging from 0·33 to 0·51 (P < 0·05). In the dietary intervention study, the plasma apigenin concentration rose after celery leaf ingestion, and fell within 28 h to below the limit of detection (2·32 nmol/l). The present results suggest that quercetin, kaempferol, isorhamnetin, apigenin and luteolin are bioavailable from the diet. The levels of fasting plasma flavonoids seem to be suitable biomarkers of short-term intake. The combination of plasma flavonoids with their intake may prove useful when the possible health-protective effects of flavonoids are studied.

Diets rich in flavonoids may reduce the risk of developing colorectal cancer. Flavonoids are widely distributed in foods of plant origin, though in the UK tea is the main dietary source. Our objective was to evaluate any independent associations of total dietary and non-tea intake of four flavonoid subclasses and the risk of developing colorectal cancer in a tea-drinking population with a high colorectal cancer incidence. A population-based case–control study (264 cases with histologically confirmed incident colorectal cancer and 408 controls) was carried out. Dietary data gathered by FFQ were used to calculate flavonoid intake. Adjusted OR and 95 % CI were estimated by logistic regression. No linear association between risk of developing colorectal cancer and total dietary flavonol, procyanidin, flavon-3-ol or flavanone intakes was found, but non-tea flavonol intake was inversely associated with colorectal cancer risk (OR 0·6; 95 % CI 0·4, 1·0). Stratification by site of cancer and assessment of individual flavonols showed a reduced risk of developing colon but not rectal cancer with increasing non-tea quercetin intake (OR 0·5; 95 % CI 0·3, 0·8; Ptrend < 0·01). We concluded that flavonols, specifically quercetin, obtained from non-tea components of the diet may be linked with reduced risk of developing colon cancer.

It is essential to have a thorough knowledge of the bioavailability and metabolism of dietary flavonols to understand their role in disease prevention. Lightly fried onions containing 275μmol flavonols, principally quercetin-4′-glucoside and quercetin-3,4′-diglucoside, were fed to healthy human volunteers and plasma and urine were collected over a 24h period. Samples were analysed by HPLC with diode array and tandem mass spectrometric detection. Five flavonol metabolites, quercetin-3′-sulphate, quercetin-3-glucuronide, isorhamnetin-3-glucuronide, a quercetin diglucuronide and a quercetin glucuronide sulphate, were detected in plasma in quantifiable amounts with trace quantities of six additional quercetin metabolites. Sub-micromolar peak plasma concentrations (cmax) of quercetin-3′-sulphate, quercetin-3-glucuronide, isorhamnetin-3-glucuronide and quercetin diglucuronide were observed 0.6–0.8h after ingestion. In contrast, the cmax of quercetin glucuronide sulphate was 2.5h. The elimination half-lives (t1/2) of quercetin-3′-sulphate, quercetin-3-glucuronide and quercetin diglucuronide were 1.71, 2.33 and 1.76h respectively, while the t1/2 of isorhamnetin-3-glucuronide was 5.34h and that of quercetin glucuronide sulphate was 4.54h. The profile of metabolites excreted in urine was markedly different to that of plasma with many of the major urinary components, including quercetin-3′-glucuronide, two quercetin glucoside sulphates and a methylquercetin diglucuronide, absent or present in only trace amounts in the bloodstream indicative of substantial phase II metabolism. Total urinary excretion of quercetin metabolites was 12·9μmol, corresponding to 4·7% of intake. If these samples had been subjected to hydrolysis, as in many previous studies, only quercetin and isorhamnetin would have been detected and quantified. The bioactivity of these metabolites should be considered.

The effect of dietary intake of flavonols (predominantly quercetin) on oxidative DNA damage was studied in thirty-six healthy human subjects (sixteen men, twenty women). The study was a randomised crossover study, comprising two 14 d treatments of either a low-flavonol (LF) or high-flavonol (HF) diet with a 14 d wash-out period between treatments. Subjects were asked to avoid foods containing flavonols, flavones and flavanols during the LF dietary treatment period and to consume one 150 g onion (Allium cepa) cake (containing 89·7 mg quercetin) and one 300 ml cup of black tea (containing 1·4 mg quercetin) daily during the HF dietary treatment. A 7 d food diary was kept during each dietary period and blood samples were taken after each dietary treatment. Products of oxidative damage to DNA bases were measured in DNA from leucocytes. The study had more than 95 % power to detect a change of 20 % in DNA damage products Plasma vitamin C and plasma quercetin concentrations were also measured. No significant differences in intake of macronutrients or assessed micronutrients, measured DNA base damage products, or plasma vitamin C were found between the HF and LF dietary treatments. The plasma quercetin concentration was significantly higher after the HF dietary treatment period (228·5 (SEM 34·7) nmol/l) than after the LF dietary treatment period (less than the limit of detection, i.e. <66·2 nmol/l). These findings do not support the hypothesis that dietary quercetin intake substantially affects oxidative DNA damage in leucocytes.