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CARDIOVASCULAR DISEASE (JHY WU, SECTION EDITOR)
The Efficacy of Quercetin in Cardiovascular Health
Nicola P. Bondonno
1
&Catherine P. Bondonno
1
&Jonathan M. Hodgson
1
&
Natalie C. Ward
1
&Kevin D. Croft
1
#Springer Science+Business Media New York 2015
Abstract Cardiovascular disease is a major cause of death
worldwide despite the majority of its risk factors being
preventable and treatable. The results of numerous epide-
miological studies suggest that a diet rich in fruits and
vegetables affords protection against CVD, and this may
be attributed, in part, to the flavonoid quercetin. The aims
of this review are to summarise the current knowledge on
the bioavailability and metabolism of quercetin as well as
discuss the current evidence behind the potential mecha-
nisms by which quercetin exerts its cardioprotective ef-
fects. This review summarises key human studies admin-
istering quercetin that have been published to date. Al-
though interesting results have been seen in animal and
cell culture studies, in general, these have not been repli-
cated in human trials. Several studies have, however,
shown that quercetin can reduce blood pressure in hyper-
tensive patients. The exact mechanisms are yet to be elu-
cidated. Further studies are required to investigate the use
of quercetin as a cardioprotective treatment, in particular
long-term and dose–response studies.
Keywords Cardiovascular disease .Flavonoids .Quercetin .
Blood pressure .Flow-mediated dilatation .Nitric oxide .
Endothelin-1 .Atherosclerosis .Antioxidant .Oxidative
stress .Lipoproteins .Heme oxygenase-1
Introduction
Cardiovascular disease (CVD) is a major cause of death
worldwide. There are many risk factors for CVD includ-
ing hypertension, smoking, hypercholesterolemia,
hyperglycaemia, obesity, physical inactivity and an un-
healthy diet [1]. Individuals with one CVD risk factor
are more likely to have other risk factors, and many
cases of CVD can be prevented by identifying a modi-
fiable risk factor and treating it [2]. Although CVD
usually affects older adults, the precursor of CVD, par-
ticularly atherosclerosis, begins early in life. This makes
primary prevention efforts such as healthy eating, exer-
cise and avoidance of smoking necessary from child-
hood [3]. It is well known that a diet rich in fruits
and vegetables is associated with a reduction in CVD
[4–6]. Recently, it has been suggested that the beneficial
effects of this diet can be attributed, in part, to flavo-
noids [7]. It is the aims of this review to summarise key
humanstudieswithquercetinpublishedtodate
(Table 1) and to discuss the current evidence behind
the potential mechanisms by which quercetin is
cardioprotective (summarised in Fig. 1).
This article is part of the Topical Collection on Cardiovascular Disease
*Kevin D. Croft
kevin.croft@uwa.edu.au
Nicola P. Bondonno
nicola.bondonno@uwa.edu.au
Catherine P. Bondonno
catherine.bondonno@uwa.edu.au
Jonathan M. Hodgson
jonathan.hodgson@uwa.edu.au
Natalie C. Ward
natalie.ward@uwa.edu.au
1
School of Medicine and Pharmacology, The University of Western
Australia, Level 4 Medical Research Foundation Building, Rear 50
Murray Street, Perth, Western Australia 6000, Australia
Curr Nutr Rep
DOI 10.1007/s13668-015-0137-3
Tab l e 1 The cardioprotective effects of quercetin in human interventional studies
Study design Cohort Significant effects observed in
the treated group
Endpoints with no observed effect Year Ref.
Supplement: Q3G 160 mg/day; 4 weeks
Design:C;DB;R;PC
N=37
Age: 66.4± 7.9 years
Health status: healthy (SBP
125–160 mmHg)
↑in plasma Q after chronic and acute on
chronic ingestion
–Change in FMD, SBP, DBP, PWA PWV,
body weight, glucose, insulin, insulin
resistance, NO, ET-1 or any cholesterols
2015 [36•]
Supplement: Q aglycone 200 and 400 mg
Design:A;DB;R;PC;CO
N=15
Age: 25.8± 5.2 years
Health status: healthy
↑in Q3GA and plasma glutathione at 2 h
↑in brachial artery diameter at 5 h
↓in urinary isoprostanes and NOx at 5 h
- change in SBP, DBP, urinary nitrites plus
nitrates
2014 [38•]
Supplement: Q3G 0, 50, 100, 200 and 400 mg
Design:A;DB;R;PC;CO
N=15
Age: 60.8± 9.3 years
Health status: healthy
–Linear dose–response in plasma Q
metabolites (P<0.001) 1 h post-intervention
–Change in BP, FMD, plasma NO production 2014 UP
Supplement: Q aglycone 500 or 1000 mg/day;
12 weeks + vitamin C+niacin
Design:C;DB;R;PC
N=100
Age:40–83 years
Health status: healthy
–A shift in plasma 163 metabolites –Change in markers of inflammation or
oxidative stress
2012 [86]
Supplement: Q aglycone 1095 mg
Design:A;DB;PC;CO
N=5 healthy
Age:24±3 years
N=12 stage 1 hypertensive
Age: 41± 12 years
−Peak in plasma Q at 10 h
↓inmeanSBP,DBPandMAP(inS1
hypertensives only)
−Change in plasma ACE activity, ET-1, nitrites
−Change in FMD
–Change in BP in normotensives
2012 [37]
Supplement: Q dihydrate 2×500 mg/day;
4 weeks
Design:C;AM;P
N=13
Age:30.1± 1.6 years
Health status: healthy males
↓in oxLDL
↓in plasma dendritic cells
–Change in NF-κB gene expression, LDL
or HDL
2011 [79]
Supplement: Q dehydrate 150 mg/day;
8 weeks
Design:C;DB;PC;R;CO
N=49
Age: 59.4± 0.9 years
Health status: healthy with APOE
genotype 3/3, 3/4 or 4/4
↓in waist circumference
↓in postprandial SBP and triacylglycerol
concentrations
↑HDL, TNF-αand plasma Q
–Change in endothelial function, glucose,
insulin, GSH, CRP, oxLDL inflammation or
urinary isoprostanes
2011 [88•]
Supplement: Q aglycone 500 or 1000 mg/day;
12 weeks + vitamin C+niacin
Design:C;DB;R;PC
N=1002
Age:18–85 years
Health status: varying
↓in serum creatinine, MAP, HDL and IL-6
↑in glomerular filtration rate and plasma Q
–ChangeinBP,glucose,CRP,LDL,
haematocrit, haemoglobin, TNF-α,
triglycerides and inflammatory markers
2011 [26]
Supplement: 4× 500 mg Q aglycone in 24 h
Design:A;DB
N=18
Age:31–69 years
Health status: untreated
sarcoidosis patients
↑in plasma Q
↓in markers of oxidative stress (MDA) and
inflammation (TNF-α;IL-10and
IL-8; IL-10)
↑in plasma oxidative capacity
−Change in plasma GSH
−Correlations between plasma Q levels and
effects observed
2011 [96]
Supplement: Q aglycone 150 mg/day; 6 weeks
Design:C;R;DB;PC;CO
N=93
Age: 45.1± 10.5 years
Health status: features of the
metabolic syndrome
↓in BP in overweight-obese carriers of
the apo ∈3/∈3 genotype but not the ∈4allele
↓in HDL cholesterol and apoA1
in apo ∈4 carriers
↓in oxidised LDL and TNF-αin
apo ∈3andapo∈4 groups
−Change in CRP or nutritional status (body
weight, waist circumference, fat mass, fat-
free mass)
2010 [41]
Supplement: Q aglycone 500 or 1000 mg/day;
12 weeks + vitamin C+niacin
Design:C;DB;R;PC
N=1002
Age:18–85 years
Health status: varying
–Dose-dependent increase in plasma
quercetin (peaked in first month)
–Change in plasma F
2
-isoprostanes, oxLDL,
GSH, FRAP or any cholesterols
2009 [85]
Supplement: Q aglycone 150 mg/days;
6 weeks
Design:C;R;DB;PC;CO
N=93
Age: 45.1± 10.5 years
Health status: features of the
metabolic syndrome
↑in plasma Q
↓in SBP
↓in PP
↓in serum HDL
–Change in body weight, total cholesterol,
TNF-αor CRP
2009 [34]
Curr Nutr Rep
Tab l e 1 (continued)
Study design Cohort Significant effects observed in
the treated group
Endpoints with no observed effect Year Ref.
↓oxidised LDL
Supplement: Q aglycone 200 mg
Design:A;R;PC;CO
N=12
Age: 43.2± 4.3 years
Health status: healthy males
↑in plasma S-nitrosothiols.
Q metabolites and nitrite
↑in urinary nitrate
↓in plasma and urinary ET-1
–Change in plasma nitrate, urinary
nitrite and F
2
-isoprostanes
–Adverse side effects
2008 [56]
Supplement: Q dihydrate 50, 100 or
150 mg/day; 2 weeks
Design:C;R
N=35
Age: 26.2± 3.7 years
Health status: healthy
–Dose-dependent increases in plasma Q
concentrations
–Change in serum uric acid, lipids and
lipoproteins, oxLDL, TNF-αand plasma
antioxidative capacity
2008 [87]
Supplement: Q aglycone 1000 mg/day;
3 weeks + vitamin C+niacin (20 mg)
Design:C;DB;PC
N=18 (quercetin)
Age: 44.2± 2 years
N=21 (placebo)
Age: 46± 2.3 years
Health status: healthy
↑in plasma Q –Difference in plasma antioxidant capacity or
F2-isoprostanes
–Oxidative damage
–Difference in plasma quercetin between the
two groups after a race
2008 [97]
Supplement: Q aglycone 730 mg/day;
28 days
Design:C;R;DB;PC;CO
N=19 pre-hypertensive
Age: 47.8± 3.5 years
N=22 stage 1 hypertensive
Age: 49.2± 2.9 years
↓in SBP, DBP and MAP
(in S1 hypertensives only)
–Change in BP in pre-hypertensives
–Change markers of oxidative stress,
antioxidant capacity, cholesterols, fasting
glucose and triglycerides
2007 [35]
Supplement: Q 1000 mg/day; 28 days
Design:C
N=22
Age: 53.1 years
Health status: patients with
interstitial cystitis
–Improvement in cystitis symptoms –Adverse side effects 2001 [123]
Supplement: rutin 500 mg/day; 6 weeks
Design:C,SB,PC
N=18
Age:18–48 years
Health status: healthy females
↑in plasma Q –Change in plasma antioxidant capacity,
phenolic content, liver function indicators,
GSH, resistance of lymphocytes to H
2
O
2
damage and markers of oxidative stress
2000 [90]
Supplement:Q30 mg/day;
14 days
Design:C
N=10
Age:33–65 years
Health status: healthy males
↑oxidative resistance of LDL –Change in cholesterol, triglycerides, ascorbic
acid and tocopherols
2000 [105]
Supplement: 250 mg Q aglycone +
50 mg rutin 1 g/day; 28 days
Design:C;DB;PC
N=27
Age: 41.5± 2.9 years
Health status: healthy
↑in plasma Q –Change in cholesterol, triglycerides, SBP,
DBP and HR or thrombogenic risk factors
1998 [39]
Aacute, ACE angiotensin-converting enzyme, AM age matched, APOE apolipoprotein E, BP blood pressure, Cchronic, CO crossover, CRP C-reactive protein, DB double blind, DBP diastolic blood
pressure, FRAP ferric-reducing ability of plasma, GSH glutathione, HDL high-density lipoprotein, LDL low-density lipoprotein, NOx nitrogen oxides, oxLDL oxidised low-density lipoprotein, Pparallel,
PC placebo controlled, PWA pulse wave analysis, PWV pulse wave velocity, Qquercetin, Q3G quercetin-3-glucoside, Q3GA quercetin-3-glucuronide, Rrandomised, SB single blind, SBP systolic blood
pressure, TNF-αtumour necrosis factor-α,UP unpublished
Curr Nutr Rep
Flavonoids
Polyphenols, compounds that are found in high concentra-
tions in some fruits and vegetables, are produced as secondary
plant metabolites and are usually involved in the defence of
the plant against stress such as UV radiation and invading
pathogens [8]. It has been suggested that molecules used by
plants as a protection against stress may work similarly in
animals that consume these plants as food [9]. The main clas-
ses of polyphenols include phenolic acids, flavonoids, stil-
benes and lignans. Flavonoids are the largest and most
researched subclass of polyphenols. All flavonoids have a
C6-C3-C6 structure made up of two aromatic rings, linked
by a 3-carbon bridge. In the past decade, many studies have
tried to find an association between flavonoid intake and prev-
alence of CVD. However, not all flavonoid-rich foods im-
prove cardiovascular risk factors, and it is likely that certain
flavonoids are more bioactive than others [10].
Quercetin
Quercetin (5,7,3′,4′-hydroxyflavonol) is the most ubiquitous
of the dietary flavonoids. The richest sources are onions, curly
kale, leeks, broccoli, apples, tea, capers and blueberries, with
onion often being the biggest contributor to total quercetin
intake containing 300 mg/kg fresh onion [11]. Quercetin and
other flavonols are mainly found in the outer and aerial tissue
of the fruit or vegetable, such as the skin and leaves, as their
biosynthesis is stimulated by light [12]. Quercetin in food is
usually in its glycosylated form with the sugar moiety often
being glucose or rhamnose, but other sugars such as galactose,
arabinose and xylose may be involved. Quercetin can be
bought over the counter in capsules that contain between
250 and 1500 mg quercetin, which are purported to be bene-
ficial for a range of ailments including allergies, asthma, bac-
terial infections, arthritis, gout, eye disorders, hypertension
and neurodegenerative disorders [13].
Absorption and Bioavailability of Quercetin
The absorption of quercetin depends on the food matrix in
which it is found and whether it is ingested as an aglycone
or in its glycosylated form. The presence and type of sugar
attached determines the site and extent of absorption, while
the position of the sugar defines the mechanisms of intestinal
uptake [14]. Absorption of glycosides in humans occurs in the
small intestine via diffusion after a crucial deglycosylation
step [15]. Absorption of quercetin aglycone can also occur
in the small intestine via diffusion [16]; however, it is not
absorbed as readily as quercetin glycosides. This may be be-
cause it is chemically unstable in the pH and temperature
conditions of the small intestine, and the intestinal mucus
layer provides a barrier for lipophilic substances such as the
quercetin aglycone. Flavonoid glycosides that are not
absorbed in the small intestine, such as rutin (quercetin-3-O-
rutinoside), pass into the colon where they are acted on by
enterobacterial β-glucosidases and microfloral rhamnosidases
[14]. Although the product that enters the epithelial cells is the
same, absorption is not as efficient due to the smaller ex-
change area and lower density of transporters in the colon.
This explains the lower bioavailability and longer time to peak
for quercetin rhamnoglucosides when compared to quercetin
aglycone or quercetin glucosides. There is higher inter-
Fig. 1 Potential mechanisms by
which quercetin exerts its
cardioprotective effects. ACE
angiotensin-converting enzyme,
AMPK adenosine
monophosphate-activated protein
kinase, eNOS endothelial nitric
oxide synthase, ET-1 endothelin-
1, HMOX-1 heme oxygenase-1,
LDL low-density lipoprotein,
NADPH nicotinamide adenine
dinucleotide phosphate, NO nitric
oxide, Nrf2 nuclear factor
erythroid 2-related factor 2,
PCSK9 proprotein convertase
subtilisin/kexin 9, PON1
paraoxonase 1, ROS reactive ox-
ygen species
Curr Nutr Rep
individual variability after ingestion of rutin, most likely due
to the large diversity of colonic microflora [17].
Metabolism and Safety of Quercetin
Following absorption, quercetin undergoes three main
types of conjugation: sulphation, methylation and
glucuronidation. This occurs in the enterocyte by the ac-
tion of sulfotransferases, catechol-O-methyl transferases
and UDP-glucuronosyltransferases [8]. This conjugation
process is very efficient and no aglycones or quercetin
glycosides are found in the plasma [18]. The main quer-
cetin metabolites found in the plasma are quercetin-3′-sul-
phate, quercetin-3-glucuronide, isorhamnetin-3-glucuro-
nide, quercetin diglucuronide and quercetin glucuronide
sulphate [19]. Ingestion of glycosylated quercetin does
not change circulating metabolites [8].
Metabolites follow two different methods of excretion:
via the urine or as part of biliary secretions back into the
small intestine [8]. Any quercetin not absorbed in the
small intestine, together with that secreted in the bile, is
degraded by colonic microflora with the resultant agly-
cone undergoing ring fission, leading to the production
of phenolic acids and hydroxycinnamates [20]. The elim-
ination of quercetin metabolites is slow with reported
half-livesrangingfrom11to28h[8]. Studies suggest
that lower doses of quercetin are more methylated than
higher doses in humans [21]. Additionally, sulphation is
generally a higher affinity, lower capacity pathway than
glucuronidation; an increase in the amount of quercetin
ingestedmayleadtoashiftfromsulphationtowards
glucuronidation. A substantial amount of research using
quercetin aglycone in vitro has been questioned due to the
very low concentrations of aglycone found in the plasma.
Furthermore, recent research has shown that the major
metabolites of quercetin found in the plasma show weaker
bioactivity in vitro than the aglycone [22,23]. It has been
hypothesised that quercetin metabolites are deconjugated
in the tissue, by β-glucuronidase, releasing quercetin
aglycone which acts as the final effector, a concept that
has been discussed in greater detail by Perez-Vizcaino
et al. [24].
The safety of quercetin has been extensively reviewed by
Harwood et al. [25]. In brief, quercetin is not classified as
carcinogenic or mutagenic in vivo. Recent studies looking at
both acute and chronic supplementation with high doses of
quercetin up to 1000 mg/day for 12 weeks have not reported
any adverse side effects [26]. It is important to note that quer-
cetin inhibits CYP3A4, an enzyme that breaks down several
commonly prescribed drugs [27]. Quercetin should not be
taken in conjunction with drugs such as alprazolam (Xanax)
and colchicine, which rely on this pathway for metabolism.
Epidemiology
The correlation between flavonoid intake and risk of CVD has
been investigated in several epidemiological studies. Most but
not all suggest an inverse association between flavonoid in-
take and CVD. A recent prospective cohort study found that
elderly women with higher total flavonoid consumption were
at a lower risk of all-cause mortality [28•]. High total flavo-
noid consumers had a 40–50 % reduced risk of CVD com-
pared to those with the lowest intake. In the same cohort,
women in the highest tertile of flavonol intake had a lower
risk of atherosclerotic vascular disease death compared with
women in the lowest tertile [29]. To date, few epidemiological
studies have looked at quercetin intake; in the Finnish Mobile
Clinic Health Examination Survey (n=10,054), it was found
that high quercetin intake was associated with lower mortality
from ischaemic heart disease. In this study, quercetin from the
diet was predominantly from apples and onions. The relative
risk (RR) between the highest and lowest quartiles was 0.79
(95 % CI 0.63, 0.99: Pfor trend=0.02) [7]. Although epide-
miological studies suggest a correlation between increased
flavonoid consumption and lower risk of CVD, these studies
have a number of limitations such as the use of food frequency
questionnaires, confounding and publication bias. Thus, we
must be careful when inferring causality using traditional ep-
idemiological methods. Plasma biomarkers are a promising
new technique for determining flavonoid consumption; how-
ever, the methods need further refinement. Currently, there are
no validated biomarkers of quercetin intake, although it has
been suggested that urinary 4-ethylphenol, benzoic acid and
4-ethylbenzoic acid may be potential markers of quercetin
intake [30]. Problems with this method arise due to large
inter-subject variability, which can result from differences in
gut microflora, as well as the food matrix.
Blood Pressure
Hypertension is a major risk factor for CVD [31] and there is a
strong relationship between arterial pressure and death from
stroke and ischaemic heart disease [32]. A diet high in fruits
and vegetables is known to reduce blood pressure, an effect
also attributed to high flavonoid content. Recent studies have
shown a decrease in systolic BP following quercetin supple-
mentation, ranging from 2.9 to 7 mmHg in hypertensive indi-
viduals [33–35] but not in pre-hypertensives or normotensives
[36•,37,35,38•,40•]. Interestingly, in a study by Egert et al.,
6 weeks of 150 mg/day quercetin supplementation led to a
significant decrease in BP (3.4 mmHg, P<0.01) in
overweight-obese carriers of the ApoE3 (Apolipoprotein E3)
gene but not in carriers of the ApoE4 gene [41]. Although the
BP reductions observed in these studies are low, the impact on
CVD for a population would be significant with a 2–3%
reduction in risk expected for each mmHg reduction in BP
Curr Nutr Rep
[42]. Long-term regular consumption of foods high in specific
flavonoids such as quercetin may be useful dietary lifestyle
changes that could help to decrease the use of pharmaceuti-
cals. The mechanisms behind the beneficial decreases in BP
remain to be elucidated; potential pathways include improve-
ment in endothelial function, increases in nitric oxide bioavail-
ability, decreases in the vasoconstrictor endothelin-1, direct
action on vascular smooth muscle and inhibition of
angiotensin-converting enzyme activity.
Endothelial Function and Dysfunction
The endothelium is a monolayer of cells that lines the lumen
of the heart and blood and lymphatic vessels. It responds to
both physical and chemical stimuli to regulate vascular tone,
inflammation, permeability and growth, as well as blood flu-
idity and coagulation [43]. Interestingly, the endothelium se-
cretes both powerful vasorelaxing (e.g. nitric oxide) and
vasoconstricting substances (e.g. endothelin-1). Endothelial
dysfunction has been defined as an impairment in
endothelium-dependent relaxation, with a tendency towards
a proinflammatory, procoagulatory and prothrombotic state
[44]. Any damage to the endothelium results in a decrease in
the bioavailability of endothelium-derived nitric oxide (NO).
This predisposes the vessel wall to leukocyte and platelet ad-
hesion, vasoconstriction and smooth muscle cell proliferation
[45]. A significant association has been observed between
endothelial dysfunction and increased risk of CVD [46]. In-
deed, endothelial dysfunction is implicated in numerous car-
diovascular pathologies including pre-hypertension, hyperten-
sion, atherosclerosis and stroke [47,48]. Quercetin can poten-
tially improve endothelial health through direct vasorelaxant
activity as well as through the prevention of oxidant-induced
endothelial dysfunction.
Flow-Mediated Dilatation In humans, ultrasonography is a
common method used to assess vascular endothelial function
as NO flow-mediated dilatation (FMD) of the brachial artery
[49]. FMD in the peripheral circulation is primarily mediated
by endothelium-derived NO in response to increased flow and
shear stress and results in smooth muscle relaxation and arte-
rial dilation [50]. The effect of quercetin on endothelial func-
tion has not been widely studied. Two studies have shown that
quercetin has neither an acute (1095 mg quercetin aglycone)
[37] nor chronic (quercetin-3-O-glucoside, 160 mg/day for
4weeks)[36•] effect on FMD. Contrastingly, studies using
whole foods (apples) or whole food extracts (onion extract)
rich in quercetin have shown significant improvements in
FMD (acute, 1.1 %) [51] and postprandial FMD (30 days,
1.6 %) [40•]. The above studies vary greatly in design and,
as a result, are hard to compare. Further investigations should
be undertaken to determine whether there is a difference be-
tween acute and chronic consumption of quercetin on FMD
and whether different effects are observed in healthy subjects
compared to subjects with risk factors for CVD such as hy-
pertension or obesity.
Nitric Oxide NO is a potent vasodilator that is synthesised in
the endothelium by endothelial NO synthase (eNOS) en-
zymes. It plays a key role in maintaining vascular integrity
through its antithrombotic, antiproliferative and
antiatherogenic properties [52]. Quercetin has been shown to
increase eNOS activity, possibly through phosphorylation of
adenosine monophosphate-activated protein kinase (AMPK),
resulting in an increase in NO production both acute and long
term [53]. Additionally, up-regulation of AMPK can increase
NO bioavailability through inhibition of NADPH oxidase ac-
tivity, reducing superoxide-activated NO depletion [54].
Quercetin increases intracellular Ca
2+
levels in aortic endothe-
lial cells and stimulates eNOS phosphorylation in a dose- and
time-dependent manner, leading to an increase in NO produc-
tion and relaxation of the vessel [55]. In humans, acute quer-
cetin (200 mg) has been shown to significantly increase plas-
ma S-nitrosothiols (metabolites of NO) [56]. Unfortunately,
neither BP nor FMD was measured in this study. Similarly,
quercetin-rich apple has been shown to significantly increase
plasma nitric oxide status (assessed by measuring S-
nitrosothiols + other nitrosylated species (RXNO)) [51]; how-
ever, it would be erroneous to attribute this to quercetin alone.
The results of these studies provide some evidence of one
possible mechanism behind the cardioprotective benefits of
quercetin. Both Larson et al. [37]andPerezetal.[38•]report-
ed no changes in plasma nitrite or NOx, despite seeing a de-
crease in BP and a large increase in brachial artery diameter,
respectively. In both studies, nitrite was measured using the
Griess reaction which is not suitable for measurement of
submicromolar levels of nitrate and nitrite due to lack of sen-
sitivity [57]. Correspondingly, Dower et al. found no changes
in NO (measured by chemiluminescence) following 4 weeks
ingestion of 160 mg/day quercetin-3-O-glucoside or after
acute on chronic ingestion (NO measured 2 h after the last
treatment) [36•]. It seems that while animal studies suggest
that quercetin can improve endothelial function by increasing
NO bioavailability, these results are not well replicated in
human studies. It is important to note, however, that many
animal studies use supra-physiological doses of pure querce-
tin; thus, care must be taken when interpreting these results.
Interestingly, it has been shown that unlike quercetin agly-
cone, conjugated quercetin metabolites lack a direct
vasorelaxant effect and are unable to modify endothelial func-
tion or NO bioactivity [23].
Nitric Oxide: Endothelin-1 Endothelial dysfunction is asso-
ciated with a diminished bioavailability of the vasodilator NO
resulting in less opposition to vasoconstrictors such as
endothelin-1 (ET-1) [50]. Quercetin has been shown to
Curr Nutr Rep
significantly down-regulate ET-1 gene expression [58], pre-
vent eNOS from endothelin-1-induced uncoupling [54]and
prevent endothelial dysfunction induced by incubation with
ET-1 [23] in isolated rat aortas. These studies support the
hypothesis that quercetin improves vascular function by alter-
ing the balance between NO and ET-1. Loke et al. showed that
urinary ET-1 was significantly lower in people given quercetin
(200 mg) compared to those receiving the placebo [56]. This
was accompanied by an increase in plasma nitrite. In contrast,
no changes in plasma ET-1 were observed in people following
4 weeks ingestion of 160 mg/day quercetin-3-O-glucoside
[36•] or after acute administration of 1095 mg quercetin agly-
cone [37]. As results are inconsistent, further clinical interven-
tion studies are needed to determine whether a reduction in
circulating levels of ET-1 is one of the mechanisms behind the
cardioprotective effects of quercetin.
Direct Action on Vascular Smooth Muscle
Up until now, we have been looking at the effects of quercetin
on the endothelium as a way of improving blood vessel reac-
tivity and decreasing BP. There is evidence that quercetin and
its methylated metabolite isorhamnetin can act directly on the
smooth muscle layer, inducing vasorelaxation independent of
the endothelium [59–61]. The results of a recent study by Hou
et al. demonstrate that quercetin possesses vasospasmolytic
effects and suggest that depression of Ca
2+
influx through L-
type voltage-gated Ca
2+
channels and augmentation of
voltage-gated K
+
channel activity in the muscle cells may
underlie coronary relaxation [62]. It is important to note that
the above-mentioned studies use quercetin aglycone. It has not
been confirmed whether this is a representative of in vivo
conditions as pure quercetin is rapidly metabolised upon in-
gestion; however, evidence shows that metabolites are cleaved
by β-glucuronidase in the target tissues, releasing the active
aglycone [24].
Angiotensin-Converting Enzyme
Angiotensin-converting enzyme (ACE) is a crucial element in
the renin-angiotensin-aldosterone system (RAAS) which reg-
ulates BP and fluid loss. The role of ACE is to convert angio-
tensin I into angiotensin II: the peptide responsible for increas-
ing BP [31]. Consequently, chronic over-activation of RAAS
is associated with hypertension [63]. Inhibition of ACE is a
method used for down-regulating RAAS. There is evidence
that plant extracts, rich in flavonoids such as quercetin, can be
effective ACE inhibitors. Evidence is derived from in vitro
models and animal studies [64,65], and several quercetin
metabolites have been shown to be moderate inhibitors of
ACE [66–68]. Quercetin has been shown to blunt the increase
in BP observed after administration of angiotensin I in rats,
findings which were further supported by a 31 % decrease in
plasma ACE activity [64]. As well as decreasing BP by
blocking angiotensin II production, resulting in an increase
in urinary volume and sodium output, quercetin has also been
shown to inhibit ACE activity through the down-regulation of
renal angiotensin II receptors [65]. In a study by Larson et al.,
quercetin lowered blood pressure in hypertensive men; how-
ever, they observed no accompanying changes in plasma ACE
activity [37]. A study by Knab et al. found an increase in
urinary output of approximately 30 mL/day after 12 weeks
of quercetin supplementation in humans [26]. Increased urine
output has been proposed as a mechanism behind the decrease
in mean arterial pressure (MAP) that has been reported in
animal models after quercetin supplementation [65]. As evi-
dence of ACE inhibitory effects of quercetin from in vitro and
animal studies has been presented, more studies are required
to investigate this mechanism in humans.
Atherosclerosis
Atherosclerosis, a deposition of lipids in the subendothelial
layer of injured blood vessels, is believed to be the primary
cause of many fatal CVDs [69]. Plaque disruption is initiated
by damage to endothelial cells by inflammatory responses or
reactive oxygen species (ROS) and oxidation of low-density
lipoprotein (LDL). Cardiovascular risk factors, such as hyper-
tension and diabetes, accelerate this process [70]. Primary cell
cultures derived from the damaged endothelium have reduced
expression of eNOS [71] and greater production of oxygen-
derived free radicals (ROS) and have been shown to take up
more LDL and oxidised LDL (oxLDL) [72]. Animal studies
have shown that long-term quercetin consumption leads to a
significant reduction in atherosclerotic lesion formation [73,
74]. Histological and gene expression analyses of aortas treat-
ed with quercetin show that quercetin affects lesional smooth
muscle cell proliferation and inflammatory factors associated
with atherogenesis [73]. Quercetin-3-glucuronide (Q3G) can
accumulate in human atherosclerotic lesions and macrophage-
derived foam cells, but not in healthy aorta cells [75]. Inflam-
matory stimulation of macrophages may initiate lactate secre-
tion, leading to acidification of the surrounds which enhances
the activity of β-glucuronidase [76]. This means that macro-
phages may serve as a potential pool of Q3G which they
deconjugate into the aglycone at the site of pathogenic lesions
[77]. The effect of quercetin on atherosclerotic lesions has not
yet been measured in humans, as the required long-term inter-
ventions are not feasible. However, several studies have in-
vestigated the effects of quercetin on oxidative stress and in-
flammation, which have been implicated in the development
of atherosclerosis [78]. Overall, quercetin has been shown to
have little effect on markers of inflammation such as C-
reactive protein (CRP), cytokines (such as IL-6, IL-1 and
TNF-α) and adhesion molecules (such as ICAM-1, VCAM-
1 and selectins) (refer to Table 1). Interestingly, quercetin
Curr Nutr Rep
(500 mg twice daily for 4 weeks) significantly reduced
plasmacytoid dendritic cells in healthy males [79] which have
been shown to contribute to the initiation of atherosclerosis by
amassing in the lipid plaque [80].
Antioxidant
Quercetinhasbeenshowntobeanexcellentantioxidant
in vitro and has been described as a potent free radical scav-
enger in numerous papers [81]. These properties are primarily
attributed to the presence of a catechol or gallate group in the
B-ring [82]. These claims are supported by studies which
found that quercetin increased total plasma antioxidant capac-
ity 6.24 times more than trolox, a reference antioxidant [83].
Thus, the role of quercetin in preventing CVD has largely
been associated with its free radical scavenging antioxidant
properties. However, the interpretation of plasma antioxidant
capacity in human blood is difficult, and there is little evidence
to support the antioxidant activity of quercetin in vivo. A
recent review by Forman et al. has presented a new concept
by which antioxidants exert their beneficial effects. Rather
than acting as free radical scavengers in vivo, as was previ-
ously thought, antioxidant compounds generate signals that
induce the transcription of protective enzymes [84•]. The
physiological concentration of polyphenols in the plasma is
insufficient to scavenge a significant portion of free radicals,
as is seen in many in vitro studies. Rather, polyphenols will be
oxidised to electrophilic hydroquinones and quinones during
their reaction with free radicals. This step appears to be crucial
to its ability to activate nuclear factor erythroid 2-related factor
2 (Nrf2), which maintains protective oxidoreductases and
their nucleophilic substrates. Quercetin and many other plant
polyphenols have been recommended as antioxidants for
many years, despite little evidence that they decrease oxida-
tive stress in humans [35,56,85–87,88•,89,90].
Oxidative Stress
Oxidative stress and inflammation are commonly thought to
contribute to the initiation and progression of atherosclerosis
[78]. Oxidative stress is defined as an increase in the produc-
tion of ROS over the ability to degrade them. Many functions
of the endothelium are known to be affected by ROS, includ-
ing endothelial cell apoptosis [91] and adhesion of inflamma-
tory cells [92], initiating and augmenting the progression of
CVD, namely atherosclerosis. As discussed above, quercetin
may decrease oxidative stress by stimulating protective de-
fences and repair systems [84•]. F
2
-isoprostanes are consid-
ered to be the Bgold standard^in vivo biomarker of oxidative
stress [93]. Another commonly used marker of oxidative
stress is malondialdehyde (MDA); however, the methods of
detection are less reliable and MDA itself is not a specific
marker of oxidative stress [94]. The ability of quercetin to
reduce oxidative stress levels has been demonstrated in some
animal studies [95]. To date, only a few studies have shown
this in humans; Boots et al. found a decrease in MDA and
markers of inflammation in the blood of patients with the
inflammatory disease, sarcoidosis [96], and Perez et al. found
a decrease in urinary F
2
-isoprostanes 5 h after supplementa-
tion of quercetin aglycone (200 and 400 mg). Other studies in
humans have failed to find decreases in oxidative stress after
quercetin consumption [35,56,90,97,98]. Some of these
results may be explained by the fact that the studies were done
in healthy volunteers or volunteers without elevated levels of
oxidative stress; the above results suggest that quercetin may
reduce markers of oxidative stress only when levels are high.
To test this hypothesis, Shanely et al. gave 500 mg or
1000 mg/day doses of quercetin for 12 weeks to a large pop-
ulation of subjects ranging widely in age, BMI and disease
state [85]. They did not find an improvement in antioxidant
capacity or a decrease in oxidative stress in any group. Over-
all, indications that quercetin may reduce or prevent CVD risk
by reducing levels of oxidative stress are much stronger in
animal studies than human studies. This may be because
higher doses of quercetin per kilogram body weight are gen-
erally used in animal studies; the resulting differences in plas-
ma quercetin concentrations may be responsible for the con-
trasting effects of quercetin on oxidative stress. Another ex-
planation may lie within the methods used to quantify oxida-
tive stress.
Lipoproteins
It has been established that the conversion of LDL to oxidised
LDL is an early event in atherosclerosis [78]. High levels of
oxidised LDL are found in patients with the metabolic syn-
drome and are associated with an increase in the risk of myo-
cardial infarction [99]. Reactive species generated by
myeloperoxidase (MPO) are thought to modify LDL in vivo
[100]. In a recent in vitro study, quercetin and some of its
major metabolites were found to protect LDL from MPO-
mediated modification in vitro [101]. One potential mecha-
nism behind this may be increasing the activity of paraoxo-
nase 1 (PON1), an esterase related to the anti-atherogenic
properties of high-density lipoprotein (HDL) [102]thathas
been shown to inhibit the oxidation of LDL [103]. Quercetin
has been shown to up-regulate PON1 activity and free radical
scavenging and protect against LDL oxidation and lipid per-
oxidation [104]. In a study by Egert et al., 150 mg of quercetin
dehydrate per day for 6 weeks reduced plasma oxidised LDL
concentrations in overweight subjects with a high CVD risk
phenotype [34]. In agreement with these results, Chopra et al.
showed that 30 mg of quercetin per day for 2 weeks signifi-
cantly inhibited LDL oxidation [105]. In contrast to these
results, several other human intervention studies found no
changes in oxidised LDL after chronic quercetin
Curr Nutr Rep
supplementation [85,87,106]. Some animal studies support
improvements in lipid profile following quercetin supplemen-
tation [74,107]. A potential mechanism for this may be in the
reduction of proprotein convertase subtilisin/kexin 9 (PCSK9)
which promotes LDL receptor degradation. Q3G has been
shown to increase LDL receptor expression, stimulate LDL
uptake and reduce PCSK9 secretion [108]. However, results
of human studies measuring lipid profiles after quercetin sup-
plementation are equivocal. Overall, most human studies,
with both acute and chronic quercetin supplementation, have
not reported any changes in the levels of plasma LDL or HDL
cholesterol (refer to Table 1). As hyperlipidemia is an inde-
pendent risk factor for atherosclerosis, it is imperative to in-
vestigate the potential for quercetin to decrease the levels of
LDL and oxidised LDL.
Heme Oxygenase-1
As mentioned previously, quercetin can act as an antioxidant
by signalling the induction of protective enzymes, one of these
being heme oxygenase-1 (HMOX-1) [84•]. HMOX-1 is the
inducible form of the enzyme that catalyses the degradation of
heme, producing iron, carbon monoxide and biliverdin, which
is then converted to bilirubin [109]. Several reports have
highlighted the important physiological and beneficial roles
of HMOX-1 in the vasculature, and this has recently been
reviewed by Calay et al. [110•]. HMOX-1 exerts an anti-
inflammatory and antioxidant action within the vasculature
and may modulate endogenous cellular ROS generation
[111]. Pharmacological inducers of HMOX-1, such as
probucol, protect against vascular disease in three different
animal models of atherosclerosis [112]. Moreover, this bene-
ficial effect is associated with enhanced protection of arteries
against endothelial dysfunction induced by oxidative stress.
Increasing evidence suggests a central role for HMOX-1 in
cardiovascular protection, and induction of vascular HMOX-1
could be an important therapeutic target [113]. Blood vessels
exposed to the oxidant hypocholorous acid (HOCl), a physi-
ologically relevant oxidant produced by myeloperoxidase, ex-
hibit a defect in endothelium-dependent NO bioavailability as
shown by impaired endothelium-dependent relaxation [114].
Pre-treatment of aortic rings from control mice with quercetin
(5 and 10 μmol/L) dose-dependently attenuated endothelial
dysfunction while maintaining eNOS activity [53]. This effect
was not seen in the rings from HMOX-1 heterozygous knock-
out mice suggesting that HMOX-1 is essential for the protec-
tive effects of quercetin. This notion is supported by the in-
creased expression of HMOX-1 protein in arteries isolated
from mice fed a diet supplemented with quercetin which
was also associated with a decrease in atherosclerotic lesions
[95,115]. Several other studies have shown that quercetin
induces the production of HMOX-1 [116,117]. Although
HMOX-1 is not detected in healthy human arteries, high
expression is seen in foam cells and atherosclerotic plaques
[118]. The majority of studies indicate a protective role for
HMOX-1 and its products in atherosclerosis; however, the
exact mechanisms remain to be determined. The potential in-
duction of HMOX-1 by dietary flavonoids, such as quercetin,
is of substantial significance; clinical trials are now required to
determine whether the benefits of quercetin in relation to CVD
are associated with HMOX-1 in humans.
Quercetin in Human Studies
In the past decade, a significant number of human intervention
studies investigating the effect of quercetin on risk factors for
CVD have been conducted. The goal of these studies was to
determine the mechanisms of action by which quercetin may
protect against CVD. Despite these studies, which have
looked at the effects of both pure quercetin (described in
Table 1) and quercetin-rich foods, the precise mechanisms
have not been elucidated. There are a number of limitations
of these studies, but perhaps the most important is the sample
size. Half of the studies presented in Table 1have a sample
size n<20, therefore decreasing the statistical power to detect
changes in the outcome of interest. Thereis a large range in the
doses and form in which quercetin is given; a strength of these
studies is that majority were assessed and showed significant
increases in plasma quercetin levels. Over half of the studies
discussed in Table 1were done in a healthy population; how-
ever, studies looking at the antioxidant effects of quercetin
need to be done on a cohort of people with increased levels
of inflammation and oxidative stress [119]. A healthy and
diverse diet generally supplies sufficient antioxidants to coun-
teract ROS production in healthy individuals, and this may
explain the lack of effect observed in studies with healthy
volunteers [35,56,86]. Additionally, quercetin has only been
shown to decrease BP in a hypertensive population. Table 1
highlights the variety of endpoints measured to demonstrate
the biological effects of quercetin; however, many of these are
not standardised or validated. Unfortunately, this makes it dif-
ficult to compare results and draw conclusions from studies
using a different methodology.
Conclusions and Future Studies
Quercetin is a promising molecule in cardiovascular
health and has been widely researched. Nonetheless, in-
teresting results seen in animal models and cell culture
studies have not been replicated in humans. There are
several possible reasons for this: firstly, many of these
studies use supra-physiological doses of quercetin, which
are not reflective of quercetin content in the human diet.
Secondly, many in vitro studies use quercetin aglycone,
Curr Nutr Rep
which may not accurately represent conditions in vivo.
Thirdly, pathways for quercetin metabolism differ be-
tween humans and rats/mice [120], and the resulting me-
tabolites may function very differently. Another vital fac-
tor to take into consideration when planning future studies
is the metabolism of quercetin by gut microflora [121].
The variability in bacterial species found in the gut be-
tween people and animals, and even between people, may
account for a lot of the variability found in flavonoid
research. Consequently, there is a real need for more hu-
man intervention studies, specifically (i) long-term inter-
vention studies, (ii) dose–response studies, (iii) studies
administering quercetin glucosides and (iv) studies that
use co-ingestion of quercetin with other flavonoids and
food constituents to improve its bioavailability and bioac-
tivity. Due to reported high inter-subject variability, future
flavonoid studies need to use a cross-over design [120].
Health status and age should play a significant role in the
selection of volunteers as structural damage and arterial
diseases can reduce the potential to improve vascular
function by nutrients alone [34]. As discussed previously,
many studies have reported that quercetin only lowers BP
in hypertensive individuals; it remains to be determined
whether quercetin benefits all forms of hypertension, irre-
spective of pathological cause. One study [34]suggests
that future studies should incorporate 24-h ambulatory
blood pressure measurements, rather than rely on one
blood pressure measurement taken at resting state, in or-
der to gain a better understanding of the effects of quer-
cetin on blood pressure throughout the day and night.
Food databases are potentially powerful tools in epidemi-
ological studies; however, there is a large amount of var-
iation in flavonoid content due to agricultural growth
methods and differing analytical techniques. Spencer
et al. have stressed the importance of establishing quality
biomarkers of flavonoid intake as a means of overcoming
food questionnaire and food database limitations [122].
Although many human studies administering pure querce-
tin yield a negative result, there is certainly evidence that
quercetin contributes to the beneficial effects of a diet rich
in fruits and vegetables.
Acknowledgments NP Bondonno acknowledges the support of an
Australian Postgraduate Award. NC Ward acknowledges the support of
a MRF/UWA Fellowship. JM Hodgson was supported by an NHMRC
Senior Research Fellowship.
Compliance with Ethics Guidelines
Conflict of Interest Nicola P. Bondonno declares that she has no con-
flict of interest.
Catherine P. Bondonno declares that she has no conflict of interest.
Jonathan M. Hodgson has received research support through grants
from the National Health and Medical Research Council of Australia,
Fruit West, Horticulture Australia Limited and Nestlé.
Natalie C. Ward declares that she has no conflict of interest.
Kevin D. Croft has received research support through grants from the
National Health and Medical Research Council of Australia, Fruit West
and the Australian National Apple Breeding Program.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
References
Papers of particular interest, published recently, have been
highlighted as:
•Of importance
•• Of major importance
1. Mendis S, Puska P, Norrving B. Global atlas on cardiovascular
disease prevention and control. World Health Organization; 2011.
2. Kannel WB. Risk stratification inhypertension: new insights from
the Framingham Study. Am J Hypertens. 2000;13(1):S3–S10.
3. Kannel WB, Dawber TR. Atherosclerosis as a pediatric problem. J
Pediatr. 1972;80(4):544–54.
4. Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP,
Sacks FM, et al. A clinical trial of the effects of dietary patterns
on blood pressure. N Engl J Med. 1997;336(16):1117–24.
5. Joshipura KJ, Ascherio A, Manson JE, Stampfer MJ, Rimm EB,
Speizer FE, et al. Fruit and vegetable intake in relation to risk of
ischemic stroke. JAMA. 1999;282(13):1233–9.
6. Joshipura KJ, Hu FB, Manson JE, Stampfer MJ, Rimm EB, Speizer
FE, et al. The effect of fruit and vegetable intake on risk for coronary
heart disease. Ann Inter Med. 2001;134(12):1106–14.
7. Knekt P, Kumpulainen J, Järvinen R, Rissanen H, Heliövaara M,
Reunanen A, et al. Flavonoid intake and risk of chronic diseases.
Am J Clin Nutr. 2002;76(3):560–8.
8. Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L.
Polyphenols: food sources and bioavailability. Am J Clin Nutr.
2004;79(5):727–47.
9. Howitz KT, Sinclair DA. Xenohormesis: sensing the chemical
cues of other species. Cell. 2008;133(3):387–91.
10. Geleijnse JM, Hollman PC. Flavonoids and cardiovascular health:
which compounds, what mechanisms? Am J Clin Nutr.
2008;88(1):12–3.
11. SamsonL,RimmE,HollmanPC,deVriesJH,KatanMB.
Flavonol and flavone intakes in US health professionals. J Am
Diet Assoc. 2002;102(10):1414–20.
12. Macheix J-J, Fleuriet A. Fruit phenolics. Boca Raton: CRC; 1990.
13. Larson AJ, Symons JD, Jalili T. Quercetin: a treatment for hyper-
tension?—a review of efficacy and mechanisms. Pharmaceuticals.
2010;3(1):237–50.
14. Donovan JL, Manach C, Faulks RM, Kroon PA. Absorption and
metabolism of dietary plant secondary metabolites. Oxford:
Blackwell; 2006.
15. Németh K, Plumb GW, Berrin J-G, Juge N, Jacob R, Naim HY,
et al. Deglycosylation by small intestinal epithelial cell β-
glucosidases is a critical step in the absorption and metabolism
of dietary flavonoid glycosides in humans. Eur J Nutr.
2003;42(1):29–42.
16. Walgren RA, Walle UK, Walle T. Transport of quercetin and its
glucosides across human intestinal epithelial Caco-2 cells.
Biochem Pharmacol. 1998;55(10):1721–7.
17. Erlund I, Kosonen T, Alfthan G, Mäenpää J, Perttunen K, Kenraali
J, et al. Pharmacokinetics of quercetin from quercetin aglycone
Curr Nutr Rep
and rutin in healthy volunteers. Eur J Clin Pharmacol. 2000;56(8):
545–53.
18. Wittig J, Herderich M, Graefe EU, Veit M. Identification of quer-
cetin glucuronides in human plasma by high-performance liquid
chromatography–tandem mass spectrometry. J Chromatogr B.
2001;753(2):237–43.
19. Mullen W, Edwards CA, Crozier A. Absorption, excretion and
metabolite profiling of methyl-, glucuronyl-, glucosyl- and
sulpho-conjugates of quercetin in human plasma and urine after
ingestion of onions. Br J Nutr. 2006;96(01):107–16.
20. Del Rio D, Rodriguez-Mateos A, Spencer JP, Tognolini M, Borges
G, Crozier A. Dietary (poly) phenolics in human health: structures,
bioavailability, and evidence of protective effects against chronic
diseases. Antioxid Redox Sig. 2013;18(14):1818–92.
21. DuPont MS, Mondin Z, Williamson G, Price KR. Effect of vari-
ety, processing, and storage on the flavonoid glycoside content
and composition of lettuce and endive. J Agric Food Chem.
2000;48(9):3957–64.
22. Winterbone MS, Tribolo S, Needs PW, Kroon PA, Hughes DA.
Physiologically relevant metabolites of quercetin have no effect on
adhesion molecule or chemokine expression in human vascular
smooth muscle cells. Atherosclerosis. 2009;202(2):431–8.
23. Lodi F, Jimenez R, Moreno L, Kroon PA, Needs PW, Hughes DA,
et al. Glucuronidated and sulfated metabolites of the flavonoid quer-
cetin prevent endothelial dysfunction but lack direct vasorelaxant
effects in rat aorta. Atherosclerosis. 2009;204(1):34–9.
24. Perez‐Vizcaino F, Duarte J, Santos‐Buelga C. The flavonoid par-
adox: conjugation and deconjugation as key steps for the biolog-
ical activity of flavonoids. J Sci Food Agr. 2012;92(9):1822–5.
25. Harwood M, Danielewska-Nikiel B, Borzelleca J, Flamm G,
Williams G, Lines T. A critical review of the data related to the
safety of quercetin and lack of evidence of in vivo toxicity, includ-
ing lack of genotoxic/carcinogenic properties. Food Chem
Toxicol. 2007;45(11):2179–205.
26. Knab AM, Shanely RA, Henson DA, Jin F, Heinz SA, Austin
MD, et al. Influence of quercetin supplementation on disease risk
factors in community-dwelling adults. J Am Diet Assoc.
2011;111(4):542–9.
27. Choi J-S, Piao Y-J, Kang KW. Effects of quercetin on the bioavail-
ability of doxorubicin in rats: role of CYP3A4 and P-gp inhibition
by quercetin. Arch Pharm Res. 2011;34(4):607–13.
28.•Ivey KL, Hodgson JM, Croft KD, Lewis JR, Prince RL. Flavonoid
intake and all-cause mortality. Am J Clin Nutr. 2015;101(5):1012–
20. Using 2 comprehensive food composition databases, this
paper provides evidence that high consumption of flavonoids
is associated with reduced risk of mortality in elderly women.
29. Ivey KL, Lewis JR, Prince RL, Hodgson JM. Tea and non-tea
flavonol intakes in relationto atheroscleroticvascular disease mor-
tality in older women. Br J Nutr. 2013;110(09):1648–55.
30. Loke WM, Jenner AM, Proudfoot JM, McKinley AJ, Hodgson
JM, Halliwell B, et al. A metabolite profiling approach to identify
biomarkers of flavonoid intake in humans. J Nutr. 2009;139(12):
2309–14.
31. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA,
Izzo Jr JL, et al. The seventh report of the joint national committee
on prevention, detection, evaluation, and treatment of high blood
pressure: the JNC 7 report. JAMA. 2003;289(19):2560–71.
32. Hooper L, Kroon PA, Rimm EB, Cohn JS, Harvey I, Le Cornu
KA, et al. Flavonoids, flavonoid-rich foods, and cardiovascular
risk: a meta-analysis of randomized controlled trials. Am J Clin
Nutr. 2008;88(1):38–50.
33. LarsonA,BrunoR,GuoY,GaleD,TannerJ,JaliliT,etal.Acute
quercetin supplementation does not lower blood pressure or ACE
activity in normotensive males. J Am Diet Assoc. 2009;109(9):A16.
34. Egert S, Bosy-Westphal A, Seiberl J,Kürbitz C, Settler U, Plachta-
Danielzik S, et al. Quercetin reduces systolic blood pressure and
plasma oxidised low-density lipoprotein concentrations in over-
weight subjects with a high-cardiovascular disease risk phenotype:
adouble-blinded, placebo-controlled cross-over study. Br J Nutr.
2009;102(07):1065–74.
35. Edwards RL, Lyon T, Litwin SE, Rabovsky A, Symons JD, Jalili
T. Quercetin reduces blood pressure in hypertensive subjects. J
Nutr. 2007;137(11):2405–11.
36.•Dower JI, Geleijnse JM, Gijsbers L, Zock PL, Kromhout D,
Hollman PC. Effects of the pure flavonoids epicatechin and quer-
cetin on vascular function and cardiometabolic health: a random-
ized, double-blind, placebo-controlled, crossover trial. Am J Clin
Nutr. 2015;101(5):914–21. Four weeks of quercetin supplemen-
tation had no effect on blood pressure, arterial stiffness, insu-
lin resistance, nitric oxide, endothelin-1 or blood lipid profile.
37. Larson A, Witman MAH, Guo Y, Ives S, Richardson RS, Bruno
RS, et al. Acute, quercetin-induced reductions inblood pressure in
hypertensive individuals are not secondary to lower plasma
angiotensin-converting enzyme activity or endothelin-1: nitric ox-
ide. Nutr Res. 2012;32(8):557–64.
38.•Perez A, Gonzalez-Manzano S, Jimenez R, Perez-Abud R, Haro
JM, Osuna A, et al. The flavonoid quercetin induces acute vaso-
dilator effects in healthy volunteers: correlation with beta-
glucuronidase activity. Pharmacol Res. 2014;89:11–8. Results
from this study show that quercetin exerts acute vasodilator
effects in vivo in normotensive, normocholesterolemic human
subjects, but has no effect on blood pressure. These findings
correlate with β-glucuronidase activity.
39. Conquer J, Maiani G, Azzini E, Raguzzini A, Holub B.
Supplementation with quercetin markedly increases plasma quer-
cetin concentration without effect on selected risk factors for heart
disease in healthy subjects. J Nutr. 1998;128(3):593–7.
40.•Nakayama H, Tsuge N, Sawada H, Higashi Y. Chronic intake of
onion extract containing quercetin improved postprandial endo-
thelial dysfunction in healthy men. J Am Coll Nutr. 2013;32(3):
160–4. Supplementation with onion extract for 4 weeks did not
significantly affect fasting FMD but significantly improved
post prandial FMD.
41. Egert S, Boesch-Saadatmandi C, Wolffram S, Rimbach G, Müller
MJ. Serum lipid and blood pressure responses to quercetin vary in
overweight patients by apolipoprotein E genotype. J Nutr.
2010;140(2):278–84.
42. BPLT Trialists’Collaboration. Effects of different blood-pressure-
lowering regimens on major cardiovascular events: results of
prospectively-designed overviews of randomised trials. Lancet.
2003;362(9395):1527–35.
43. Widlansky ME, Gokce N, Keaney Jr JF, Vita JA. The clinical
implications of endothelial dysfunction. J Am Coll Nutr.
2003;42(7):1149–60.
44. Herrmann J, Lerman A. The endothelium—the cardiovascular
health barometer. Herz. 2008;33(5):343–53.
45. Cooke JP, Tsao PS. Is NO an endogenous antiatherogenic mole-
cule? Arterioscler Thromb Vasc Biol. 1994;14(5):653–5.
46. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A,
Waclawiw MA, et al. Prognostic value of coronary vascular endo-
thelial dysfunction. Circ J. 2002;106(6):653–8.
47. Cosentino F, Volpe M. Hypertension, stroke, and endothelium.
Curr Hypertens Rep. 2005;7(1):68–71.
48. Yang Z, Ming X-F. Recent advances in understanding endothelial
dysfunction in atherosclerosis. J Clin Med Res. 2006;4(1):53–65.
49. Celermajer DS, Sorensen K, Gooch V, Sullivan I, Lloyd J,
Deanfield J, et al. Non-invasive detection of endothelial dysfunc-
tion in children and adults at risk of atherosclerosis. Lancet.
1992;340(8828):1111–5.
50. Böhm F, Pernow J. The importance of endothelin-1 for vascular
dysfunction in cardiovascular disease. Cardiovasc Res.
2007;76(1):8–18.
Curr Nutr Rep
51. Bondonno CP, Yang X, Croft KD, Considine MJ, Ward NC, Rich
L, et al. Flavonoid-rich apples and nitrate-rich spinach augment
nitric oxide status and improve endothelial function in healthy
men and women: a randomized controlled trial. Free Radic Biol
Med. 2012;52(1):95–102.
52. Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells syn-
thesize nitric oxide from L-arginine. Nature. 1988;333(6174):664–6.
53. Shen Y, Croft KD, Hodgson JM, Kyle R, Lee I, Ling E, et al.
Quercetin and its metabolites improve vessel function by inducing
eNOS activity via phosphorylation of AMPK. Biochem
Pharmacol. 2012;84(8):1036–44.
54. Romero M, Jiménez R, Sánchez M, López-Sepúlveda R, Zarzuelo
MJ, O’Valle F, et al. Quercetin inhibits vascular superoxide pro-
duction induced by endothelin-1: role of NADPH oxidase,
uncoupled eNOS and PKC. Atherosclerosis. 2009;202(1):58–67.
55. Khoo NK, White CR, Pozzo-Miller L, Zhou F, Constance C,
Inoue T, et al. Dietary flavonoid quercetin stimulates vasorelax-
ation in aortic vessels. Free Radic Biol Med. 2010;49(3):339–47.
56. Loke WM, Hodgson JM, Proudfoot JM, McKinley AJ, Puddey
IB, Croft KD, et al. Pure dietary flavonoids quercetin and (−)-
epicatechin augment nitric oxide products and reduce
endothelin-1 acutely in healthy men. Am J Clin Nutr.
2008;88(4):1018–25.
57. Granger DL, Taintor RR, Boockvar KS, Hibbs Jr JB.
Measurement of nitrate and nitrite in biological samples using
nitrate reductase and Griess reaction. Methods Enzymol.
1996;268:142–51.
58. Nicholson SK, Tucker GA, Brameld JM. Effects of dietary poly-
phenols on gene expression in human vascular endothelial cells.
Proc Nutr Soc. 2008;67(01):42–7.
59. Pérez-Vizcaíno F, Ibarra M, Cogolludo AL, Duarte J, Zaragozá-
Arnáez F, Moreno L, et al. Endothelium-independent vasodilator
effects of the flavonoid quercetin and its methylated metabolites in
rat conductance and resistance arteries. J Pharmacol Exp Ther.
2002;302(1):66–72.
60. Chen CK, Pace-Asciak CR. Vasorelaxing activity of resveratrol and
quercetin in isolated rat aorta. Gen Pharmacol. 1996;27(2):363–6.
61. Rendig SV, Symons DJ, Longhurst JC, Amsterdam EA. Effects of
red wine, alcohol, and quercetin on coronary resistance and con-
ductance arteries. J Cardiovasc Pharmacol. 2001;38(2):219–27.
62. Hou X, Liu Y, Niu L, Cui L, Zhang M. Enhancement of voltage-
gated K+ channels and depression of voltage-gated Ca2+ channels
are involved in quercetin-induced vasorelaxation in rat coronary
artery. Planta Med. 2014;80(6):465.
63. Curtiss C, Cohn J, Vrobel T, Franciosa JA. Role of the renin-
angiotensin system in the systemic vasoconstriction of chronic
congestive heart failure. Circulation. 1978;58(5):763–70.
64. Häckl L, Cuttle G, Sanches Dovichi S, Lima-Landman M,
Nicolau M. Inhibition of angiotensin-converting enzyme by quer-
cetin alters the vascular response to bradykinin and angiotensin I.
Pharmacology. 2002;65(4):182–6.
65. Mackraj I, Govender T, Ramesar S. The antihypertensive effects
of quercetin in a salt-sensitive model of hypertension. J
Cardiovasc Pharmacol. 2008;51(3):239–45.
66. Oh H, Kang D-G, Kwon J-W, Kwon T-O, Lee S-Y, Lee D-B, et al.
Isolation of angiotensin converting enzyme (ACE) inhibitory fla-
vonoids from Sedum sarmentosum. Biol Pharm Bull.
2004;27(12):2035–7.
67. Loizzo MR, Said A, Tundis R, Rashed K, Statti GA, Hufner A,
et al. Inhibition of angiotensin converting enzyme (ACE) by fla-
vonoids isolated from Ailanthus excelsa (Roxb) (Simaroubaceae).
Phytother Res. 2007;21(1):32–6.
68. Kiss A, Kowalski J, Melzig M. Compounds from Epilobium
angustifolium inhibit the specific metallopeptidases ACE. NEP
and APN Planta Medica. 2004;70(10):919–23.
69. Ross R. Atherosclerosis—an inflammatory disease. N Engl J
Med. 1999;340(2):115.
70. Shimokawa H, Aarhus LL, Vanhoutte PM. Porcine coronary ar-
teries with regenerated endothelium have a reduced endothelium-
dependent responsiveness to aggregating platelets and serotonin.
Circ Res. 1987;61(2):256–70.
71. Tschudi MR, Barton M, Bersinger NA, Moreau P, Cosentino
F, Noll G, et al. Effect of age on kinetics of nitric oxide
release in rat aorta and pulmonary artery. J Clin Invest.
1996;98(4):899.
72. Kennedy S, Fournet-Bourguignon M-P, Breugnot C, Castedo-
Delrieu M, Lesage L, Reure H, et al. Cells derived from re-
generated endothelium of the porcine coronary artery contain
more oxidized forms of apolipoprotein-B-100 without a mod-
ification in the uptake of oxidized LDL. J Vasc Res.
2003;40(4):389–98.
73. Kleemann R, Verschuren L, Morrison M, Zadelaar S, van Erk MJ,
Wielinga PY, et al. Anti-inflammatory, anti-proliferative and anti-
atherosclerotic effects of quercetin in human in vitro and in vivo
models. Atherosclerosis. 2011;218(1):44–52.
74. JuŸwiak S, Wójcicki J, Mokrzycki K, Marchlewicz M, Białecka
M, Wenda-Różewicka L, et al. Effect of quercetin on experimental
hyperlipidemia and atherosclerosis in rabbits. Pharmacol Rep.
2005;57(57):604–9.
75. Kawai Y, Nishikawa T, Shiba Y, Saito S, Murota K, Shibata N,
et al. Macrophage as a target of quercetin glucuronides in human
atherosclerotic arteries implication in the anti-atherosclerotic
mechanism of dietary flavonoids. J Biol Chem. 2008;283(14):
9424–34.
76. Ishisaka A, Kawabata K, Miki S, Shiba Y, Minekawa S,
Nishikawa T, et al. Mitochondrial dysfunction leads to
deconjugation of quercetin glucuronides in inflammatory macro-
phages. PLoS One. 2013;8(11):e80843.
77. Kawabata K, Mukai R, Ishisaka A. Quercetin and related poly-
phenols: new insights and implications for their bioactivity and
bioavailability. Food Funct. 2015;6(5):1399–417.
78. Stocker R, Keaney Jr JF. Role of oxidative modifications in ath-
erosclerosis. Physiol Rev. 2004;84(4):1381–478.
79. Nickel T, Hanssen H, Sisic Z, Pfeiler S, Summo C, Schmauss D,
et al. Immunoregulatory effects of the flavonol quercetin in vitro
and in vivo. Eur J Clin Nutr. 2011;50(3):163–72.
80. Döring Y, Zernecke A. Plasmacytoid dendritic cells in atheroscle-
rosis. Front Physiol. 2012;3.
81. Boots AW, Haenen GR, Bast A. Health effects of quercetin: from
antioxidant to nutraceutical. Eur J Clin Pharmacol. 2008;585(2):
325–37.
82. Williams RJ, Spencer JP, Rice-Evans C. Flavonoids: antioxidants
or signalling molecules? Free Rad Biol Med. 2004;36(7):838–49.
83. Arts MJ, Sebastiaan Dallinga J, Voss H-P, Haenen GR, Bast A. A
new approach to assess the total antioxidant capacity using the
TEAC assay. Food Chem. 2004;88(4):567–70.
84.•Forman HJ, Davies KJ, Ursini F. How do nutritional antioxidants
really work: nucleophilic tone and para-hormesis versus free rad-
ical scavenging in vivo. Free Rad Biol Med. 2014;66:24–35.
Polyphenols exert their antioxidant effects by being oxidised
to electrophilic hydroquinones and quinones during their re-
action with free radicals, activaing Nrf2 which induces the
transcription of protective enzymes.
85. Shanely RA, Knab AM, Nieman DC, Jin F, McAnulty SR,
Landram MJ. Quercetin supplementation does not alter antioxi-
dant status in humans. Free Rad Res. 2010;44(2):224–31.
86. Cialdella-Kam L, Nieman DC, Sha W, Meaney MP, Knab AM,
Shanely RA. Dose–response to 3 months of quercetin-containing
supplements on metabolite and quercetin conjugate profile in
adults. Br J Nutr. 2013;109(11):1923–33.
Curr Nutr Rep
87. Egert S, Wolffram S, Bosy-Westphal A, Boesch-Saadatmandi C,
Wagner AE, Frank J, et al. Daily quercetin supplementation dose-
dependently increases plasma quercetin concentrations in healthy
humans. J Nutr. 2008;138(9):1615–21.
88.•Pfeuffer M, Auinger A, Bley U, Kraus-Stojanowic I, Laue C,
Winkler P, et al. Effect of quercetin on traits of the metabolic
syndrome, endothelial function and inflammation in men with
different APOE isoforms. Nutr Metab Cardiovasc Dis.
2013;23(5):403–9. Quercetin supplementation decreased
postprandial systolic blood pressure and triglycerides and
increased HDL-cholesterol and TNF-α.Genotype-
dependent effects were seen only on waist circumference
and BMI.
89. Larson AJ, Symons JD, Jalili T. Therapeutic potential of quercetin
to decrease blood pressure: review of efficacy and mechanisms.
Adv Nutr. 2012;3(1):39–46.
90. Boyle S, Dobson V, Duthie S, Hinselwood D, Kyle J, Collins
A. Bioavailability and efficiency of rutin as an antioxidant: a
human supplementation study. Eur J Clin Nutr. 2000;54(10):
774–82.
91. Touyz R, Schiffrin E. Reactive oxygen species in vascular biolo-
gy: implications in hypertension. Histochem Cell Biol.
2004;122(4):339–52.
92. Taniyama Y, Griendling KK. Reactive oxygen species in the vas-
culature molecular and cellular mechanisms. Hypertension.
2003;42(6):1075–81.
93. Musiek ES, Yin H, Milne GL, Morrow JD. Recentadvances inthe
biochemistry and clinical relevance of the isoprostane pathway.
Lipids. 2005;40(10):987–94.
94. Del Rio D, Stewart AJ, Pellegrini N. A review of recent stud-
ies on malondialdehyde as toxic molecule and biological
marker of oxidative stress. Nutr Metab Cardiovasc Dis.
2005;15(4):316–28.
95. Shen Y, Ward NC, Hodgson JM, Puddey IB, Wang Y, Zhang D,
et al. Dietary quercetin attenuates oxidant-induced endothelial
dysfunction and atherosclerosis in apolipoprotein E knockout
mice fed a high-fat diet: a critical role for heme oxygenase-1.
Free Rad Biol Med. 2013;65:908–15.
96. Boots AW, Drent M, de Boer VC, Bast A, Haenen GR. Quercetin
reduces markers of oxidative stress and inflammation in sarcoid-
osis. Clin Nutr. 2011;30(4):506–12.
97. Quindry JC, McAnulty SR, Hudson MB, Hosick P, Dumke C,
McAnulty LS, et al. Oral quercetin supplementation and blood
oxidative capacity in response to ultramarathon competition. Int
J Sport NutrExerc Metab. 2008;18:601.
98. Jalili T, Beisinger S, Quadros A, Rabovsky A. A mixture of grape
seed and skin extract, green tea extract, resveratrol, and quercetin
reduces blood pressure in hypertensive subjects with metabolic
syndrome. FASEB J. 2012;26:385.2.
99. Holvoet P. Relations between metabolic syndrome, oxidative
stress and inflammation and cardiovascular disease.
Verhandelingen-Koninklijke Academie voor Geneeskunde van
Belgie. 2007;70(3):193–219.
100. Wang Z, Nicholls SJ, Rodriguez ER, Kummu O, Hörkkö S, Barnard
J, et al. Protein carbamylation links inflammation, smoking, uremia
and atherogenesis. Nat Med. 2007;13(10):1176–84.
101. Loke WM, Proudfoot JM, Mckinley AJ, Needs PW, Kroon PA,
Hodgson JM, et al. Quercetin and its in vivo metabolites inhibit
neutrophil-mediated low-density lipoprotein oxidation. J Agric
Food Chem. 2008;56(10):3609–15.
102. Mackness M, Mackness B. Paraoxonase 1 and atherosclerosis: is
the gene or the protein more important? Free Rad Biol Med.
2004;37(9):1317–23.
103. Aviram M, Rosenblat M. Paraoxonases 1, 2, and 3, oxida-
tive stress, and macrophage foam cell formation during
atherosclerosis development. Free Rad Biol Med.
2004;37(9):1304–16.
104. Jaiswal N, Rizvi SI. Onion extract (Allium cepa L.), quercetin and
catechin up‐regulate paraoxonase 1 activity with concomitant protec-
tion against low‐density lipoprotein oxidation in male Wistar rats
subjected to oxidative stress. J Sci Food Agr. 2014;94(13):2752–7.
105. Chopra M, Fitzsimons PE, Strain JJ, Thurnham DI, Howard AN.
Nonalcoholic red wine extract and quercetin inhibit LDL oxida-
tion without affecting plasma antioxidant vitamin and carotenoid
concentrations. Clin Chem. 2000;46(8):1162–70.
106. McAnlis G, McEneny J, Pearce J, Young I. Absorption and anti-
oxidant effects of quercetin from onions, in man. Eur J Clin Nutr.
1999;53(2):92–6.
107. Odbayar T-O, Badamhand D, Kimura T, Takahashi Y, Tsushida T,
Ide T. Comparative studies of some phenolic compounds (querce-
tin, rutin, and ferulic acid) affecting hepatic fatty acid synthesis in
mice. J Agric Food Chem. 2006;54(21):8261–5.
108. Mbikay M, Sirois F, Simoes S, Mayne J, Chrétien M.
Quercetin-3-glucoside increases low-density lipoprotein re-
ceptor (LDLR) expression, attenuates proprotein convertase
subtilisin/kexin 9 (PCSK9) secretion, and stimulates LDL up-
take by Huh7 human hepatocytes in culture. FEBS open bio.
2014;4:755–62.
109. Datla SR, Dusting GJ, Mori TA, Taylor CJ, Croft KD, Jiang F.
Induction of heme oxygenase-1 in vivo suppresses NADPH
oxidase-derived oxidative stress. Hypertension. 2007;50(4):
636–42.
110.•Calay D, Mason JC. The multifunctional role and therapeutic po-
tential of HO-1 in the vascular endothelium. Antioxid Redox Sig.
2014;20(11):1789–809. This review presents evidence for the
potential therapeutic significance of HO-1 and its products,
highlighting their beneficial effects on the endothelium in vas-
cular diseases.
111. Dulak J, Loboda A, Jozkowicz A. Effect of heme oxygenase-1 on
vascular function and disease. Curr Opin Lipidol. 2008;19(5):505–12.
112. Wu BJ, Kathir K, Witting PK, Beck K, Choy K, Li C, et al.
Antioxidants protect from atherosclerosis by a heme oxygenase-
1 pathway that is independent of free radical scavenging. J Exp
Med. 2006;203(4):1117–27.
113. Wu M-L, Ho Y-C, Yet S-F. A central role of heme oxygenase-1
in cardiovascular protection. Antioxid Redox Sig. 2011;15(7):
1835–46.
114. Stocker R, Huang A, Jeranian E, Hou JY, Wu TT, Thomas
SR, et al. Hypochlorous acid impairs endothelium-derived
nitric oxide bioactivity through a superoxide-dependent
mechanism. Arterioscler Thromb Vasc Biol. 2004;24(11):
2028–33.
115. Loke WM, Proudfoot JM, Hodgson JM, McKinley AJ, Hime N,
Magat M, et al. Specific dietary polyphenols attenuate atheroscle-
rosis in apolipoprotein E-knockout mice by alleviating inflamma-
tion and endothelial dysfunction. Arterioscler Thromb Vasc Biol.
2010;30(4):749–57.
116. Chow J-M, Shen S-C, Huan SK, Lin H-Y, Chen Y-C.
Quercetin, but not rutin and quercitrin, prevention of H
2
O
2
-
induced apoptosis via anti-oxidant activity and heme oxygen-
ase 1 gene expression in macrophages. Biochem Pharmacol.
2005;69(12):1839–51.
117. Yao P, Nussler A, Liu L, Hao L, Song F, Schirmeier A, et al.
Quercetin protects human hepatocytes from ethanol-derived oxi-
dative stress by inducing heme oxygenase-1 via the MAPK/Nrf2
pathways. J Hepatol. 2007;47(2):253–61.
118. Wang L-J, Lee T-S, Lee F-Y, Pai R-C, Chau L-Y. Expression of
heme oxygenase-1 in atherosclerotic lesions. Am J Pathol.
1998;152(3):711.
119. Boots AW, Wilms LC, Swennen EL, Kleinjans J, Bast A,
Haenen GR. In vitro and ex vivo anti-inflammatory activity
Curr Nutr Rep
of quercetin in healthy volunteers. Nutrition. 2008;24(7):
703–10.
120. Graefe EU, Wittig J, Mueller S, Riethling AK, Uehleke B,
Drewelow B, et al. Pharmacokinetics and bioavailability of quer-
cetin glycosides in humans. J Clin Pharmacol. 2001;41(5):492–9.
121. Scalbert A, Williamson G. Dietary intake and bioavailability of
polyphenols. J Nutr. 2000;130(8):2073S–85S.
122. Spencer JP, Abd El Mohsen MM, Minihane A-M, Mathers JC.
Biomarkers of the intake of dietary polyphenols: strengths, limi-
tations and application in nutrition research. Br J Nutr.
2008;99(01):12–22.
123. Katske F, Shoskes D, Sender M, Poliakin R, Gagliano K, Rajfer J.
Treatment of interstitial cystitis with a quercetin supplement. Tech
Urol. 2001;7(1):44–6.
Curr Nutr Rep
