Quercetin: A flavonol with multifaceted therapeutic applications?

Gabriele D’Andrea

PII: S0367-326X(15)30092-7
DOI: doi: 10.1016/j.fitote.2015.09.018
Reference: FITOTE 3271

To appear in: Fitoterapia

Received date: 22 July 2015

Revised date: 16 September 2015
Accepted date: 18 September 2015

Please cite this article as: Gabriele D’Andrea, Quercetin: A flavonol with multifaceted
therapeutic applications?, Fitoterapia (2015), doi: 10.1016/j.fitote.2015.09.018

This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.
 ACCEPTED MANUSCRIPT
Quercetin: A flavonol with multifaceted therapeutic applications?

Gabriele D’Andrea*

University of L’Aquila, Dept. of Biotechnological and Applied Clinical Sciences, Via Vetoio,

T
Coppito 2, 67100 L’Aquila, Italy

R IP
SC
*: Corresponding author

NU
Phone: +39-862-433464

Fax: +39-862-433433
MA
email: gabriele.dandrea@cc.univaq.it
D
P TE
CE

Keywords: quercetin; dietary sources; metabolism; therapeutic applications; toxicity; drug

interactions.
AC

1
 ACCEPTED MANUSCRIPT
ABSTRACT

Great interest is currently centered on the biologic activities of quercetin a polyphenol belonging to the class of

flavonoids, natural products well known for their beneficial effects on health, long before their biochemical

characterization. In particular, quercetin is categorized as a flavonol, one of the five subclasses of flavonoid compounds.

Although flavonoids occur as either glycosides (with attached glycosyl groups) or as aglycones, most altogether of the

T
IP
dietary intake concerning quercetin is in the glycoside form. Following chewing, digestion, and absorption sugar

moieties can be released from quercetin glycosides. Several organs contribute to quercetin metabolism, including the

R
small intestine, the kidneys, the large intestine, and the liver, giving rise to glucuronidated, methylated, and sulfated

SC
forms of quercetin; moreover, free quercetin (such as aglycone) is also found in plasma. Quercetin is now largely

utilized as a nutritional supplement and as a phytochemical remedy for a variety of diseases like diabetes/obesity,

NU
circulatory dysfunction, including inflammation as well as mood disorders. Owing to its basic chemical structure the

most obvious feature of quercetin is its strong antioxidant activity which potentially enables it to quench free radicals
MA
from forming resonance-stabilized phenoxyl radicals.

In this review the molecular, cellular, and functional bases of therapy will be emphasized taking strictly into
D

account data appearing in the peer-reviewed literature and summarizing the main therapeutic applications of quercetin;
TE

furthermore, the drug metabolism and the main drug interaction as well as the potential toxicity will be also spotlighted.
P
CE
AC

2
 ACCEPTED MANUSCRIPT
1. INTRODUCTION

Most of the successful medical treatments in ancient times seem due to the employment of flavonoids, which

use has persevered until now. Consequently, new interest by the scientific community towards flavonoids and their

derivatives centers on numerous flavonoid compounds and their diverse biological properties (e.g. antioxidative,

antimicrobial, anticarcinogenic, cardioprotective). Certainly, in this context quercetin is one of the most often studied

T
IP
dietary flavonoid ubiquitously present in various vegetables as well as in tea and red wine [1-3]. In a typical Western

diet the daily intake of quercetin is estimated to be in the range of 0 and 30 mg (median of 10 mg). Tea, red wine, fruits,

R
and vegetables are the chief dietary sources of quercetin in Western populations [4, 5]. In some countries quercetin is

SC
available as a dietary supplement with daily doses between 200 and 1200 mg. In addition, as a nutraceutical for

functional foods, quercetin may be used within 0.008-0.5% or 10-125 mg/serving [6].

NU
Yet, like other similar antioxidant flavonoids quercetin is an exceptional free radical scavenger [7] and from

that feature arises the ability of quercetin to scavenge highly reactive species such as peroxynitrite and the hydroxyl
MA
radical; for this reason quercetin is suggested to be involved in imaginable beneficial health effects. On the contrary,

only few, and mostly in vitro, studies report some damaging effects of quercetin; in particular, its oxidation product
D

such as quercetin-quinone seems to be very reactive towards thiols and can instantaneously form an adduct with
TE

glutathione, the most abundant endogenous thiol [8, 9]. Furthermore, amongst other damaging effects quercetin has

also been reported to display genotoxic effects in vitro, but these mutagenic effects of quercetin have been found only in
P

bacteria and are suggested to require the quinone formation as mediators as well [10-13].
CE

In any case, it is assumed that the bioactivity of quercetin is mainly due to its metabolization in the intestines

and/or liver starting from various naturally occurring conjugated isoforms that are absorbed and extensively distributed
AC

in animal tissues [14-16]. In particular, quercetin-3-O-β-D-glucuronide (Q3GA), a major metabolite of quercetin and

found as such in many foods (Table 1), seems to exert the foremost beneficial functions in target tissues [17].

3
 ACCEPTED MANUSCRIPT
Table 1. Quercetin-3-O-β-D-glucuronide content in selected food1

Fruits and fruit products

Fruits - Berries Grape, black 2.15 mg/100 g
Strawberry, raw 1.74 mg/100 g
Grape, green 1.50 mg/100 g

T
Cloudberry 0.79 mg/100 g

IP
Red raspberry, raw 0.63 mg/100 g
Non-alcoholic beverages

R
Fruit juices - Berry juices Red raspberry, pure juice 6.18 mg/100 mL

SC
Fennel, tea 3.26 mg/100 mL
Herb infusion Grape, green, pure juice 0.05 mg/100 mL
Vegetables

NU
Leafy vegetables Lettuce, red, raw 2.65 mg/100 g
Lettuce, green, raw 1.34 mg/100 g
Pod vegetables Green bean, raw 0.80 mg/100 g
MA
1
: Adapted from Phenol-Explorer, Database on polyphenol content in foods [205].

Thus, since numerous studies have been performed to gather scientific evidence for these beneficial health
D

claims the principal aim of this review is to evaluate these studies in order to elucidate the possible health-beneficial
TE

effects of quercetin. In particular, among the beneficial effects, the antihypertensive effects of quercetin in humans and
P

the improvement of endothelial function seem to be the most relevant. Nevertheless, besides its anti-thrombotic and
CE

anti-inflammatory effects, quercetin could be used for preventing obesity related diseases, but also to treat some kinds

of cancer. Most exciting are the recent findings that quercetin enhances physical power by yet unclear mechanisms.
AC

Even though quercetin bioavailability is generally poor it is a critical mediator of its bioactivities, in this

review besides the molecular, cellular, and functional bases of therapy that will be emphasized and critically evaluated,

the quercetin metabolism and its main drug interaction as well as its potential toxicity will be also spotlighted.

2. CHEMICAL FEATURES OF QUERCETIN

2.1. Structural features of quercetin

The name quercetin derives from quercetum (oak forest), after Quercus and has been used since 1857.

Naturally, quercetin is a polar auxin transport inhibitor [18] whose structure is shown in Fig. 1 whereas its main

identifiers and properties are reported in Table 2.

4
 ACCEPTED MANUSCRIPT

T
Figure 1. The chemical structure of quercetin.

IP
Table 2. Quercetin identifiers and properties1

R
IDENTIFIERS

SC
IUPAC Name 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one
PubChem CID 5280343
1S/C15H10O7/c16-7-4-10(19)12-11(5-7)22-15(14(21)13(12)20)6-1-2-
InChl
8(17)9(18)3-6/h1-5,16-19,21H

NU
InChl Key REFJWTPEDVJJIY-UHFFFAOYSA-N
Canonical SMILE C1=CC(=C(C=C1C2=C(C(=O)C3=C(C=C(C=C3O2)O)O)O)O)O
CAS 117-39-5
EC Number 204-187-1
MA
UN Number 2811
UNII 9IKM0I5T1E
1. 3,3',4',5,7-pentahydroxyflavone
MeSH Synonyms 2. dikvertin
3. quercetin
D

Trivial Chemical Names Sophoretin; Xanthaurine; Meletin

Molecular Weight 302.2357 g/mol
TE

Molecular Formula C15H10O7

PROPERTIES
Yellow needles or yellow powder. Converts to anhydrous form at 203-207 °F.
Physical Description
P

Alcoholic solutions taste very bitter.

Density 1.799 g/cm3
CE

Color Yellow needles (dilute alcohol, + 2 water)

Boiling Point Sublimes
Melting Point 316.5 °C
In water: 60 mg/mL at 16 °C; < 1mg/mL at 70 °F
AC

Solubility
Very soluble in ether, methanol; soluble in ethanol, acetone, pyridine, acetic acid.
Vapor Pressure 2.81x10-14 mm Hg at 25 °C
Decomposition When heated to decomposition it emits acrid smoke and irritating fumes.
Dissociation Constants
pKa1 = 7.17; pKa2 = 8.26; pKa3 = 10.13; pKa4 = 12.30; pKa5 = 13.11
(in phenol)
Spectral Properties Max Absorption: 256 nm (log E= 4.32); 301 nm (log E= 3.89); 373 nm (log E=
4.32); Sadler Ref. Number: 594 (IR, PRISM)
1
: Adapted from U.S. National Library of Medicine [206].

Chemically speaking quercetin belongs to the class of flavonoids (from flavus which means yellow, their

common color), natural products derived from 2-phenylchromen-4-one (flavone) (Fig. 2).

5
 ACCEPTED MANUSCRIPT

T
IP
Figure 2. The chemical structure of 2-phenylchromen-4-one.

R
SC
However, further derivations encompass the reduction of the 2(3) carbon-carbon double bond (flavanones)

(Fig. 3), the reduction of the keto group (flavanols), and the hydroxylation at diversified positions. (Fig. 4).

NU
MA
D
TE

Figure 3. The chemical structure of major flavanones.

P
CE
AC

Figure 4. The chemical structure of major flavanols.

Anyway, and more precisely, quercetin is a representative of the flavonols family (Fig. 5) that is compounds

that have the 3-hydroxyflavone backbone. Flavonols (with an "o") (Fig. 5) are not to be misled with flavanols (with an

"a"), another subclass of flavonoids containing the 2-phenyl-3,4-dihydro-2H-chromen-3-ol skeleton (Fig. 4).

6
 ACCEPTED MANUSCRIPT

T
R IP
Figure 5. Molecules belonging to the flavonols’ family and their chemical structures.

SC
Interestingly, flavonoids were formerly referred to as Vitamin P, presumably due to the effect they had on the

NU
permeability of vascular capillaries, but this term is rarely used now [19].
MA
2.2. Antioxidative properties of quercetin

Quercetin is considered to be a strong antioxidant due to its ability to scavenge free radicals and bind transition
D

metal ions [20]. Its antioxidative capacities are primarily ascribed to the presence of two antioxidant pharmacophores
TE

within the molecule that have the optimal configuration for free radical scavenging, i.e. the catechol group in the B ring

and the OH group at position 3 of the A ring [21] (Fig. 1). As accounted by some research teams, within the flavonoid
P

family, quercetin is the most potent scavenger of ROS, including O2 (- [22-25] and ONOO− [26, 27]. These properties
CE

make quercetin a good lipid peroxidation inhibitor [28, 29]; this type of peroxidation can create deleterious effects

throughout the body, such as cardiovascular and neurodegenerative diseases; however, lipid peroxidation can be
AC

terminated by antioxidants, like quercetin, which interfere by reacting with the radicals formed [28, 30, 31]. In

addition, quercetin does not only stop the propagation of lipid peroxidation, but also increases glutathione levels [32]

contributing in preventing free radicals formation [31]. In this context, the oxidation of lipid biomolecules such as low-

density lipoproteins (LDL) can give rise to the formation of atherosclerotic plaques responsible of cardiovascular

diseases [28]; moreover, brain lipid membranes damages due to lipid peroxidation are thought to lead to

neurodegenerative conditions, such as Alzheimer’s and Parkinson’s disease [31].

By scavenging free radicals quercetin can also reduce inflammation [33]. Interestingly, by preventing Ca2+-

dependent cell death quercetin can protect cells suffering oxidative stress [28]. Furthermore, quercetin can also protect

against smoking that is the more obvious environmental cause of free radicals. In fact, Begum and Terao [34] found that

the quercetin aglycone and its conjugate metabolites (i.e. quercetin-3-O-β-glucuronide and quercetin-3-O- β -glucoside)

could protect erythrocytes from the damage caused by smoking. Moreover, as reported in a study of 40 athletes [35],

quercetin could prevent the increased oxidative stress induced by exercise.

7
 ACCEPTED MANUSCRIPT
Additionally, whereas the contribution of both vitamin C and uric acid virtually equals that of trolox (6-

hydroxy-2, 5,7,8-tetramethylchroman-2-carboxylic acid) quercetin is suggested to substantially empower the

endogenous antioxidant shield due to its contribution to the total plasma antioxidant capacity (6.24 times higher than the

reference antioxidant trolox) [36]. The antioxidative properties of quercetin were also investigated against sodium

fluoride induced oxidative stress in rats. In particular, pretreatment with quercetin (as well as with vitamin C) before

T
IP
NaF administration prevented either liver and renal injury and led to a significant revival of the oxidative status, thus

the antioxidant activity of quercetin played an important protective role in the liver and kidneys of rats, respectively

R
[37, 38]. In a similar study, investigating upon the cardioprotective properties of quercetin, authors found that although

SC
NaF intoxication significantly altered all the indices related to the pro-oxidant-antioxidant status of the heart, quercetin

treatment prior to NaF administration prevented these alterations, probably via antioxidant quercetin’s properties [39].

NU
Anyway, like many antioxidant compounds, quercetin might show pro-oxidant activity, at least under some

circumstances. This happens because quercetin-quinone (QQ), the main oxidation product of quercetin, strongly react
MA
with thiols causing the loss of the protein function. Such QQ-induced toxicity has been demonstrated in various in

vitro studies and has recently been defined as the quercetin paradox, i.e. while offering protection by scavenging ROS
D

quercetin is converted into a potential toxic product [40]. Moreover, QQ is so very reactive that it instantaneously
TE

forms an adduct with glutathione, the most abundant endogenous thiol [8, 9]. However, although based on the Ames

test [41] quercetin has to be considered a mutagenic compound, in 1999 the International Agency for Research on
P

Cancer (IARC) concluded that quercetin should not be classified as carcinogenic to humans [42, 43].
CE

Among other interesting features, quercetin is an excellent free radical scavenging antioxidant [8] and as such

could form products that usually have got over some of the responsiveness of the radical that has been scavenged [44].
AC

This antioxidant activity recognized for flavonoids such as quercetin has often been associated with the reduced risk of

oxidative-stress related chronic diseases such as diabetes, coronary heart disease and stroke [45, 46]. In this regard,

catechol products containing antioxidants such as quercetin react with thiols impairing - in isolated membranes and

blood plasma - several enzymes [47, 48]. In any event, in relation to the protective power of the flavonoid itself, the

potential toxicity of quercetin metabolites formed during the shelter offered by quercetin has not been measured in

intact cells before. However, Mendoza and Burd [49] explored the fine structure and mechanical properties of quercetin

as they pertain to its ability to work as a chemopreventative compound.

3. DIETARY SOURCES

The edible portions of many food plants, leafy vegetables, tubers and bulbs, various fruits, herbs and spices,

as well as tea and wine contain flavonols mainly in the form of glycosides [50]. Amongst flavonols molecules quercetin

is the most abundant (see Table 3 for selected foods containing quercetin), anyway the majority of the dietary intake of

8
 ACCEPTED MANUSCRIPT
quercetin-type flavonols consists of quercetin glycosides a kind of conjugates in which quercetin is linked either with

one or two glucose residues (quercetin glucosides) or with rutinose (quercetin rutinoside) (Fig. 6); thus fewer amounts

of (aglycones) quercetin are found in the common diet. Fascinatingly, the amount of quercetin in food might

significantly be influenced by growing conditions, e.g., organically grown tomatoes show a higher quercetin aglycone

content than conventionally cultivated tomatoes [51]. In any case, vegetables and fruits, particularly onions, peppers

T
IP
cranberries, blueberries, apples, cherries and grapes which contain the flavonol at levels as high as about 350 ppm

(expressed as the aglycones) are the primary sources of naturally-occurring dietary quercetin of the typical Western diet

R
[52, 53]. Brewed black tea, as well as red table wine and various fruit juices, also were identified as dietary sources

SC
abundant of quercetin [54, 55].

In addition, although occurring relatively rarely in nature, first identified in Ageratina calophylla [56], C-

NU
glycosides are another type of quercetin derivatives where the most frequent site of the C-glycosylation is the C-6

carbon. One more very rare quercetin derivative, such as quercetin 3-O-α-L-fucopyranoside, was found both in the red
MA
alga Acanthophora spicifera [57] and in the Vitis vinifera [58]; in this case quercetin is attached to a α-L-fucopyranosyl

moiety at position C-3 via a glycosidic linkage. Anyway, for these very rare quercetin derivatives, no clinical studies are
D

at the moment reported in the scientific literature.

TE

Table 3. Quercetin content of selected foods1

P

Quercetin amount
Food source (mg/100 g)
CE

edible portion
Capers, raw 233.84
Peppers, hot, yellow, raw 50.73
Onions, red, raw 39.21
AC

Asparagus, cooked 15.16

Cranberries, raw 14.84
Peppers, hot, green, raw 14.70
Lingonberries, raw 13.30
Blueberries, raw 7.67
Lettuce, red leaf, raw 7.61
Onions, white, raw 6.17
Tomato, canned 4.12
Apples, Red delicious, with skin 3.86
Apples, Gala, with skin 3.80
Apples, Golden delicious, with skin 3.69
Broccoli, raw 3.26
Tea, green, brewed 2.49
Cherries, sweet, raw 2.29
Tea, black, brewed 2.19
Grapes, black 2.08
Grapes, white 1.12
Wine, red, table 1.04
Wine, white, table 0.04

1
: Adapted from USDA Database for the Flavonoid Content of Selected Foods [207].

9
 ACCEPTED MANUSCRIPT

T
R IP
SC
Figure 6. a): quercetin-3-glucoside (isoquercetin); b): quercetin-3,4’-diglucoside; c): quercetin-3-rutinoside (rutin;
sophorin).

NU
In the United States, from a normal mixed diet the average daily intake of all flavonoids (i.e. flavanones,
MA
flavones, flavonols, anthocyanins, catechins, and biflavans) is calculated to be about 1 g/day [expressed as quercitrin

equivalents, considering that one biflavan molecule equals to 2 molecules of quercitrin], of which, depending on

seasonal changes, 160-175 mg/day is accounted only for flavanones, flavones, and flavonols [50, 59]. However,
D

expressed as quercetin equivalents, it is estimated that flavonol glycosides are consumed at levels of up to about 100
TE

mg/day [50, 55, 60, 61]. On the other hand, the national dietary record-based cohort assessments (i.e. from Australia,

Croatia, Finland, Italy, Japan, the Netherlands, and the United States) of the intake of quercetin from the customary diet
P
CE

indicated mean consumption levels in the range < 5 mg to about 40 mg quercetin/day [61-66]; however, daily amounts

of quercetin as high as 200-500 mg may be reached by high-end consumers of fruits and vegetables, notably in cases
AC

where the individuals ingest the peel portion of quercetin-rich fruits and vegetables, such as tomatoes, apples, and

onions [60].

4. QUERCETIN BIOAVAIABILITY

Bioavailability is defined as a ratio between the amount of an orally administered substance and the amount

which is absorbed and then available for physiologic activity or storage [67]. Founded on its pharmacokinetics

assessment bioavailability could be sorted out as absolute or relative [68]. Absolute bioavailability is more accurate,

whereas relative bioavailability is simpler, but less accurate [53]. As already reported [69] the factors that most

influence quercetin absorption are the “nature of the attached sugar, and secondly, the solubility as modified by ethanol,

fat, and emulsifiers”. The earliest human quercetin research suggested very poor oral bioavailability after a single oral

dose (~2%) [70]; subsequently, the absolute bioavailability of quercetin in humans was estimated at 44.8% when

radiolabeled quercetin aglycone solubilized in ethanol was administered prior to measuring the total radioactivity of

10
 ACCEPTED MANUSCRIPT
plasma [71]. Moreover, to produce an adequate plasma response, > 50 mg quercetin aglycone or quercetin aglycone

equivalents are usually provided, which is higher than typical dietary intakes (i.e., 6-18 mg/day) [1, 55, 72]. However,

in view of the potential clinical use of the molecule, quercetin half-life and tissue distribution provide useful

information. Being the half-life of the atom and its metabolites in the range of 11-28 h, this indicates a likely significant

increased plasma concentration consequent to continuous supplementation [73, 74]. Nonetheless, until nowadays

T
IP
researches conducted upon animal and human beings have enlightened an extensive understanding about quercetin

bioavailability.

R
SC
5. QUERCETIN METABOLISM

5.1. Quercetin metabolism in vivo overview

NU
As stated above quercetin as such is usually found linked to a sugar moiety giving rise β-glycosides derivatives

which, once ingested, undergo hydrolysis by the glycosidase activity of intestinal bacteria releasing quercetin (the
MA
aglycone form) and the sugar moiety [75]. However, it was recently demonstrated that the predominant quercetin

conjugates in human plasma, in which the quercetin as such could not be detected, are quercetin 3-O-β-D-glucuronide
D

(Q3GA) and quercetin-3′-sulfate [76-78]. Upon ingestion, quercetin glycosides are rapidly hydrolyzed during the transit
TE

through the small intestine or by bacterial activity in the colon to generate quercetin aglycone, which is further

metabolized in the so-called phase II reactions into the glucuronidated and/or sulfated derivatives (Fig. 7).
P
CE
AC

Figure 7. a): quercetin 3-O-β-D-glucuronide (Q3GA); b): quercetin-3′-sulfate.

Studies using rodents have also demonstrated that orally administered quercetin is converted to its conjugates

before accumulation in plasma [79, 80]. In addition, it was reported and clarified that conjugated metabolites of

quercetin accumulate in human plasma in the concentration range of 10–7-10–6 M after the periodic ingestion of onions

with meals for 1 week [77]. Thus, the pharmacological role of dietary quercetin, including its antioxidant action, should

be reached solely by its conjugated metabolites. In any case, most of the in vitro pharmacological studies have been

done by utilizing only the quercetin aglycone form.

11
 ACCEPTED MANUSCRIPT

5.2. Quercetin metabolism

Quercetin metabolism is complex and involves intestinal uptake and/or deglycosylation, glucuronidation,

sulfation, methylation, possible deglucuronidation and ring fission [81]. Various quercetin metabolites are generated

following its biotransformation; in particular, as above described, it has been recently demonstrated that quercetin 3-O-

T
β-D-glucuronide (Q3GA) and quercetin-3′-sulfate are the predominant quercetin conjugates in human plasma [76-78].

IP
In any case, factors regulating absorption, metabolism and elimination are important mediators of its bioavailability.

R
Typically, the human quercetin plasma concentration is in the order of nanomolar, but upon quercetin

SC
supplementation it may increase in between the high nanomolar and the low micromolar range [82, 83]. Generally,

depending on eating habits, average daily intake of quercetin could vary between 10 and 100 mg although high

NU
concentrations (>170 mg per 100 g) of quercetin are particularly found in capers and lovage leaves (Table 3; [207]).

Nevertheless, an ingested amount of 500-1000 mg per day can be easily achieved using selected nutraceuticals with
MA
highly purified quercetin extracts [84].
D

5.3. Quercetin absorption

TE

The site and the manner in which quercetin is absorbed depends upon its chemical structure. Studies using rat

models indicate that quercetin aglycone absorption occurs either in the stomach and at the small intestine level [85, 86].
P

Although the mechanisms explaining gastric absorption of quercetin aglycone remain unclear, in vitro studies support
CE

that human intestinal absorption of quercetin aglycone occurs primarily by passive diffusion and secondarily by organic

anion transporting polypeptide (OATP) [87]. By contrast, quercetin aglycone and glycosylated forms of quercetin
AC

(quercetin glucoside, quercetin rutinoside) are not absorbed in the stomach [85]. However, prior to absorption at the

small intestine, specifically quercetin glycosides (i.e. quercetin glucosides, quercetin galactoside, quercetin

arabinoside) are deglycosylated to quercetin aglycone [88] by the lactase phlorizin hydrolase (LPH), a β-glucosidase

residing in the brush border [89]. Thus, only the quercetin aglycone is subsequently passively absorbed [90].

Fascinatingly, quercetin rutinoside is absorbed in the colon following deglycosylation [91] which seems to be mediated

by gut microbiota-derived β-glucosidase [92] that generates quercetin aglycone facilitating its colonic absorption [60].

In this regard, a study in an in vitro model showed that 60% of quercetin rutinoside were degraded to 3,4-

dihydroxyphenylacetic acid within 2 h by the colonic microbiota [93], suggesting that most quercetin rutinoside is

initially deglycosylated to quercetin aglycone prior to degradation to 3,4-dihydroxyphenylacetic acid. Anyway, further

studies are required to better determine the possible health benefits of quercetin metabolites [74] and than the influence

of gut microbiota composition on their formation.

12
 ACCEPTED MANUSCRIPT

5.4. Quercetin biotransformation

Being a xenobiotic quercetin biotransformation occurs through the classical xenobiotic metabolism pathway

[94]. In general, xenobiotic metabolism consists of three phases: phase I modification, phase II conjugation and phase

III elimination [95]. Phase I metabolism of quercetin has not been described, but it is said to be structurally similar to

T
IP
the flavone apigenin [96]. Phase II conjugation of quercetin at the small intestine involves glucuronidation, sulfation

and methylation, as evidenced by the appearance of glucuronidated, sulfated and methylated metabolites of quercetin

R
following incubation of quercetin aglycone with human small intestinal microsomes [97]. Therefore, numerous phase II

SC
metabolites arise from quercetin including quercetin monoglucuronide, quercetin diglucuronide, quercetin sulfate,

quercetin monoglucuronide sulfate and methylated quercetin monoglucuronide sulphate [14, 98]. Other metabolites

NU
include isorhamnetin and tamarixetin which are methylated forms of quercetin. Phase II metabolites of quercetin are

secreted into the portal and lymph circulation, with evidence that most quercetin in the portal vein plasma or lymph
MA
appears as conjugated quercetin being quercetin aglycone below the detection limit [88, 99]. Phase III efflux of phase

II metabolites of quercetin also occurs in the small intestine. Studies in a rat model showed that glucuronides and
D

sulfates of quercetin, isorhamnetin and tamarixetin appear in the effluent collected from the intestinal lumen [86].
TE

Intestinal efflux of quercetin metabolites is likely mediated through breast cancer resistance protein 1 (BCRP1) and

multidrug resistance associated-protein 2 (MRP2), the phase III transporters occur on the apical side of enterocytes
P

[100, 101]. On the other hand, phase II metabolites of quercetin secreted from the small intestine reach the liver via the
CE

portal vein [88]. Hepatocyte uptake of quercetin metabolites involves passive diffusion as well as organic anion

transporters (OAT) and/or anion transporting polypeptide (OATP)-mediated transport [102]. Following hepatic uptake,
AC

quercetin metabolites are further metabolized by phase II conjugating enzymes. However, quercetin metabolites formed

in the liver either enter the circulation or are directed to biliary excretion [88], with the latter likely occurring in a

MRP2-dependent manner [103]. Additionally, renal phase II metabolism of quercetin may also take place, but no

reports currently exist to directly support renal phase II metabolism of quercetin.

5.5. Degradation and disposition of quercetin

Ingested quercetin is rapidly eliminated via feces and urine [104]. The profile of metabolites excreted via feces

and urine, while also comprised of glucuronide and sulfate conjugates, appears to differ significantly from those found

in the plasma. However, many of the major urinary components, including quercetin-3’-glucuronide, two quercetin

glucoside sulphates, and a methylquercetin diglucuronide, are either absent or present only in trace amounts in the

bloodstream, for that after they arrive in the blood quercetin metabolites probably undergo a further phase II

metabolism [105, 106]. The fecal recovery appears to be in the range of 1.6-4.6 percent of an oral dose. In one study,

13
 ACCEPTED MANUSCRIPT
the majority of the quercetin that was unaccounted for in urinary and fecal excretion was recovered as exhaled carbon

dioxide (CO2), suggesting that a high amount of absorbed quercetin is extensively metabolized and eventually

eliminated by the lungs [71]. However, and in particular, most quercetin-derived metabolites are identified as 3-

hydroxyphenylacetic acid, benzoic acid and hippuric acid [104], suggesting that phase II metabolites of quercetin are

deconjugated to quercetin aglycone prior to ring fission to yield phenolic acids. The mechanism by which conjugated

T
IP
metabolites of quercetin are degraded in vivo is not well defined, but it should be considered that both the colonic

microflora and kidneys express β-glucuronidase activity [93, 107], supporting deglucuronidation of quercetin

R
glucuronides prior to degradation of quercetin aglycone to phenolic acids, and their subsequent elimination.

SC
6. THERAPEUTIC APPLICATIONS OF QUERCETIN

NU
6.1. Clinical trials

Since the first Phase I clinical trial in which, following a tyrosine kinase inhibition, an evidence of antitumor
MA
activity was seen [108], several very recent randomized, double-blind, placebo-controlled, crossover trials have been

performed with quercetin demonstrating that: a) quercetin supplementation reduced systolic blood pressure
D

significantly but had no effect on other cardiovascular risk factors and inflammatory biomarker [109]; b) quercetin (3-
TE

glucoside) supplementation had no effect on flow-mediated dilation, insulin resistance, or other CVD risk factors [110];

c) quercetin may contribute to the cardioprotective effects of tea possibly by improving endothelial function and
P

reducing inflammation [111]; d) no significant therapeutic effect can be considered for quercetin in treatment of oral
CE

Lichen planus [112].

Nevertheless, in addition to the above mentioned clinical trials, quercetin as such or as a derivative has been
AC

tried and applied for many different specific multifaceted therapeutic applications of which the most prominent will

now be reported.

6.2. Aging

The biological processes responsible of ageing can be positively counteracted by few environmental factors,

such as natural antioxidants. In this context vitamin E [113], kinetin [114], carnosine [115] and garlic [116] are only

few examples of natural sources that have been shown to exert a noticeable pro-longevity effect on human primary

cultures. Passed on the antioxidant properties of quercetin and the association between ageing and oxidative stress

[117], Chondrogianni et al. [118] investigating the role of quercetin established a positive influence on survival,

viability, and lifespan of primary human fibroblasts (HFL-1); moreover, when senescent fibroblasts were grown in the

presence of quercetin, a rejuvenating effect was observed.

14
 ACCEPTED MANUSCRIPT
Attractively, other authors [119] report that quercetin, considered a senolytic agent, is positively effective also

against senescent human endothelial cells likely showing a special promise in eliminating senescent cells as already

reported [120, 121].

6.3. Allergy

T
IP
Like histamine and most cyclin-dependent kinases quercetin inhibits the in vitro growth of certain malignant

cells and also displays unique anti-cancer properties, moreover quercetin is a natural compound that blocks substances

R
involved in allergies and is able to act as an inhibitor of mast cell secretion, causing a decrease in the release of tryptase,

SC
MCP-1 and IL-6 and the down-regulation of histidine decarboxylase (HDC) mRNA from few mast cell lines [122].

As other flavonoids polyphenolic compounds that exert many anti-inflammatory and anti-microbial effects,

NU
and exhibit an anti-allergic action, quercetin has been recently shown as a potential drug against allergy; thus, quercetin

appears to possess the same potential of Food Allergy Herbal Formula (FAHF) as a safe anti-allergic substance but it
MA
opens only a wide perspective, at the moment, due to several complex issues that hamper the possibility to use natural

medicine and phytochemicals as a true drug [123].

D
TE

6.4. Angioprotective Properties

Considerable attention has been directed to quercetin also as a promising compound to be dispensed for heart
P

disease, prevention, and therapy; in fact, it has been linked to decreased mortality from heart disease and decreased
CE

incidence of stroke. In this regard, Pashevin et al. [124] report new data from which the angioprotective properties of

quercetin seem to be mediated by its effects on proteasomal proteolysis. In particular, by using rabbits with cholesterol-
AC

induced atherosclerosis the study investigated the ability of quercetin to modulate proteasomal activity. First, following

an 8 week cholesterol-rich diet, results indicated that the proteasomal trypsin-like (TL) activity increased up to 2.4-fold,

whereas chymotrypsin-like (CTL) activity and peptidyl-glutamyl peptide-hydrolyzing (PGPH) activity increased by

43% and up to 10%, respectively. A remarkable decrease of proteasomal TL activity (1.85-fold in monocytes), and a

decrease of both the CTL and PGPH activities (more than 2-fold in polymorphonuclear leukocytes) were observed

after 2 h following a single intravenous injection of the water-soluble form of quercetin (Corvitin). Furthermore, after a

cholesterol-rich diet the prolonged administration (1 month) of Corvitin significantly decreased all types of proteolytic

proteasome activities both in tissues and in circulating leukocytes, additionally a reduction of atherosclerotic lesions in

the aorta was detected.

Unfortunately, besides their antioxidant effect, flavonols like quercetin interfere with a great bit of biochemical

signaling pathways and therefore with many physio- pathological processes. However, there are strong evidences that

quercetin as well as related flavonols exert in vitro protective effects on nitric oxide and endothelial function under

15
 ACCEPTED MANUSCRIPT
oxidative stress, endothelium-independent vasodilator and platelet anti-aggregant effects, inhibition of LDL oxidation,

reduction of adhesion molecules and other inflammatory markers, prevention of neuronal oxidative and inflammatory

damage [125]. Nevertheless, all these effects could be primarily due to quercetin metabolites which in general protect

the endothelium from LDL oxidation.

Furthermore, as meta-analysis studies of epidemiological studies report, quercetin produces undisputed anti-

T
IP
hypertensive and anti-atherogenic effects, preventing endothelial dysfunction and protecting the myocardium from

ischemic damage [125]. Quercetin had no clear effects on serum lipid profile and on insulin resistance, but although

R
there is no solid proof yet a substantial body of evidence suggests that quercetin may prevent the most common forms

SC
of cardiovascular disease contributing to the protective effects afforded by fruits and vegetables. Worthwhile, recent

work using hypertensive animals and humans (> 140 mm Hg systolic and > 90 mm Hg diastolic) indicates a reduction

NU
in blood pressure after quercetin supplementation [126].

Noteworthy, two very recent studies demonstrate further evidence backing up the point of view that quercetin
MA
should be regarded a possible healing agent against cardiovascular diseases [127, 128]. In particular, Hung et al. [128]

findings provide new insight regarding the possible molecular mechanisms of quercetin; in fact quercetin seems to
D

suppress oxLDL-induced endothelial oxidative injuries by activating SIRT1 and by modulating the AMPK/NADPH
TE

oxidase/AKT/eNOS signaling pathway.

P

6.5. Anti-Cancer
CE

As found for many other flavonoids, a number of reports have assessed the pro-apoptotic activity of quercetin

in cancer cells; in fact, quercetin is a forthright inhibitor of PI3K, NF-B, and other kinases involved in intracellular
AC

signaling [129]. Nevertheless, although mitochondria seem to be targeted by quercetin inducing apoptosis and the

cancer cell death in vitro [130] until nowadays a reliable quercetin intracellular target has not yet been found; of course,

the challenge is to identify an eligible target in order to better define possible natural compounds to be added in food

extracts or pharmaceuticals.

Certainly, the antioxidative effects as well as the kinase and cell cycle inhibition, and the induced apoptosis are

all essential for the anti-cancer properties shown by quercetin. In particular, the different interactions and activities of

quercetin that fine tunes the phosphorylation state of molecules as well as the gene expression would act upon the

intracellular signaling equilibrium, either inhibiting or reinforcing survival signals. Anyhow, these mechanisms, which

have been mainly observed in in vitro studies, cannot easily explain the anti-cancer effects observed in vivo because of

the relatively low quercetin bioavailability in plasma and also because the nature of the actual active molecules is not

clearly known [131]. Thus, to partly explain the molecular effect of quercetin on cancer cells, among the different

16
 ACCEPTED MANUSCRIPT
substrates suspected to be triggered by quercetin a study reports the capability of quercetin to inhibit some protein

kinases involved in deregulating the cell growth in cancer cells [132].

Furthermore, quercetin can exert its anti-cancer effect also inhibiting the mTOR activity by multiple pathways

[133]. On the other hand, in ascite cells of lymphoma-bearing mice, it is suggested that the cancer preventive activity of

quercetin is accomplished via the induction of apoptosis and modulation of the PKC signaling which brings to the

T
IP
reduction of oxidative stress [134].

It has been proven that the most effective quercetin action is on blood, brain, lung, uterine, and salivary gland

R
cancer as good as upon melanoma with a cytotoxic activity much higher in the more aggressive cells than in the slow

SC
growing cells suggesting that the most harmful cells are the ones mainly targeted [135].

NU
6.6. Anti-Inflammatory

What is nowadays known is that quercetin inhibits the in vitro production of enzymes usually induced by
MA
inflammation (i.e. cyclooxygenase [COX] and lipoxygenase [LOX]) [136, 137]; however, also in vivo experiments

substantiate the anti-inflammatory effect. In particular, as already reported [138] quercetin significantly inhibits pro-
D

inflammatory cytokines in cultured fibroblasts from Graves' orbitopathy (GO). This study investigated the inhibitory
TE

effect of quercetin on inflammation in cultured whole orbital tissue. Therefore, inhibition of pro-inflammatory

cytokines by the natural product quercetin in both primary orbital fibroblasts and tissue culture could provide the
P

foundation for its potential use as an anti-inflammatory agent in the treatment of GO.
CE

However, the mechanisms behind the anti-inflammatory properties of quercetin are poorly understood.

Certainly, in inflammation, nitric oxide (NO) acts as a pro-inflammatory mediator and is synthesized by the inducible
AC

nitric oxide synthase (iNOS) in response to pro-inflammatory compounds such as lipopolysaccharide (LPS). As

described elsewhere [139] pretreatment of H9c2 cardiomyoblasts with quercetin inhibited LPS-induced iNOS

expression and NO production and counteracted oxidative stress induced by the unregulated NO production that

normally contributes to the generation of peroxynitrite and other reactive nitrogen species. In addition, quercetin

pretreatment remarkably counteracted apoptosis cell death as measured by immunoblotting of the cleaved caspase 3 and

caspase 3 activity. Besides the induction of apoptosis, quercetin inhibited the phosphorylation (LPS-induced) of two

kinases such as the stress-activated protein kinases (JNK/SAPK) and the p38 MAP kinase, enzymes that are involved

in the inhibition of cell growth.

In closing, these outcomes indicate that quercetin might serve as a valuable protective agent at least in

cardiovascular inflammatory diseases. Interestingly, since at nanomolar doses quercetin has shown a biphasic behavior

in basophils a beneficial action on cells involved in allergic inflammation could be hypothesized [140].

17
 ACCEPTED MANUSCRIPT
6.7. Anti-Obesity

As aforementioned quercetin is the most abundant flavonoid and it is thought to have protective functions

against the pathogenesis of multiple diseases associated with oxidative stress. In this setting, a peculiar study upon 3T3-

L1 cells investigated the molecular mechanisms through which quercetin could influence adipogenesis and apoptosis

[141]. The exposure of 3T3-L1 preadipocytes to quercetin resulted in decreased expression of adipogenesis-related

T
IP
factors and enzymes and then attenuated adipogenesis. Moreover, the levels of phosphorylated adenosine

monophosphate-activated protein kinase (AMPK) and one of its substrates, namely acetyl-CoA carboxylase (ACC),

R
were up-regulated in the presence of quercetin; in the same time apoptosis was induced and a concomitant decrease in

SC
ERK and JNK phosphorylation was observed. Put together, these data indicate that quercetin could exert its anti-

adipogenesis activity by activating the AMPK signal pathway, whereas the quercetin-induced apoptosis of mature

NU
adipocytes seems to be mediated by the fine tuning of the ERK and JNK pathways which play crucial roles during

apoptosis.
MA
On the other hand, to ascertain the molecular mechanisms influenced by quercetin on the physiological effects

of hyperlipidemia, some authors found that quercetin regulates the hepatic gene expression related to lipid metabolism
D

[142]. In particular, quercetin supplementation in mice significantly diminished the high-fat diet (HFD) -induced
TE

obesity, reducing the weight of the body, liver, and white adipose tissue compared with the mice fed only with HFD. It

also deeply reduced the HFD-induced increments in serum lipids, including cholesterol, triglyceride, and thiobarbituric
P

acid-reactive substance (TBARS). Consistent with the reduced liver weight and white adipose tissue weight, hepatic
CE

lipid accumulation and the size of lipid droplets, pads in the epididymal fat were also reduced by quercetin

supplementation. To further investigate how quercetin might reduce obesity, lipid metabolism-related genes in the liver
AC

were also examined. In this case, relative to those in HFD control mice, the quercetin supplementation modified the

expression profiles of several lipid metabolism-related genes, including Fnta, Pon1, Pparg, Aldh1b1, Apoa4, Abcg5,

Gpam, Acaca, Cd36, Fdft1, and Fasn, The expression patterns of these genes observed by quantitative reverse

transcriptase-polymerase chain reaction were confirmed by immunoblot assays. Jointly, these results indicated that

quercetin prevents HFD-induced obesity in C57B1/6 mice, and its anti-obesity effects may be linked to the regulation of

lipogenesis at the level of transcription.

More lately, several valuable reviews have been published on the role of dietary phytochemicals in obesity,

quercetin included [143, 144]. Nevertheless, it is necessary to establish a clean differentiation between the anti-obesity

effects of quercetin when it is meted out as pure aglycone, from its putative functions, and when it is present in

polyphenolic extracts, as described in many works cited in the above mentioned last two reviews [143, 144].

18
 ACCEPTED MANUSCRIPT
6.8. Arthritis

In combination with other nutrients, quercetin might reduce symptoms of osteoarthritis (OA), but at the same

time it does not appear to be beneficial in rheumatoid arthritis (RA). In fact, as a study report [145], twenty patients

with rheumatoid arthritis daily received three capsules of quercetin (166 mg/capsule) plus vitamin C (133 mg/capsule),

-lipoic acid (300 mg/capsule), or placebo for four weeks allowing a two-week washout period before the next

T
IP
supplementation. After this period the serum concentrations of pro-inflammatory cytokines or C-reactive protein (CRP)

did not show considerable differences and disease scores severity did not differ among treatment periods. When

R
glucosamine, chondroitin, and quercetin glucoside were given for three months to 46 persons with OA and 22 persons

SC
with RA, appreciable ameliorations in daily activities (walking and climbing up and down stairs), pain symptoms,

visual analogue scale, and synovial fluid properties were observed in OA subjects; conversely, no beneficial effects

NU
were noticed in RA subjects [146].
MA
6.9. Asthma

Point of interest, human epidemiological researches indicate an inverse association between intakes of
D

quercetin and asthma incidence [147]. Nevertheless, although human intervention studies investigating the effect of
TE

quercetin upon asthma and other atopic disease are currently missing, two written reports have looked into the effects

of an enzymatically-modified isoquercitrin (a quercetin glycoside) on allergic symptoms [148, 149]. In this case,
P

starting four weeks prior to the onset of pollen release, subjects took 100-200 mg/day of isoquercitrin or a placebo for
CE

eight weeks. Results proved that this specific quercetin glycoside enzymatically-modified provided a statistically

relevant relief of ocular symptoms, but no statistically significant relief of nasal symptoms caused by pollen.
AC

6.10. Diabetes

Quite recently, in an animal model with type 2 diabetes mellitus the hypoglycemic, hypolipidemic, and

antioxidant effects of dietary quercetin have been investigated. In this study [150] to C57BL/KsJ-db/db mice (n = 18)

were offered an AIN-93G diet or a diet containing quercetin at 0.04% (low quercetin, LQE) or 0.08% of the diet (high

quercetin, HQE) for 6 weeks after 1 week of adaptation. Plasma glucose, insulin, adiponectin, lipid profiles, and lipid

peroxidation of the liver were determined. At the end of the experiment, glucose plasma levels were markedly lower in

the LQE group than in the control group, and those in the HQE group were even further reduced than the LQE group.

Lower values were found for both LQE and HQE groups than in the control group with no changes in insulin levels by

considering the homeostasis model assessment of insulin resistance (HOMA-IR). Furthermore, compared with the

control group, 0.08% of dispensed quercetin increased plasma adiponectin, decreased plasma total cholesterol and

increased HDL-cholesterol. Nevertheless, plasma triacylglycerols in both the LQE and HQE groups were lower than

19
 ACCEPTED MANUSCRIPT
those in the control group. Moreover, either low and high quercetin reduced thiobarbituric acid reactive substances

(TBARS) levels incremented the activity of specific liver enzymes deeply involved in detoxification processes from

ROS (reactive oxygen species) i.e. superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px).

Thus, quercetin could be efficient in improving hyperglycemia, dyslipidemia, and the antioxidant status in type 2

diabetes.

T
IP
On the other hand, one of the primary causes of end-stage renal disease is diabetic nephropathy (DN). Many

studies have pointed out that the transforming growth factor-β1 (TGF-β1) and the connective tissue growth factor

R
(CTGF) are both involved in the DN pathophysiological mechanisms. Since quercetin has been proposed to alleviate

SC
DN, researchers have investigated whether quercetin ameliorates the renal function likely affecting the expressions of

TGF-β1 and CTGF in streptozotocin (STZ)-induced diabetic Sprague-Dawley rats [151]. Rats were then subdivided in

NU
control group, diabetic group and quercetin therapy group. At the end of the 12th week, body weight, kidney

weight/body weight ratio, blood glucose, urine albumin excretion (UAE), serum creatinine (sCr), blood urea nitrogen
MA
(BUN), and creatinine clearance (Ccr) were measured. The expressions of TGF-β1 and CTGF in the kidneys were

determined by using real-time PCR and Western blot method. The study reports that diabetic rats showed conspicuous
D

increases in kidney weight/body weight ratio, blood glucose, UAE, sCr, BUN, and Ccr; whereas quercetin treatment
TE

improved these parameters except for blood glucose. The expressions of TGF-β1 and CTGF were higher in the diabetic

group than in the control group. However, the overexpression of both TGF-β1 and CTGF in the renal tissues of diabetic
P

rats were reduced following quercetin administration. These results clearly suggest that quercetin improved renal
CE

function in DN rats by inhibiting the overexpressions of TGF-β1 and CTGF in the kidney.

Moreover, aldose reductase, the enzyme that catalyzes the conversion of glucose to sorbitol, is particularly
AC

important in the eye and plays an essential role in the formation of diabetic cataracts. Thus, it has been demonstrated

that quercetin is an in vitro inhibitor of lens aldose reductase [152, 153] and effectively blocks polyol accumulation in

intact rat lenses immersed in a medium with a high sugar concentration [154]. In humans with diabetes type 1 or 2 and

diabetic neuropathy, a decrease in the severity of numbness, jolting pain, and irritation was reported, as well as an

improvement in quality-of-life measures with active treatment [155].

However, from the molecular basis point of view, it is reported that the antidiabetic action of quercetin is

fulfilled by stimulating glucose uptake through an insulin-independent mechanism involving adenosine

monophosphate-activated protein kinase (AMPK) whose activation in skeletal muscle leads to the glucose transporter

GLUT4 translocation to the plasma membrane; whereas, in liver, AMPK decreases glucose production mainly through

the downregulation of the key gluconeogenesis enzymes such as phosphoenolpyruvate carboxykinase (PEPCK) and

glucose -6-phosphatase (G6Pase) [156].

20
 ACCEPTED MANUSCRIPT
6.11. Exercise Performance

Besides studies that have investigated whether quercetin supplementation can prevent post-exercise immune

system changes and sensitivity to infections (discussed in the subsection below on “Immunity and Infections”), other

studies have sought to determine whether quercetin shows some ergogenic potential. Existing evidence seems to

support some ergogenic effect of quercetin in untrained people, but not in trained athletes.

T
IP
In this contest, eleven studies were identified and a total of 254 human subjects were engaged [157]. Across

all studies, before supplementation VO2max ranged from 41 to 64 mL·kg-1·min-1 (median = 46), whereas median

R
treatment duration was 11 d with a median dosage of 1000 mg·d-1. Effect sizes (ES) were computed as the standardized

SC
mean difference, and meta-analyses were done by using a random-effects model.

On average, quercetin provided a statistically noticeable benefit in human endurance exercise capacity

NU
(VO2max) and performance, but the effect was irrelevant or of a small magnitude, with ES = 0.15 equating roughly to a

3% improvement with quercetin over the placebo group. Unluckily, these studies designed to examine human
MA
performance following quercetin administration did not show the same level of efficacy as formerly observed in mice.

Experimental factors that explain the between-study variation have to be still elucidated.
D
TE

6.12. Gastroprotection

Some in vivo studies report a protective effect of quercetin against ethanol-induced gastric ulceration [158,
P

159] as well as against the oesophagitis reflux [160, 161]. In any case, it has been demonstrated that quercetin weakly
CE

inhibits the growth of Helicobacter pylori in vitro [162]. However, Helicobacter pylori-infected guinea pigs treated for

15 days with 200 mg/kg of quercetin exhibited a decreased bacterial infection in the gastric mucosa and also a reduced
AC

inflammatory response [163]. Worthy of interest, topical quercetin directly spread on minor mouth aphthous ulcers

three times daily relieved pain and produced a complete healing in 35% of subjects within 2-4 days, 90% of subjects

within 4-7 days, and 100% of subjects within 7-10 days 193 [164].

Nevertheless, although quercetin has been found to possess gastroprotective activity, whether it has a

protective activity against less related injury to gastric epithelial cells remains unknown. Anyhow, at least in human

gastric epithelial GES-1cells pretreated with quercetin and then challenged with H2O2 it has been observed: a) a

decrease of H2O2-induced cell viability loss; b) a reduction of intracellular reactive oxygen species and Ca 2+ influx; c)

upregulation of the peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) expression under the state of

oxidative stress; d) a significant decline of the downstream cell apoptosis, then there is a strong evidence that

quercetin can protect gastric epithelial GES-1 cells from oxidative damage and ameliorate reactive oxygen species

production during acute gastric mucosal injury [165].

21
 ACCEPTED MANUSCRIPT
6.13. Human Prostate Adenocarcinoma

Prostate cancer is a common male malignant disease and its incidence is increasing worldwide with an

incidence rate of new cases around 27% occupying the first place and the mortality rate of about 10% occupying the

second place only inferior to lung cancer among body sites where tumorigenesis may occur [156]. Concerning human

prostate adenocarcinoma, some authors evaluated the effects of quercetin on PC-3 cells [157]. Lactate dehydrogenase

T
IP
(LDH) release, microculture tetrazolium test (MTT assay) and real-time PCR array were employed to evaluate the

effects of quercetin on cell cytotoxicity, cell proliferation and expression of various genes. Results showed that

R
quercetin inhibited cell proliferation and modulated the expression of factors involved in DNA repair, matrix

SC
degradation and tumor spreading, cell cycle, programmed cell death, angiogenesis, and metabolism (i.e. glycolysis). No

cytotoxicity of quercetin on PC-3 cells was observed. These findings indicate that quercetin could be recommended as

NU
an effective anti-cancer agent to be used in the future nutritional transcriptomic studies and in multi-target therapy thus

to overcome the current therapeutic approaches against prostate cancer.

MA
Anyhow, previous findings demonstrated that quercetin treatment of prostate cancer cells caused a decreased

cell proliferation and viability [168]. In particular, it was shown that quercetin induced cancer cell apoptosis by down-
D

regulating the levels of heat shock protein (Hsp) 90 and this Hsp90 decrease was conceivable bound to the decreased
TE

cell viability, the apoptosis induction and the caspases activation in cancer cells but not in normal prostate epithelial

cells. Noteworthy, as indicated by annexin V staining knockdown of Hsp90 by short interfering RNA (siRNA)
P

originated the induction of apoptosis in a similar way like that of cancer cells quercetin-treated [168]. Another
CE

interesting study suggests that in the presence of quercetin the c-Jun protein might play an important role in the

androgen receptor (AR) suppression; in fact, the ternary protein complex (i.e. c-Jun/Sp1/AR) induced by quercetin
AC

represents a peculiar mechanism that in prostate cancer cells could be involved in down-regulation of the AR function

[169].

Remarkably, it has been lately established that the combination of quercetin and 2-methoxyestradiol can serve

as a novel clinical treatment regiment owning the potential of enhancing antitumor effect on prostate cancer in vivo and

lessening the dose and side effects of either quercetin or 2-methoxyestradiol [170]; these in vivo results will lay a further

solid basis for subsequent researches on this novel therapeutic regimen in human prostate cancer.

However, a complete list of mechanisms of the in vitro and in vivo effects of quercetin on prostate cancer is

elsewhere summarized [171].

6.14. Immunity and Infections

As elsewhere reported quercetin exhibits an in vitro antiviral activity against HIV as well as against other

retroviruses [172, 173]; moreover, as above mentioned it also shows in vitro and in vivo antibacterial activity against

22
 ACCEPTED MANUSCRIPT
Helicobacter pylori [162, 163]. Despite positive results obtained both in vitro and in vivo from animal studies, evidence

in human beings is mixed as to whether chronic quercetin supplementation has plausible positive effects on the

immune system. Usually, quercetin (100 mg/day) does not alter exercise-induced changes in several components

belonging to the immune system [174] and no differences are found in the post-race illness rates between quercetin-

treated and placebo groups [175].

T
IP
In addition, the natural compounds epigallocatechin gallate (1) and quercetin (2) alone and in combination

have been recently tested as potential antimicrobial clinical therapies [176]. In this latter study authors report a strong

R
antimicrobial activity produced by 1 alone against methicillin-resistant Staphylococcus aureus, whereas the activity was

SC
significantly increased in the presence of 2. Furthermore, a synergistic interaction was observed between the two

compounds with a bactericidal effect over 24 h when the two compounds were administered in combination.

6.14. Mood Disorders NU

MA
Quercetin has shown anxiolytic- and antidepressant-like effects in animal experiments; anyway, no studies

have investigated whether quercetin has similar effects in humans. However, quercetin dose dependently increases
D

social interaction time decreasing immobility time; it also minimizes changes in the animal behavior, such as the swim
TE

test or forced immobilization, tests which are planned to cause anxiety and behavioral despair [177-179]. In diabetic rats

this effect was comparable to that of the antidepressants fluoxetine and imipramine [180]. Nonetheless, it is suggested
P

that the antidepressant effect of quercetin is dependent on the inhibition of the NMDA receptors and/or synthesis of
CE

nitric oxide, findings that contribute to the understanding of the mechanisms involved in the antidepressant effect of

quercetin and reinforce the involvement of the NMDA receptors and the nitric oxide on the pathophysiology of
AC

depression [181].

Quercetin also helps protect against changes in behavior caused by alcohol withdrawal [182]. Several possible

mechanisms might explain the ability of quercetin to improve mood. Thus, in vitro and in vivo evidences indicate that

quercetin can inhibit monoamine oxidase A [183], whereas in vivo experiments indicate that quercetin can decrease the

levels of the stress-induced brain corticotrophin releasing factor (CRF) which is associate to anxiety and depression

[178]. In addition, quercetin-treatment also reduces the stress-induced increases of both the plasma corticosterone and

the adrenocorticotropic hormone [184].

However, some latest studies report more information about the protection of quercetin against behavioral

deficiencies and memory impairment. Specifically, lead treated rats showing a marked behavioral impairment, when

treated with quercetin maintain their normal behavioral functions despite the increased oxidative stress; from a

molecular point of view this happens because quercetin seems to restore the normal morphology of the brain and the

expressions of Bak, Bcl-2 and Hsp-70 [185]. On the other hand cadmium (Cd) exposure is recognized to cause

23
 ACCEPTED MANUSCRIPT
impairment of memory and anxiogenic-like behavior. Thus, rats exposed to Cd (2.5mg/kg) and quercetin (5, 25 or

50mg/kg) by gavage for 45days, compared to rats exposed only to Cd (2.5mg/kg), did not show neither the reduction of

total thiols, reduced glutathione , and reductase glutathione activities nor the rise of glutathione S-transferase activity,

furthermore, the administration of quercetin prevented alterations in acetylcholinesterase and Na+,K+-ATPase activities,

consequently preventing anxiogenic-like behavior and memory impairment displayed by Cd exposure [186].

T
IP
7. DRUG INTERACTION

R
Quercetin exhibits an in vivo inhibitory effect both on CYP3A4 [187, 188] and CYP1A2 whereas it increases

SC
CYP2A6, xanthine oxidase, and N-acetyltransferase activity [189]. Quercetin in vivo inhibits also the P-glycoprotein

(Pgp), a drug efflux transporter that can play a pivotal role in the intestinal and biliary transport and elimination of

NU
many drugs and their metabolites [187, 188, 190, 191]. Due to these interactions, quercetin might alter the serum levels

of all drugs metabolized by these enzymes. However, although the daily administration of rutin (quercetin rutinoside)
MA
reduces the anticoagulant effect of racemic warfarin [192], reliable interactions between quercetin as such and

anticoagulants have not yet been investigated. Interactions between quercetin and different drugs have been however
D

studied especially because of its interaction with the CYP3A4 and the P-glycoprotein. In this regard, Fig. 8 shows the
TE

severity grade of known interactions between quercetin and different drugs. In most of the interactions reported in Fig.

8 quercetin decreases the level or the effect of the drug by P-glycoprotein (MDR1) efflux transporter; on the other hand,
P

particularly in the case of “Minor severity”, quercetin decreases the effect(s) of the drug by pharmacodynamic
CE

antagonism. As expected, drug-nutrient interaction might also be influenced by the quercetin dose. Thus, a study carried

out on pigs reported a lethal interaction between digoxin – a substrate of P-glycoprotein with very narrow therapeutic
AC

range – and quercetin; in fact, the co-administration of quercetin (50 mg/kg) and digoxin (0.02 mg/kg) resulted in the

sudden death of two out of the three pigs within 30 minutes of administration.

Surprisingly, although the co-administration with a lower dose of quercetin (40 mg/kg) powerfully elevated the

Cmax (maximum concentration) of digoxin by 413% it did not have lethal effects [191]. As can be imagined quercetin

might also alter the bioavailability of some dietary supplements; for example, it appears to improve the bioavailability

of epigallocatechin gallate [193] and possibly other flavonoids [194]. Finally, preliminary evidence indicates that

quercetin might have synergistic effects with some drugs [195] and might play a character in multi-drug resistance

[196].

24
 ACCEPTED MANUSCRIPT

T
R IP
SC
NU
Figure 8. Quercetin drug interaction severity. Adapted from [208].

8. TOXICITY
MA
Most in vivo animal studies certify that quercetin is not carcinogenic; anyway, based on the Ames test

quercetin is regarded as mutagenic. Interestingly, in 1999 the International Agency for Research on Cancer (IARC)
D

ascertained that quercetin should not be classified as carcinogenic to humans [42, 43, 197]. Although in vitro studies
TE

suggest that quercetin might have mild negative effects on embryo development [198], until nowadays there is no

definitive evidence regarding some teratogenic effects of quercetin on embryonic development. Intriguingly, prenatal
P

exposure to quercetin yielded a slight increase in the incidence of malignancies in mice offspring [199]. However, in
CE

human studies, quercetin has been mostly well tolerated. Doses up to 1,000 mg/day for several months did not produce

adverse effects on blood parameters, liver and kidney function, hematology, or serum electrolytes. On the other hand,
AC

the results of numerous genotoxicity and mutagenicity on short- and long-term animal as well as on human subjects

consistently demonstrated that the quercetin-related mutagenicity did not develop carcinogenicity in vivo; thus, in

general, the plentiful available evidences support the safety of quercetin for addition to food [6]. In fact, in the U.S. and

Europe supplements of quercetin are commercially purchasable subsequently the quercetin supplements beneficial

effects described in clinical trials [42].

Unfortunately, depending on the dose, quercetin as such or as its analogue. quercetin-3-O-glucoside has been

shown to inhibit topoisomerase II catalytic activity bringing to an extraordinarily high yields of metaphases showing

diplochromosomes [200-202], for that given the established relationship of polyploidy with tumor development via

aneuploidy and genetic instability, these results partly question the usefulness of quercetin.

Conversely, synthetic quercetin acylglycoside analogues (i.e. 3,7-diacylquercetin, quercetin 6-acylgalactoside,

and quercetin 2',6'-diacylgalactoside) have been shown to inhibit either DNA gyrase and topoisomerase IV [203].

25
 ACCEPTED MANUSCRIPT
Anyway, from a molecular point of view toxic effects of quercetin are most likely connected with the

formation of possible toxic products upon oxidation of quercetin during its ROS scavenging activities. As stated above,

the most important oxidation product of quercetin that is quercetin-quinone is highly thiol reactive and reacts almost

immediately with glutathione or in its absence with protein sulfhydryl groups, thereby damaging the function of several

crucial enzymes [8, 9, 40]. Consequently, during in vivo quercetin supplementation care should be needed of the

T
IP
possible toxicity of its metabolites; especially in a chronic disorder, when supplementation has to extend over a much

longer time period, the safety, tolerability and efficacy of (long term) quercetin supplementation remain to be

R
established [73].

SC
CONCLUSIONS

NU
The bioflavonoid quercetin has an extended spectrum of well characterized biological effects that include the

promotion of health, the enhancement of physical and mental activity, and several distinct pharmacological effects. Of
MA
course, bioavailability of quercetin is an important mediator of its health benefits and, for that, a better understanding of

the factors regulating quercetin metabolism and bioavailability is expected to confirm its potential role in managing
D

different diseases.
TE

Despite the plethora of studies on quercetin and its derivatives, it is not yet possible to establish dietary

recommendations with regard to the types and amounts to be consumed. The inherent diversity of its derivatives
P

analogous structure, chemistry, and natural distribution in foods lends itself to errors in reporting the types and/or
CE

amounts consumed, as well as incomplete recognition of requirements for intervention studies that aim to assess their

benefits in a clinical setting. Thus, in the face of the scientific progress made over the past decades, several critical
AC

issues in the design and reporting of studies continue to limit progress in leveraging quercetin research findings into

meaningful recommendations for consumers. These issues mainly include: 1) incomplete/inappropriate application of

analytic methods, making determination of food content and dietary intake levels challenging; 2) limited data and/or

description of test materials used in dietary intervention trials; 3) challenges with the application of appropriate methods

for assessment of relevant bioavailability and metabolite formation in biological tissues that can provide key insights

into food and clinical markers/outcomes.

In particular, as elsewhere already reported [204] high-priority areas suggested for research of quercetin should

include:

a) Large clinical trials to compare the efficacy of different doses of quercetin versus standard-of-care angiotensin

converting enzyme inhibitors for control of hypertension;

b) Investigation of the biologic activity of quercetin aglycone versus quercetin glycosides, versus quercetin metabolites;

26
 ACCEPTED MANUSCRIPT
c) Quercetin has multiple modes of action, but it is not known whether all of these actions are required for specific

biologic effects. For instance, does quercetin’s ability to inhibit cell proliferation work through multiple mechanisms,

similar to its effect on the cardiovascular system?

d) Large multi-institutional trial with a stringent protocol to resolve the disparate results of quercetin treatment on

exercise tolerance;

T
IP
e) The ability of quercetin to either sensitize cells to cancer chemotherapeutic agents or to counteract the resistance to

these drugs needs to be translated into animal studies using a variety of models. If results verify the findings observed

R
with tissue culture cells, then phase I/II clinical trials need to be carried on.

SC
However, in this review after reporting the main chemical features of quercetin and its metabolism, - when and

where possible – pointing out the molecular, cellular, and functional bases of therapy, data appearing in the peer-

NU
reviewed literature and focusing on the main therapeutic applications of quercetin are summarized. In particular, since

the quercetin therapeutic applications are very spread out (Fig. 9), in the present review only the ones established by
MA
scientific researchers have been taken into account.
D
P TE
CE
AC

Figure 9. Quercetin prominent therapeutic applications. Thick arrows: most suggested uses in humans; thin arrows:
uses mainly derived from animal studies. Partly adapted from [209].

Nonetheless, it is worth mentioning that many of these therapeutic applications require safety and quite often

for most of them effectiveness has not been rigorously proven. Furthermore, some of these ill conditions are potentially

grave and should be treated by a qualified healthcare staff.

Due to all these features, the question mark which ends the title of the present review is justified because it

underlines a key issue; in fact, although for several of the above mentioned therapeutic treatments there is some a strong

evidence in humans and as a consequence a suggested use of quercetin, in most cases results derive from in vitro studies

and/or from other animal species. On the other hand, scientific evidences for these specific treatments are sometimes

good and well supported, but in other cases they are quite unclear, whereas for all other uses there are only unclear

results. For that, since numerous studies herein described and regarding the therapeutic applications of quercetin have

27
 ACCEPTED MANUSCRIPT
been performed either in vitro, by using cell cultures, and in vivo utilizing animal models, additional data are warranted

to better assess the quercetin antioxidant activity and biological properties in human beings. Thus, it is hoped that in the

near future well designed clinical studies in healthy individuals as well as in patients will be carried out to confirm the

aforementioned beneficial quercetin effects, setting the optimal doses and forms of delivery, comparing quercetin with

established procedures and assessing the possible side effects most of which are probably due to quercetin drug

T
IP
interaction.

R
SC
CONFLICT OF INTEREST

The author declares that there are no conflicts of interest.

NU
MA
ACKNOWLEDGEMENTS

Financial support from MIUR (Ministero dell’Istruzione, Università e Ricerca), Rome, Italy, is gratefully
D

acknowledged. Susan Edwards deserves sincere thanks for her considerable skill in helping to edit the manuscript.
P TE
CE
AC

28
 ACCEPTED MANUSCRIPT
REFERENCES

[1] Hertog, M.G.; Hollman, P.C.; Katan, M.B.; Kromhout, D. Intake of potentially anticarcinogenic flavonoids and their

determinants in adults in The Netherlands. Nutr. Cancer, 1993, 20, 21-29.

[2] Formica, J.V.; Regelson, W. Review of the biology of quercetin and related bioflavonoids. Food Chem. Toxicol.,

T
IP
1995, 33, 1061-1080.

[3] Beecher, G.R.; Warden, B.A.; Merken, H. Analysis of tea polyphenols. Proc. Soc. Exp. Biol. Med., 1999, 220, 267-

R
270.

SC
[4] Linseisen, J.; Radtke, J.; Wolfram, G. Flavonoidzufuhr erwachsener in einem bayrischen teilkollektiv der nationalen

verzehrsstudie. Z. Ernahrungswiss, 1997, 36, 403-412.

NU
[5] Böhm, H.; Boeing, H.; Hempel, J.; Raab, B.; Kroke, A. Flavonols, flavone and anthocyanins as natural antioxidants

of food and their possible role in the prevention of chronic diseases. Z. Ernahrungswiss, 1998, 37, 147-163.
MA
[6] Harwood, M.; Danielewska-Nikiel, B.; Borzelleca, J.F.; Flamm, G.W.; Williams, G.M.; Lines, T.C. A critical

review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of
D

genotoxic/carcinogenic properties. Food Chem. Toxicol., 2007, 45, 2179-2205.

TE

[7] Bors, W.; Michel, C.; Saran, M. Flavonoid antioxidants: rate constants for reactions with oxygen radicals. Methods

Enzymol., 1994, 234, 420-429.

P

[8] Galati, G.; Moridani, M.Y.; Chan, T.S.; O'Brien, P.J. Peroxidative metabolism of apigenin and naringenin versus
CE

luteolin and quercetin: glutathione oxidation and conjugation. Free Radic. Biol. Med., 2001, 30, 370-382.

[9] Awad, H.M.; Boersma, M.G.; Boeren, S.; van Bladeren, P.J.; Vervoort, J.; Rietjens, I.M. The regioselectivity of
AC

glutathione adduct formation withflavonoid quinone/quinone methides is pH-dependent. Chem. Res. Toxicol.,

2002, 15, 343-351.

[10] Vrijsen, R.; Michotte, Y.; Boeye, A. Metabolic activation of quercetin mutagenicity. Mutat. Res., 1990, 232, 243-

248.

[11] Jurado, J.; Alejandre-Duran, E.; Alonso-Moraga, A.; Pueyo, C.. Study on the mutagenic activity of 13

bioflavonoids with the Salmonella Ara test. Mutagenesis, 1991, 6, 289-295.

[12] Rueff, J.; Gaspar, J.; Laires, A. Structural requirements for mutagenicity of flavonoids upon nitrosation. A

structure-activity study. Mutagenesis, 1995, 10, 325-328.

[13] Silva, I.D.; Gaspar, J.; da Costa, G.G.; Rodrigues, A.S.; Laires, A.; Rueff, J. Chemical features offlavonols

affecting their genotoxicity. Potential implications in their use as therapeutical agents. Chem. Biol. Interact.,

2000, 124, 29-51.

29
 ACCEPTED MANUSCRIPT
[14] de Boer, V.C.; Dihal, A.A.; van der Woude, H.; Arts, I.C.; Wolffram, S.; Alink, G.M.; Rietjens, I.M.; Keijer, J.;

Hollman, P.C. Tissue distribution of quercetin in rats and pigs. J. Nutr., 2005, 135, 1718-1725.

[15] Chen, X.; Yin, O.Q.; Zuo, Z.; Chow, M.S. Pharmacokinetics and modeling of quercetin and metabolites.

Pharmaceut. Res., 2005, 22, 892-901.

[16] Graefe, E.U.; Wittig. J.; Mueller, S.; Riethling, A.K.; Uehleke, B.; Drewelow, B.; Pforte, H.; Jacobasch, G.;

T
IP
Derendorf, H.; Veit, M. Pharmacokinetics and bioavailability of quercetin glycosides in humans. J. Clin.

Pharmacol., 2001, 41, 492-499.

R
[17] Kawabata, K.; Mukai, R.; Ishisaka, A. Quercetin and related polyphenols: new insights and implications for their

SC
bioactivity and bioavailability. Food Funct., 2015, 6, 1399-1417.

[18] Fischer, C.; Speth, V.; Fleig-Eberenz, S.; Neuhaus, G. Induction of zygotic polyembryos in wheat: influence of

NU
auxin polar transport. Plant Cell, 1997, 9, 1767–1780.

[19] Shiro, M. Research for vitamin P. J. Biochem., 1938, 29, 487-501

MA
[20] de Souza, R.F.; De Giovani, W.F. Antioxidant properties of complexes of flavonoids with metal ions. Redox Rep.,

2004, 9, 97-104.
D

[21] Heijnen, C.G.; Haenen, G.R.M.M.; Oostveen, R.M.; Stalpers, E.M.; Bast, A. Protection of flavonoids against lipid
TE

peroxidation: the structure activity relationship revisited. Free Radic. Res., 2002, 36, 575-581.

[22] Hanasaki, Y.; Ogawa, S.; Fukui, S. The correlation between active oxygens scavenging and antioxidative effects of
P

flavonoids. Free Radic. Biol. Med., 1994, 16, 845-850.

CE

[23] Cushnie, T.P.; Lamb, A.J. Antimicrobial activity of flavonoids. Int. J. Antimicrob. Agents, 2005, 26, 343-356.

[24] van Acker, S.A.; Tromp, M.N.; Haenen, G.R.M.M.; van der Vijgh, W.J.; Bast, A. Flavonoids as scavengers of
AC

nitric oxide radical. Biochem. Biophys. Res. Commun., 1995, 214, 755-759.

[25] Haenen, G.R.M.M.; Bast, A. Nitric oxide radical scavenging of flavonoids. Methods Enzymol., 1999, 301, 490-

503.

[26] Haenen, G.R.M.M.; Paquay, J.B.; Korthouwer, R.E.; Bast, A. Peroxynitrite scavenging byflavonoids. Biochem.

Biophys. Res. Commun., 1997, 236, 591-593.

[27] Heijnen, C.G.; Haenen, G.R.M.M.; van Acker, F.A.; van der Vijgh, W.J.; Bast, A. Flavonoids as peroxynitrite

scavengers: the role of the hydroxyl groups. Toxicol. in Vitro, 2001, 15, 3-6.

[28] Hollman, P.C.H.; Katan, M.B. Absorption, metabolism and health effects of dietary flavonoids in man. Biomed.

Pharmacother., 1997, 51, 305-310.

[29] Sakanashi, Y.; Oyama, K.; Matsui, H.; Oyama, T.B.; Oyama, T.M.; Nishimura, Y.; Sakai, H.; Oyama, Y. Possible

use of quercetin, an antioxidant, for protection of cells suffering from overload of intracellular Ca 2+: a model

experiment. Life Sci., 2008, 83, 164-169.

30
 ACCEPTED MANUSCRIPT
[30] Kahl, R.; Hildebrandt, A.G. Methodology for studying antioxidant activity and mechanisms of action of

antioxidants. Food Chem. Toxicol., 1986, 24, 1007-1014.

[31] Balazs, L.; Leon, M. Evidence of an oxidative challenge in the Alzheimer's brain. Neurochem. Res., 1994, 19,

1131-1137.

[32] Ansari, M.A.; Hafiz, M.A.; Joshi, G.; Opii, W.O. ; Butterfield, D.A. Protective effect of quercetin in primary

T
IP
neurons against Aβ (1-42): relevance to Alzheimer's disease. J. Nutr. Biochem., 2009, 20, 269-275.

[33] Shoskes, D.A.; Zeitlin, S.I. Shahed, A.; Rajfer J. Quercetin in men with category III chronic prostatitis: a

R
preliminary prospective, double blinded, placebo controlled trial. Urology, 1999, 54, 960-963.

SC
[34] Begum, A.N.; Terao, J. Protective effect of quercetin against cigarette tar extract induced impairment of

erythrocyte deformability. J. Nutr. Biochem., 2002, 13, 265-272.

NU
[35] McAnulty, S.R.;,McAnulty, L.S.; Nieman, D.C.; Quindry, J.C.; Hosick, P.A.; Hudson, M.H.; Still, L.; Henson,

D.A.; Milne, G.L.; Morrow, J.D.; Dumke, C.L.; Utter, A.C.; Triplett, N.T. Chronic quercetin ingestion and
MA
exercise-induced oxidative damage and inflammation. Appl. Physiol. Nutr. Metab., 2008, 33, 254-262.

[36] Arts, M.J.T.J.; Dallinga, J.S.; Voss, H.P., Haenen, G.R.M.M.; Bast, A. A new approach to assess the total
D

antioxidant capacity using the TEAC assay. Food Chem., 2004, 88, 567-570.
TE

[37] Nabavi , S.M; Nabavi, S.F.; Eslami, S.; Moghaddam, A.H. In vivo protective effects of quercetin against sodium

fluoride-induced oxidative stress in the hepatic tissue. Food Chem., 2012, 132, 931-935.
P

[38] Nabavi, S.M.; Nabavi, S,F,; Habtemariam, S.; Moghaddam, A.H.; Latifi, A.M. Ameliorative effects of quercetin
CE

on sodium fluoride-induced oxidative stress in rat's kidney. Ren. Fail., 2012, 34, 901-906.

[39] Nabavi, S.F.; Nabavi, S.M.; Mirzaei, M.; Moghaddam, A.H. Protective effect of quercetin against sodium fluoride
AC

induced oxidative stress in rat's heart. Food Funct., 2012, 3, 437-441.

[40] Boots, A.W.; Li, H.; Schins, R.P.F.; Duffin, R.; Heemskerk, J.W.M.; Bast, A.; Haenen, G.R.M.M. The quercetin

paradox. FEBS Lett., 2007, 222, 89-96.

[41] Ames, B.N.; Lee, F.D.; Durston, W.E. An improved bacterial test system for the detection and classification of

mutagens and carcinogens. Proc. Natl. Acad. Sci. USA, 1973, 70, 782-786.

[42] Okamoto, T. Safety of quercetin for clinical application (Review). Int. J. Mol. Med., 2005, 16, 275-278.

[43] Utesch, D.; Feige, K.; Dasenbrock, J.; Broschard, T.H.; Harwood, M.; Danielewska-Nikiel, B.; Lines, T.C.

Evaluation of the potential in vivo genotoxicity of quercetin. Mutat. Res., 2008, 654, 38-44.

[44] Bast, A.; Haenen, G.R.M.M.. The toxicity of antioxidants and their metabolites. Environ. Toxicol. Pharmacol.,

2002, 11, 251-258.

[45] Hollman, P.C.; Katan, M.B. Dietary flavonoids: intake, health effects and bioavailability. Food Chem. Toxicol.,

1999, 37, 937-942.

31
 ACCEPTED MANUSCRIPT
[46] Skibola, C.F.; Smith, M.T. Potential health impacts of excessive flavonoid intake. Free Radic. Biol. Med., 2000,

29, 375-383.

[47] Boots, A.W.; Haenen, G.R.M.M.; den Hartog, G.J.; Bast, A. Oxidative damage shifts from lipid peroxidation to

thiol arylation by catechol-containing antioxidants. Biochim. Biophys. Acta, 2002, 1583, 279-284.

[48] Boots, A.W.; Kubben, N.; Haenen, G.R.M.M.; Bast, A. Oxidized quercetin reacts with thiols rather than with

T
IP
ascorbate: implication for quercetin supplementation. Biochem. Biophys. Res. Commun., 2003, 308, 560-565.

[49] Mendoza, E.E.; Burd, R. Quercetin as a systemic chemopreventative agent: structural and functional mechanisms.

R
Mini Rev. Med. Chem., 2011, 11, 1216-1221.

SC
[50] Brown, J.T. A review of the genetic effects of naturally occurring flavonoids, anthraquinones and related

compounds. Mutat. Res., 1980, 75, 243-277.

NU
[51] Mitchell, A.E.; Hong, Y.J.; Koh, E.; Barrett, D.M.; Bryant, D.E.; Denison, R.F.; Kaffka, S. Ten-year comparison of

the influence of organic and conventional crop management practices on the content of flavonoids in tomatoes. J.
MA
Agric. Food Chem., 2007, 55, 6154-6159.

[52] Day, A.J.; Williamson, G. Human metabolism of dietary quercetin glycosides. In: Plant Polyphenols 2: Chemistry,
D

Biology, Pharmacology, Ecology. In: Basic Life Sciences, Gross, G.G.; Hemingway, R.W.; Yoshida, T. (Eds.);
TE

Kluwer Academic/Plenum Publishers: New York, 1999; Vol. 66, pp. 415-434.

[53] Harnly, J.M.; Doherty, R.F.; Beecher, G.R.; Holden, J.M.; Haytowitz, D.B.; Bhagwat, S.; Gebhardt, S. Flavonoid
P

content of US fruits, vegetables, and nuts. J. Agric. Food. Chem., 2006, 54, 9966-9977.
CE

[54] Hertog, M.G.L.; Hollman, P.C.H.; van de Putte, B. Content of potentially anticarcinogenic flavonoids of tea

infusions, wines, and fruit juices. J. Agric. Food Chem., 1993, 41, 1242-1246.
AC

[55] Sampson, L.; Rimm, E.; Hollman, P.C.; de Vries, J.H.; Katan, M.B. Flavonol and flavone intakes in US health

professionals. J. Am. Diet. Assoc., 2002, 102, 1414-1420.

[56] Fang. N; Yu, S.; Mabry, T.J. Flavonoids from Ageratina calophylla. Phytochemistry, 1986, 25, 2684-2686.

[57] Zeng, L.-M.; Wang, C.-J.; Su, J.-Y.; Li, Du; Owen, N.L.; Lu, Y. Flavonoids from the red alga Acanthophora

spicifera. Chin. J. Chem., 2010; 19, 1097-1100.

[58] Del Santo, S.; Guzzo, F. The plasticity of the grapevine berry transcriptome. MetaboLights, 2013, 39.

[59] Kühnau, J. The flavonoids: A class of semi-essential food components: Their role in human nutrition. World Rev.

Nutr. Diet., 1976, 24, 117-191.

[60] Jones, E.; Hughes, R.E. Quercetin, flavonoids and the life-span of mice. Exp. Gerontol., 1982 17, 213-221.

[61] Rimm, E.C.; Katan, M.B.; Ascherio, A. Stampfer, M.J.; Willett, W.C. Relation between intake of flavonoids and

risk for coronary heart disease in male health professionals. Ann. Int. Med., 1996, 125, 384-389.

32
 ACCEPTED MANUSCRIPT
[62] Hertog, M.G.L.; Kromhout, D.; Aravanis, C.; Blackburn, H.; Buzina, R.; Fidanza, F.; Giampaoli, S.; Jansen, A.;

Menotti, A.; Nedeljkovic, S.; Pekkarinen, M.; Simic, B.S.; Toshima, H.; Feskens, E.J.M.; Hollman, P.C.H.;

Katan, M.B. Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries

study. Arch. Int. Med., 1995, 155, 381-386.

[63] Knekt, P.; Järvinen, R.; Seppänen, R.; Heliövaara, M.; Teppo, L.; Pukkala, E.; Aromaa, A. Dietary intake of

T
IP
flavonoids and the risk of lung cancer and other malignant neoplasms. Am. J. Epidemiol., 1997, 146, 223-230.

[64] Kimira, M.; Arai, Y.; Shimoi, K.; Watanabe, S. Japanese intake of flavonoids and isoflavonoids from foods. J.

R
Epidemiol., 1998, 8, 168-175.

SC
[65] Johannot, L.; Somerset, S.M. Age-related variations in flavonoid intake and sources in the Australian population.

Public Health Nutr., 2006, 9, 1045-1054.

NU
[66] Lin, J.; Zhang, S.M.; Wu, K.; Willett, W.C.; Fuchs, C.S.; Giovannucci, E. Flavonoid intake and colorectal cancer

risk in men and women. Am. J. Epidemiol., 2006, 164, 644-651.

MA
[67] Jackson, M.J. The assessment of bioavailability of micronutrients: introduction. Eur. J. Clin. Nutr., 1997, 51, S1-2.

[68] Toutain, P.L.; Bousquet-Melou, A. Bioavailability and its assessment. J. Vet. Pharmacol. Ther., 2004, 27, 455-466.
D

[69] Scholz, S; Williamson, G. Interactions affecting the bioavailability of dietary polyphenols in vivo. Int. J. Vitam.
TE

Nutr. Res., 2007, 77, 224-235.

[70] Gugler, R.; Leschik, M.; Dengler, H.J. Disposition of quercetin in man after single oral and intravenous doses. Eur.
P

J. Clin. Pharmacol., 1975, 9, 229-234.

CE

[71] Walle, T; Walle, U.K.; Halushka, P.V. Carbon dioxide is the major metabolite of quercetin in humans. J. Nutr.,

2001, 131, 2648-2652.

AC

[72] Zhang, Y.; Li, Y.; Cao, C.; Cao, J.; Chen, W.; Zhang, Y.; Wang, C.; Wang, J.; Zhang, X.; Zhao, X. Dietary

flavonol and flavones intakes and their major food sources in Chinese adults. Nutr. Cancer., 2010, 62, 1120-

1127.

[73] Boots, A.W.; Haenen, G.R.; Bast, A. Health effects of quercetin: from antioxidant to nutraceutical. Eur. J.

Pharmacol., 2008, 585, 325-337.

[74] Manach, C.; Williamson, G.; Morand, C.; Scalbert, A.; Remesy, C. Bioavailability and bioefficacy of polyphenols

in humans. Review of 97 bioavailability studies. Am. J. Clin. Nutr., 2005, 81, 230S–242S.

[75] Tamura, G.; Gold, C.; Ferro-Luzzi, A.; Ames, B.N. Fecalase: a model for activation of dietary glycosides to

mutagens by intestinal flora. Proc. Natl. Acad. Sci. USA, 1980, 77, 4961-4965.

[76] Manach, C.; Morand, C.; Crespy, V.; Demigné, C.; Texier, O.; Régérat, F.; Rémésy, C. Quercetin is recovered in

human plasma as conjugated derivatives which retain antioxidant properties. FEBS Lett., 1998; 426, 331-336.

33
 ACCEPTED MANUSCRIPT
[77] Moon, J.H.; Nakata, R.; Oshima, S.; Inakuma, T.; Terao, J. Accumulation of quercetin conjugates in blood plasma

after the short-term ingestion of onion by women. Am. J. Physiol. Regul. Integr. Comp. Physiol., 2000, 279,

R461-R467.

[78] Moon, J.; Tsushida, T.; Nakahara, K.; Terao, J. Identification of quercetin 3-O-β-D-glucuronide an antioxidative

metabolite in rat plasma after oral administration of quercetin. Free Radic. Biol. Med., 2001, 30, 1274-1285.

T
IP
[79] Manach, C.; Texier, O.; Régérat, F.; Agullo, G.; Demigné, C.; Rémésy, C. Dietary quercetin is recovered in rat

plasma as conjugated derivatives of isorhamnetin and quercetin. Nutr. Biochem., 1996; 7, 375-380.

R
[80] da Silva, E.L.; Piskula, M.K.; Yamamoto, N.; Moon, J.H.; Terao, J. Quercetin metabolites inhibit copper ion-

SC
induced lipid peroxidation in rat plasma. FEBS Lett., 1998, 430, 405-408.

[81] Guo, Y.; Bruno, R.S. Endogenous and exogenous mediators of quercetin bioavailability. J. Nutr. Biochem., 2015,

NU
26, 201-210.

[82] Hollman, P.C.; van der Gaag, M.; Mengelers, M.J.; van Trijp, J.M.; de Vries, J.H.; Katan, M.B. Absorption and
MA
disposition kinetics of the dietary antioxidant quercetin in man. Free Radic. Biol. Med., 1996, 21, 703-707.

[83] Conquer, J.A.; Maiani, G.; Azzini, E.; Raguzzini, A.; Holub, B.J. Supplementation with quercetin markedly
D

increases plasma quercetin concentration without effect on selected risk factors for heart disease in healthy
TE

subjects. J. Nutr., 1998, 128, 593-597.

[84] Bischoff, S.C. Quercetin: potentials in the prevention and therapy of disease. Curr. Opin. Clin. Nutr. Metab. Care,
P

2008, 11, 733-740.

CE

[85] Crespy, V.; Morand, C.; Besson, C.; Manach, C.; Demigne, C.; Remesy, C. Quercetin, but not its glycosides, is

absorbed from the rat stomach. J. Agric. Food Chem., 2002, 50, 618-621.
AC

[86] Crespy, V.; Morand, C.; Manach, C.; Besson, C.; Demigne, C.; Remesy, C. Part of quercetin absorbed in the small

intestine is conjugated and further secreted in the intestinal lumen. Am. J. Physiol., 1999, 277, 120-126.

[87] Nait Chabane, M.; Al Ahmad, A.; Peluso. J.; Muller, C.D.; Ubeaud, G. Quercetin and naringenin transport across

human intestinal Caco-2 cells. J. Pharm. Pharmacol., 2009, 61,1473-1483.

[88] Arts, I.C.; Sesink, A.L.; Faassen-Peters, M.; Hollman, P.C. The type of sugar moiety is a major determinant of the

small intestinal uptake and subsequent biliary excretion of dietary quercetin glycosides. Br. J. Nutr., 2004, 91,

841-847.

[89] Nemeth, K.; Plumb, G.W.; Berrin, J.G.; Juge, N.; Jacob, R.; Naim, H.Y.; Williamson, G.; Swallow, D.M.; Kroon,

P.A. 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, 29-42.

34
 ACCEPTED MANUSCRIPT
[90] Day, A.J.; Gee, J.M.; DuPont, M.S.; Johnson, I.T.; Williamson, G. Absorption of quercetin-3-glucoside and

quercetin-4′-glucoside in the rat small intestine: the role of lactase phlorizin hydrolase and the sodium-dependent

glucose transporter. Biochem. Pharmacol., 2003, 65, 1199-1206.

[91] Jaganath, I.B.; Mullen, W.; Edwards, C.A.; Crozier, A. The relative contribution of the small and large intestine to

the absorption and metabolism of rutin in man. Free Radic. Res., 2006, 40, 1035-1046.

T
IP
[92] Kim, D.H.; Jung, E.A.; Sohng, I.S.; Han, J.A.; Kim, T.H.; Han, M.J. Intestinal bacterial metabolism of flavonoids

and its relation to some biological activities. Arch. Pharm. Res., 1998, 21, 17-23.

R
[93] Aura, A.M.; O'Leary, K.A.; Williamson, G.; Ojala, M.; Bailey, M.; Puupponen-Pimiä, R.; Nuutila, A.M.; Oksman-

SC
Caldentey, K.M.; Poutanen, K. Quercetin derivatives are deconjugated and converted to hydroxyphenylacetic

acids but not methylated by human fecal flora in vitro. J. Agric. Food Chem., 2002, 50, 1725-1730.

NU
[94] Del Rio, D.; Rodriguez-Mateos, A.; Spencer, J.P.; Tognolini, M.; Borges, G.; Crozier, A. Dietary (poly)phenolics

in human health: structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxid.
MA
Redox Signal., 2013, 18, 1818-1892.

[95] Omiecinski, C.J.; Vanden Heuvel, J.P.; Perdew, G.H.; Peters, J.M. Xenobiotic metabolism, disposition, and
D

regulation by receptors: from biochemical phenomenon to predictors of major toxicities. Toxicol. Sci., 2011, 120,
TE

49-75.

[96] Gradolatto, A.; Canivenc-Lavier, M.C.; Basly, J.P.; Siess, M.H.; Teyssier, C. Metabolism of apigenin by rat liver
P

phase I and phase ii enzymes and by isolated perfused rat liver. Drug Metab. Dispos., 2004, 32, 58-65.
CE

[97] van der Woude, H.; Boersma, M,G,; Vervoort, J.; Rietjens, I.M. Identification of 14 quercetin phase II mono- and

mixed conjugates and their formation by rat and human phase II in vitro model systems. Chem. Res. Toxicol.,
AC

2004, 17, 1520-1530.

[98] Graf, B.A.; Ameho, C.; Dolnikowski, G.G.; Milbury, P.E.; Chen, C.Y.; Blumberg, J.B. Rat gastrointestinal tissues

metabolize quercetin. J. Nutr., 2006, 136, 39-44.

[99] Murota, K.; Cermak, R.; Terao, J.; Wolffram, S. Influence of fatty acid patterns on the intestinal absorption

pathway of quercetin in thoracic lymph duct-cannulated rats. Br. J. Nutr., 2013, 109, 2147-2153.

[100] Sesink, A.L.; Arts, I.C.; de Boer, V.C.; Breedveld, P.; Schellens, J.H.; Hollman, P.C.; Russel, F.G. Breast cancer

resistance protein (Bcrp1/Abcg2) limits net intestinal uptake of quercetin in rats by facilitating apical efflux of

glucuronides. Mol. Pharmacol., 2005, 67, 1999-2006.

[101] Williamson, G.; Aeberli, I.; Miguet, L.; Zhang, Z.; Sanchez, M.B.; Crespy, V.; Barron, D.; Needs, P.; Kroon,

P.A.; Glavinas, H.; Krajcsi, P.; Grigorov, M. Interaction of positional isomers of quercetin glucuronides with the

transporter ABCC2 (cMOAT, MRP2). Drug Metab. Dispos., 2007, 35, 1262-1268.

35
 ACCEPTED MANUSCRIPT
[102] Wong, C.C.; Akiyama, Y.; Abe, T.; Lippiat, J.D.; Orfila, C.; Williamson, G. Carrier-mediated transport of

quercetin conjugates: involvement of organic anion transporters and organic anion transporting polypeptides.

Biochem. Pharmacol., 2012, 84, 564-570.

[103] O'Leary, K.A.; Day, A.J.; Needs, P.W.; Mellon, F.A.; O'Brien, N.M.; Williamson, G. Metabolism of quercetin-7-

and quercetin-3-glucuronides by an in vitro hepatic model: the role of human beta glucuronidase,

T
IP
sulfotransferase, catechol-O-methyltransferase and multi-resistant protein 2 (MRP2) in flavonoid metabolism.

Biochem. Pharmacol., 2003, 65, 479-491.

R
[104] Mullen, W.; Rouanet, J.M.; Auger, C.; Teissèdre, P.L.; Caldwell, S.T.; Hartley, R.C.; Lean, M.E.; Edwards,

SC
C.A.; Crozier, A. Bioavailability of [2-(14)C]quercetin-4′-glucoside in rats. J. Agric. Food Chem., 2008, 56,

12127-12137.

NU
[105] Mullen, W.; Edwards, C.A.; 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.,
MA
2006, 96, 107-116.

[106] Gross, M.; Pfeiffer, M.; Martini, M.; Campbell, D.; Slavin, J.; Potter, J. The quantitation of metabolites of
D

quercetin flavonols in human urine. Cancer Epidemiol. Biomarkers Prev., 1996, 5, 711-720.
TE

[107] Bieger, J.; Cermak, R.; Blank, R.; de Boer, V.C.; Hollman, P.C.; Kamphues, J.; Wolffram, S. Tissue distribution

of quercetin in pigs after long-term dietary supplementation. J. Nutr., 2008, 138, 1417-1420.
P

[108] Ferry, D.R.; Smith, A.; Malkhandi, J.; Fyfe, D.W.; de Takats, P.G.; Anderson, D.; Baker, J.; Kerr, D.J. Phase I
CE

clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition.

Clin. Cancer Res., 1996, 4, 659-668.

AC

[109] Zahedi, M.; Ghiasvand, R.; Feizi, A.; Asgari, G.; Darvish, L. Does quercetin improve cardiovascular risk factors

and inflammatory biomarkers in women with Type 2 diabetes: A double-blind randomized controlled clinical

trial. Int. J. Prev. Med., 2013, 4, 777-785.

[110] Dower, J.I.; Geleijnse, J.M.; Gijsbers, L.; Zock, P.L.; Kromhout, D.; Hollman, P.C. Effects of the pure flavonoids

epicatechin and quercetin on vascular function and cardiometabolic health: a randomized, double-blind, placebo-

controlled, crossover trial. Am. J. Clin. Nutr., 2015, 101, 914-921.

[111] Dower, J.I.; Geleijnse, J.M.; Gijsbers, L.; Schalkwijk, C.; Kromhout, D.; Hollman, P.C. Supplementation of the

pure flavonoids epicatechin and quercetin affects some biomarkers of endothelial dysfunction and inflammation

in (pre)hypertensive adults: A randomized double-blind, placebo-controlled, crossover trial. J. Nutr., 2015, 145,

1459-1463.

36
 ACCEPTED MANUSCRIPT
[112] Amirchaghmaghi, M.; Delavarian, Z.; Iranshahi, M.; Shakeri, M.T.; Mosannen Mozafari, P.; Mohammadpour,

A.H.; Farazi, F.; Iranshahy, M. A. Randomized placebo-controlled double blind clinical trial of quercetin for

treatment of oral Lichen planus. J. Dent. Res. Dent. Clin. Dent. Prospects, 2015, 9, 23-28

[113] Packer, L.; Smith, J.R. Extension of the lifespan of cultured normal human diploid cells by vitamin E. Proc. Natl.

Acad. Sci. USA, 1974, 71, 4763-4767.

T
IP
[114] Rattan, S.I.; Clark, B.F. Kinetin delays the onset of ageing characteristics in human fibroblasts. Biochem. Biophys.

Res. Commun., 1994, 201, 665-672.

R
[115] McFarland, G.A.; Holliday, R. Retardation of the senescence of cultured human diploidfibroblasts by carnosine.

SC
Exp. Cell Res., 1994, 212, 167-175.

[116] Svendsen, L.; Rattan, S.I.; Clark, B.F. Testing garlic for possible anti-ageing effects on long-term growth

NU
characteristics, morphology and macromolecular synthesis of humanfibroblasts in culture. J. Ethnopharmacol.,

1994, 43, 125-133.

MA
[117] Trougakos, I.P.; Chondrogianni, N.; Pimenidou, A.; Katsiki, M.; Tzavelas, C.; Gonos, E.S. Slowing down cellular

ageing in vitro. In: Modulating ageing and longevity; Rattan, S.I. (Ed.); Kluwer Academic Publishers: Dordrecht,
D

2003, pp. 65-83.

TE

[118] Chondrogianni, N.; Kapeta, S.; Chinou, I.; Vassilatou, K.; Papassideri, I.; Gonos, E.S. Anti-ageing and

rejuvenating effects of quercetin. Exp. Gerontol., 2010, 45, 763-771.

P

[119] Zhu, Y.; Tchkonia, T.; Pirtskhalava, T.; Gower, A.C.; Ding, H.; Giorgadze, N.; Palmer, A.K.; Ikeno, Y.; Hubbard,
CE

G.B.; Lenburg, M.; O’Hara, S.P.; LaRusso, N.F.; Miller, J.D.; Roos, C.M.; Verzosa, G.C.; LeBrasseur, N.K.;

Wren, J.D.; Farr, J.N.; Khosla, S.; Stout, M.B.; McGowan, S.J.; Fuhrmann-Stroissnigg, H.; Gurkar, A.U.; Zhao,
AC

J.; Colangelo, D.; Dorronsoro, A.; Ling, Y.Y.; Barghouthy, A.S.; Navarro, D.C.; Sano, T.; Robbins, P.D.;

Niedernhofer, L.J.; Kirkland, J.L. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs.

Aging Cell, 2015, pp.1-15.

[120] Kirkland, J.L. Inflammation and cellular senescence: potential contribution to chronic diseases and disabilities

with aging. Public Policy Aging Rep., 2013, 23,12-15.

[121] Kirkland, J.L.; Tchkonia, T. Clinical strategies and animal models for developing senolytic agents. Exp.

Gerontol., 2014, S0531-5565, 291-295.

[122] Shaik, Y.B.; Castellani, M.L.; Perrella, A.; Conti, F.; Salini, V.; Tete, S.; Madhappan, B.; Vecchiet, J.; De Lutiis,

M.A.; Caraffa, A.; Cerulli, G. Role of quercetin (a natural herbal compound) in allergy and inflammation. J.

Biol. Regul. Homeost. Agents, 2006, 20, 47-52.

[123] Chirumbolo, S. Quercetin as a potential anti-allergic drug: which perspectives? Iran J. Allergy Asthma Immunol.,

2011, 10, 139-140.

37
 ACCEPTED MANUSCRIPT
[124] Pashevin, D.A.; Tumanovska, L.V.; Dosenko, V.E.; Nagibin, V.S.; Gurianova, V.L.; Moibenko, A.A.

Antiatherogenic effect of quercetin is mediated by proteasome inhibition in the aorta and circulating leukocytes.

Pharmacol. Rep., 2011, 63, 1009-1018.

[125] Perez-Vizcaino, F.; Duarte, J. Flavonols and cardiovascular disease. Mol. Aspects Med., 2010, 31, 478-494.

[126] Larson, A.J.; Symons, J.D.; Jalili, T. Therapeutic potential of quercetin to decrease blood pressure: review of

T
IP
efficacy and mechanisms. Adv. Nutr., 2012, 3, 39-46.

[127] Yang, F.; Song, L.; Wang, H.; Wang, J.; Xu, Z.; Xing, N. Combination of quercetin and 2-methoxyestradiol

R
enhances inhibition of human prostate cancer lncap and PC-3 cells xenograft tumor growth. PLoS One, 2015, 26.

SC
[128] Hung, C.H,; Chan, S.H.; Chu, P.M.; Tsai, K.L. Quercetin is a potent anti-atherosclerotic compound by activation

of SIRT1 signaling under oxLDL stimulation. Mol. Nutr. Food Res., 2015, Jul 23 [Epub ahead of print].

NU
[129] Chirumbolo, S. Quercetin in cancer prevention and therapy. Integr. Cancer Ther., 2013, 12, 97-102.

[130] Gorlach, S.; Fichna, J.; Lewandowska, U. Polyphenols as mitochondria-targeted anticancer drugs. Cancer Lett.,
MA
2015, 366, 141-149.

[131] Dajas, F. Life or death: neuroprotective and anticancer effects of quercetin. J. Ethnopharmacol., 2012, 143, 383-
D

396.
TE

[132] Russo, G.L.; Russo, M.; Spagnuolo, C.; Tedesco, I.; Bilotto, S.; Iannitti, R.; Palumbo, R. Quercetin: a pleiotropic

kinase inhibitor against cancer. Cancer Treat. Res., 2014, 159, 185-205.
P

[133] Bruning, A. Inhibition of mTOR signaling by quercetin in cancer treatment and prevention. Anticancer Agents
CE

Med. Chem., 2013, 13, 1025-1031.

[134] Maurya, A.K.; Vinayak, M. Modulation of PKC signaling and induction of apoptosis through suppression of
AC

reactive oxygen species and tumor necrosis factor receptor 1 (TNFR1): key role of quercetin in cancer

prevention. Tumour Biol., 2015, Jun 16 [Epub ahead of print].

[135] Sak, K. Site-specific anticancer effects of dietary flavonoid quercetin. Nutr. Cancer., 2014, 66, 177-193.

[136] Kim, H.P.; Mani, I.; Ziboh, V.A. Effects of naturally-occurring flavonoids and bioflavonoids on epidermal

cyclooxygenase from guinea pigs. Prostaglandins Leukot. Essent. Fatty Acids, 1998, 58, 17-24.

[137] Lee, K.M.; Hwang, M.K. ; Lee, D.E.; Lee, K.W.; Lee, H.J. Protective effect of quercetin against arsenite-induced

COX-2 expression by targeting PI3K in rat liver epithelial cells. J. Agric. Food Chem., 2010, 58, 5815-5820.

[138] Yoon, J.S.; Chae, M.K.; Lee, S.Y.; Lee, E.J. Anti-inflammatory effect of quercetin in a whole orbital tissue

culture of Graves' orbitopathy. Br. J. Ophthalmol., 2012, 96, 1117-1121.

[139] Angeloni, C.; Hrelia, S. Quercetin reduces inflammatory responses in LPS-stimulated cardiomyoblasts. Oxid.

Med. Cell. Longev., 2012, 2012, 837104.

38
 ACCEPTED MANUSCRIPT
[140] Chirumbolo, S. The role of quercetin, flavonols and flavones in modulating inflammatory cell function. Inflamm.

Allergy Drug Targets, 2010, 9, 263-285.

[141] Ahn, J.; Lee, H.; Kim, S.; Park, J.; Ha, T. The anti-obesity effect of quercetin is mediated by the AMPK and

MAPK signaling pathways. Biochem. Biophys. Res. Commun., 2008, 373, 545-549.

[142] Jung, C.H.; Cho, I.; Ahn, J.; Jeon, T.I.; Ha, T.Y. Quercetin reduces high-fat diet-induced fat accumulation in the

T
IP
liver by regulating lipid metabolism genes. Phytother. Res., 2013, 27, 139-143.

[143] Siriwardhana, N.; Kalupahana, N. S.; Cekanova, M.; LeMieux, M.; Greer, B.; Moustaid Moussa, N. Modulation

R
of adipose tissue inflammation by bioactive food compounds. J. Nutr. Biochem., 2013, 24, 613-623.

SC
[144] Kobori, M. Dietary quercetin and other polyphenols: Attenuation of obesity. In: Polyphenols in Human Health

and Disease; Watson, R. R.; Preedy, V. R.; Zibadi, S. Eds.; Elsevier Science B. V: Amsterdam, 2014, pp. 163-

NU
175.

[145] Bae, S.C.; Jung, W.J.; Lee, E.J.; Yu, R.; Sung, M.K. Effects of antioxidant supplements intervention on the level
MA
of plasma inflammatory molecules and disease severity of rheumatoid arthritis patients. J. Am. Coll. Nutr., 2009,

28, 56-62.
D

[146] Matsuno, H.; Nakamura, H.; Katayama, K.; Hayashi, S.; Kano, S.; Yudoh, K.; Kiso, Y. Effects of an oral
TE

administration of glucosamine-chondroitin-quercetin glucoside on the synovial fluid properties in patients with

osteoarthritis and rheumatoid arthritis. Biosci. Biotechnol. Biochem., 2009, 73, 288-292.
P

[147] Knekt, P.; Kumpulainen, J.; Järvinen, R.; Rissanen, H.; Heliövaara, M.; Reunanen, A.; Hakulinen, T.; Aromaa,
CE

A. Flavonoid intake and risk of chronic diseases. Am. J. Clin. Nutr., 2002, 76, 560-568.

[148] Hirano, T.; Kawai, M.; Arimitsu, J.; Ogawa, M.; Kuwahara, Y.; Hagihara, K.; Shima, Y.; Narazaki, M.; Ogata,
AC

A.; Koyanagi, M.; Kai, T.; Shimizu, R.; Moriwaki, M.; Suzuki, Y.; Ogino, S.; Kawase, I.; Tanaka, T.

Preventative effect of a flavonoid, enzymatically modified isoquercitrin on ocular symptoms of Japanese cedar

pollinosis. Allergol. Int., 2009, 58, 373-382.

[149] Kawai, M.; Hirano, T.; Arimitsu, J.; Higa, S.; Kuwahara, Y.; Hagihara, K.; Shima, Y.; Narazaki, M,; Ogata, A.;

Koyanagi, M.; Kai, T.; Shimizu, R.; Moriwaki, M.; Suzuki, Y.; Ogino, S.; Kawase, I.; Tanaka, T. Effect of

enzymatically modified isoquercitrin, a flavonoid, on symptoms of Japanese cedar pollinosis: a randomized

double-blind placebo controlled trial. Int. Arch. Allergy Immunol., 2009, 149, 359-368.

[150] Jeong, S.M.; Kang, M.J.; Choi, H.N.; Kim, J.H.; Kim, J.I. Quercetin ameliorates hyperglycemia and dyslipidemia

and improves antioxidant status in type 2 diabetic db/db mice. Nutr. Res. Pract., 2012, 6, 201-207.

[151] Lai, P.B.; Zhang, L.; Yang, L.Y. Quercetin ameliorates diabetic nephropathy by reducing the expressions of

transforming growth factor-β1 and connective tissue growth factor in streptozotocin-induced diabetic rats. Ren.

Fail., 2012, 34, 83-87.

39
 ACCEPTED MANUSCRIPT
[152] Chaudry, P.S.; Cabera, J.; Juliani, H.R.; Varma, S.D. Inhibition of human lens aldose reductase by flavonoids,

sulindac, and indomethacin. Biochem. Pharmacol., 1983, 32, 1995-1998.

[153] Varma, S.D.; Mikuni, I.; Kinoshita, J.H. Flavonoids as inhibitors of lens aldose reductase. Science, 1975, 188,

1215-1216.

[154] Varma, S.D.; Mizuno, A.; Kinoshita, J.H. Diabetic cataracts and flavonoids. Science, 1977, 195, 205-206.

T
IP
[155] Valensia, P.; Devehath, C.L.; Richards, J.L.; Farez, C.; Khodabandehlou, T.; Rosenbloom, R.A.; LeFante, C. A

multicenter, double-blind, safety study of QR-333 for the treatment of symptomatic diabetic peripheral

R
neuropathy: a preliminary report. J. Diabetes Complications, 2005, 19, 247-253.

SC
[156] Eid, H.M.; Nachar, A.; Thong, F.; Sweeney, G.; Haddad, P.S. The molecular basis of the antidiabetic action of

quercetin in cultured skeletal muscle cells and hepatocytes. Pharmacogn. Mag., 2015, 11, 74-81.

NU
[157] Kressler, J.; Millard-Stafford, M.; Warren, G.L. Quercetin and endurance exercise capacity: a systematic review

and meta-analysis. Med. Sci. Sports Exerc., 2011, 43, 2396-2404

MA
[158] Alarcón de la Lastra, C.; Martín, M.J.; Motilva, V. Antiulcer and gastroprotective effects of quercetin: a gross and

histologic study. Pharmacology, 1994, 48, 56-62.

D

[159] Mizui, T.; Sato, H.; Hirose, F.; Doteuchi, M. Effect of antiperoxidative drugs on gastric damage induced by
TE

ethanol in rats. Life Sci., 1987, 41, 755-763.

[160] Rao, C.V.; Vijayakumar, M. Effect of quercetin, flavonoids and alpha-tocopherol, an antioxidant vitamin, on
P

experimental reflux oesophagitis in rats. Eur. J. Pharmacol., 2008, 589, 233-238.

CE

[161] Wu, P.; Zhou, L.; Li, Y.J.; Luo, B.; Yi, L.S.; Chen, S.F.; Sun,; H.H.; Chen, Y.; Cao, Z.J.; Xu, S.C. Protective

effects of quercetin against chronic mixed reflux esophagitis in rats by inhibiting the nuclear factor-κB p65 and
AC

interleukin-8 signaling pathways. J. Dig. Dis., 2015, 16, 319-326.

[162] Shin, J.E.; Kim, J.M.; Bae, E.A.; Hyun, Y.J.; Kim, D.H. In vitro inhibitory effect of flavonoids on growth,

infection and vacuolation of Helicobacter pylori. Planta Med., 2005, 71, 197-201.

[163] González-Segovia, R.; Quintanar, J.L.; Salinas, E.; Ceballos-Salazar, R.; Aviles-Jiménez, F.; Torres-López, J.

Effect of the flavonoid quercetin on inflammation and lipid peroxidation induced by Helicobacter pylori n gastric

mucosa of guinea pig. J. Gastroenterol., 2008, 43, 441-447.

[164] Hamdy, A.A.; Ibrahem, M.A. Management of aphthous ulceration with topical quercetin: a randomized clinical

trial. J. Contemp. Dent. Pract., 2010, 11, E009-E016.

[165] Hu, X.T.; Ding, C.; Zhou, N.; Xu, C. Quercetin protects gastric epithelial cell from oxidative damage in vitro and

in vivo. Eur. J. Pharmacol., 2015, 754, 115-124.

[166] Siegel, R.; Ma, J.; Zou, Z.; Jemal, A: Cancer statistics, 2014. CA Cancer J. Clin., 2014, 64, 9-29.

40
 ACCEPTED MANUSCRIPT
[167] Noori-Daloii, M.R.; Momeny, M.; Yousefi, M.; Shirazi, F.G.; Yaseri, M.; Motamed, N.; Kazemialiakbar, N.;

Hashemi, S. Multifaceted preventive effects of single agent quercetin on a human prostate adenocarcinoma cell

line (PC-3): implications for nutritional transcriptomics and multi-target therapy. Med. Oncol., 2011, 28, 1395-

1404.

[168] Aalinkeel, R.; Bindukumar, B.; Reynolds, J.L.; Sykes, D.E.; Mahajan, S.D.; Chadha, K.C.; Schwartz, S.A. The

T
IP
dietary bioflavonoid, quercetin, selectively induces apoptosis of prostate cancer cells by down-regulating the

expression of heat shock protein 90. Prostate, 2008, 68, 1773-1789.

R
[169] Young, C.Y.; Tian, Y.; Liu, Z.; Zhang, M.; Lou, H. Suppression of the androgen receptor function by quercetin

SC
through protein-protein interactions of Sp1, c-Jun, and the androgen receptor in human prostate cancer cells. Mol.

Cell. Biochem., 2010, 339, 253-262.

NU
[170] Yang, F.; Song, L.; Wang, H.; Wang, J.; Xu, Z.; Xing, N. Combination of quercetin and 2-methoxyestradiol

enhances inhibition of human prostate cancer LNCaP and PC-3 cells xenograft tumor growth. PLoS One, 2015,
MA
10.

[171] Yang, F.; Song, L.; Wang, H.; Wang, J.; Xu, Z.; Xing, N. Quercetin in prostate cancer: Chemotherapeutic and
D

chemopreventive effects, mechanisms and clinical application potential (Review). Oncol. Rep., 2015, 33, 2659-
TE

2668.

[172] Kaul, T.N.; Middleton, E. Jr.; Ogra, P.L. Antiviral effect of flavonoids on human viruses. J. Med. Virol., 1985,
P

15, 71-79.
CE

[173] Gonzalez, O.; Fontanes, V.; Raychaudhuri, S.; Loo, R.; Loo, J.; Arumugaswami, V.; Sun, R.; Dasgupta, A.;

French, S.W. The heat shock protein inhibitor quercetin attenuates hepatitis C virus production. Hepatology,
AC

2009, 50, 1756-1764.

[174] Nieman, D.C.; Henson, D.A.; Gross, S.J.; Jenkins, D.P.; Davis, J.M.; Murphy, E.A.; Carmichael, M.D.; Dumke,

C.L.; Utter, A.C.; McAnulty, S.R.; McAnulty, L.S.; Mayer, E.P. Quercetin reduces illness but not immune

perturbations after intensive exercise. Med. Sci. Sports Exerc., 2007, 39, 1561-1569.

[175] Henson, D.; Nieman, D.; Davis, J.M.; Dumke, C.; Gross, S.; Murphy, A.; Carmichael, M.; Jenkins, D.P.;

Quindry, J.; McAnulty, S.; McAnulty, L.; Utter, A.; Mayer, E. Post-160-km race illness rates and decreases in

granulocyte respiratory burst and salivary IgA output are not countered by quercetin ingestion. Int. J. Sports

Med., 2008, 29, 856-863.

[176] Betts, J.W.; Sharili, A,S,; Phee, L.M.; Wareham, D.W. In vitro activity of epigallocatechin gallate and quercetin

alone and in combination versus clinical isolates of methicillin-resistant Staphylococcus aureus. J. Nat. Prod.,

2015, Aug 12 [Epub ahead of print].

41
 ACCEPTED MANUSCRIPT

[177] Anjaneyulu, M.; Chopra, K.; Kaur, I. Antidepressant activity of quercetin, a bioflavonoid, in streptozotocin-

induced diabetic mice. J. Med. Food, 2003, 6, 391-395.

[178] Bhutada, P.; Mundhada, Y.; Bansod, K.; Ubgade, A.; Quazi, M.; Umathe, S.; Mundhada, D. Reversal by

quercetin of corticotrophin releasing factor induced anxiety- and depression-like effect in mice. Prog.

T
IP
Neuropsychopharmacol. Biol. Psychiatry, 2010, 34, 955-960.

[179] Priprem, A.; Watanatorn, J.; Sutthiparinyanont, S.; Phachonpai, W.; Muchimapura, S. Anxiety and cognitive

R
effects of quercetin liposomes in rats. Nanomedicine, 2008, 4, 70-78.

SC
[180] Adewole, S.O.; Caxton-Martins, E.A.; Ojewole, J.A. Protective effect of quercetin on the morphology of

pancreatic beta-cells of streptozotocintreated diabetic rats. Afr. J. Tradit. Complement. Altern. Med., 2006, 4, 64-

NU
74.

[181] Holzmann, I.; da Silva, L.M.; Corrêa da Silva, J.A.; Steimbach, V.M.; de Souza, M.M. Antidepressant-like effect
MA
of quercetin in bulbectomized mice and involvement of the antioxidant defenses, and the glutamatergic and

oxidonitrergic pathways. Pharmacol. Biochem. Behav., 2015, 136, 55-63.

D

[182] Joshi, D.; Naidu, P.S.; Singh, A.; Kulkarni, S.K. Protective effect of quercetin on alcohol abstinence-induced
TE

anxiety and convulsions. J. Med. Food, 2005, 8, 392-396.

[183] Dixon Clarke, S.E.; Ramsay, R.R. Dietary inhibitors of monoamine oxidase A. J. Neural. Transm., 2011, 118,
P

1031-1041.
CE

[184] Kawabata, K.; Kawai, Y.; Terao, J. Suppressive effect of quercetin on acute stress-induced hypothalamic-pituitary

adrenal axis response in Wistar rats. J. Nutr. Biochem., 2010, 21, 374-380.
AC

[185] Chander, K.; Vaibhav, K.; Ejaz Ahmed, M.; Javed, H.; Tabassum, R.; Khan, A.; Kumar, M.; Katyal, A.; Islam, F.;

Siddiqui, M.S. Quercetin mitigates lead acetate-induced behavioral and histological alterations via suppression of

oxidative stress, Hsp-70, Bak and upregulation of Bcl-2. Food Chem. Toxicol., 2014, 68, 297-306.

[186] Abdalla, F.H.; Schmatz, R.; Cardoso, A.M.; Carvalho, F.B.; Baldissarelli, J.; de Oliveira, J.S.; Rosa, M.M.;

Gonçalves Nunes, M.A.; Rubin, M.A.; da Cruz, I.B.; Barbisan, F.; Dressler, V.L.; Pereira, L.B.; Schetinger,

M.R.; Morsch, V.M.; Gonçalves, J.F.; Mazzanti, C.M. Quercetin protects the impairment of memory and

anxiogenic-like behavior in rats exposed to cadmium: Possible involvement of the acetylcholinesterase and

Na+,K+-ATPase activities. Physiol. Behav., 2014, 135, 152-167.7

[187] Pal, D.; Mitra, A.K. MDR- and CYP3A4-mediated drug-herbal interactions. Life Sci., 2006, 78, 2131-2145.

[188] Choi, J.S.; Piao, Y.J.; Kang, K.W. Effects of quercetin on the bioavailability of doxorubicin in rats: Role of

CYP3A4 and P-gp inhibition by quercetin. Arch. Pharm. Res., 2011, 34, 607-613.

42
 ACCEPTED MANUSCRIPT
[189] Chen, Y.; Xiao, P.; Ou-Yang, D.S.; Fan, L.; Guo, D.; Wang, Y.N.; Han, Y,; Tu, J.H.; Zhou, G.; Huang, Y.F.;

Zhou, H.H. Simultaneous action of the flavonoid quercetin on cytochrome P450 (CYP) 1A2, CYP2A6, N-

acetyltransferase and xanthine oxidase activity in healthy volunteers. Clin. Exp. Pharmacol. Physiol., 2009, 36,

828-833.

[190] Kim, K.A.; Park, P.W.; Park, J.Y. Short-term effect of quercetin on the pharmacokinetics of fexofenadine, a

T
IP
substrate of P-glycoprotein, in healthy volunteers. Eur. J. Clin. Pharmacol., 2009, 65, 609-614.

[191] Wang, Y.H.; Chao, P.D.; Hsiu, S.L.; Wen, K.C.; Hou, Y.C. Lethal quercetin-digoxin interaction in pigs. Life Sci.,

R
2004, 74, 1191-1197.

SC
[192] Chan, E.; Hegde, A.; Chen, X. Effect of rutin on warfarin anticoagulation and pharmacokinetics of warfarin

enantiomers in rats. J. Pharm. Pharmacol., 2009, 61, 451-458.

NU
[193] Kale, A.; Gawande, S.; Kotwal, S.; Netke, S.; Roomi, W.; Ivanov, V.; Niedzwiecki, A.; Rath, M. Studies on the

effects of oral administration of nutrient mixture, quercetin and red onions on the bioavailability of
MA
epigallocatechin gallate from green tea extract. Phytother. Res., 2010, 24, S48-S55.

[194] Moon, Y.J.; Morris, M.E. Pharmacokinetics and bioavailability of the bioflavonoid biochanin A: effects of
D

quercetin and EGCG on biochanin A disposition in rats. Mol. Pharm., 2007, 4, 865-872.
TE

[195] Naidu, P.S.; Singh, A.; Joshi, D.; Kulkarni, S.K. Possible mechanisms of action in quercetin reversal of morphine

tolerance and dependence. Addict. Biol., 2003, 8, 327-336.

P

[196] Chen, C.; Zhou, J.; Ji, C. Quercetin: A potential drug to reverse multidrug resistance Life Sci., 2010, 87, 333-338.
CE

[197] Morino, K.; Matsukara, N.; Kawachi, T.; Ohgaki, H.; Sugimura, T.; Hirono, I. Carcinogenicity test of quercetin

and rutin in golden hamsters by oral administration. Carcinogenesis, 1982, 3, 93-97.

AC

[198] Pérez-Pastén, R.; Martínez-Galero, E.; Chamorro-Cevallos, G. Quercetin and naringenin reduce abnormal

development of mouse embryos produced by hydroxyurea. J. Pharm., Pharmacol., 2010, 62, 1003-1009.

[199] Vanhees, K.; de Bock, L.; Godschalk, R.W.; van Schooten, F.J.; van Waalwijk van Doorn-Khosrovani, S.B.

Prenatal exposure to flavonoids: implication for cancer risk. Toxicol. Sci., 2011, 120, 59-67.

[200] Cantero, G.; Campanella, C.; Mateos, S.;.Corte´s, F. Topoisomerase II inhibition and high yield of

endoreduplication induced by the flavonoids luteolin and quercetin. Mutagenesis, 2006, 21, 321-325.

[201] Sudan, S.; Rupasinghe, H.P. Quercetin-3-O-glucoside induces human DNA topoisomerase II inhibition, cell cycle

arrest and apoptosis in hepatocellular carcinoma cells. Anticancer Res., 2014, 34, 1691-1699.

[202] Sudan, S.; Rupasinghe, H.V. Antiproliferative activity of long chain acylated esters of quercetin-3-O-glucoside in

hepatocellular carcinoma HepG2 cells. Exp. Biol. Med. (Maywood), 2015, Feb 13 [Epub ahead of print].

43
 ACCEPTED MANUSCRIPT
[203] Hossion, A.M.; Zamami, Y.; Kandahary, R.K.; Tsuchiya, T.; Ogawa, W.; Iwado, A.; Sasaki, K. Quercetin

diacylglycoside analogues showing dual inhibition of DNA gyrase and topoisomerase IV as novel antibacterial

agents. J. Med. Chem., 2011, 54, 3686-3703.

[204] Miles, S.L.; McFarland, M., Niles, R.M. Molecular and physiological actions of quercetin: need for clinical trials

to assess its benefits in human disease. Nutr. Rev., 2014, 72, 720-734.

T
IP
[205] Phenol-Explorer, Database on polyphenol content in food, Food composition; http://phenol-

explorer.eu/contents/polyphenol/330 (Accessed September 16, 2015).

R
[206] U.S. National Library of Medicine, Open Chemistry Database,

SC
http://pubchem.ncbi.nlm.nih.gov/compound/5280343#section=Top (Accessed September 16, 2015).

[207] USDA Database for the Flavonoid Content of Selected Foods, Release 3.1, December 2013, Slightly revised, May

NU
2014, prepared by Bhagwat, S.; Haytowitz, D.B.; Holden, J.M. (ret.),

http://www.ars.usda.gov/News/docs.htm?docid=6231 (Accessed September 16, 2015).

MA
[208] Medscape, Drug & Disease, Quercetin (Herbs/Suppl.), http://reference.medscape.com/drug/quercetin-344495#3

(Accessed September 16, 2015).

D

[209] Medscape, Drug & Disease, Quercetin (Herbs/Suppl.), http://reference.medscape.com/drug/quercetin-344495#2

TE

(Accessed September 16, 2015).

P
CE
AC

44
 ACCEPTED MANUSCRIPT
Tables (1-3) to:

Quercetin: A flavonol with multifaceted therapeutic applications?

Gabriele D’Andrea
University of L’Aquila, Dept. of BACS, Coppito 2, 67100 L’Aquila, Italy
email: gadan@cc.univaq.it

T
IP
Table 1. Quercetin-3-O-β-D-glucuronide content in selected food1

R
Fruits and fruit products

SC
Fruits - Berries Grape, black 2.15 mg/100 g
Strawberry, raw 1.74 mg/100 g
Grape, green 1.50 mg/100 g

NU
Cloudberry 0.79 mg/100 g
Red raspberry, raw 0.63 mg/100 g
Non-alcoholic beverages
MA
Fruit juices - Berry juices Red raspberry, pure juice 6.18 mg/100 mL
Fennel, tea 3.26 mg/100 mL
Herb infusion Grape, green, pure juice 0.05 mg/100 mL
D

Vegetables
Leaf vegetables Lettuce, red, raw 2.65 mg/100 g
TE

Lettuce, green, raw 1.34 mg/100 g

Pod vegetables Green bean, raw 0.80 mg/100 g
P

1
: Adapted from Phenol-Explorer, Database on polyphenol content in foods [205].
CE
AC

45
 ACCEPTED MANUSCRIPT
Table 2. Quercetin identifiers and properties1
IDENTIFIERS
IUPAC Name 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one
PubChem CID 5280343
1S/C15H10O7/c16-7-4-10(19)12-11(5-7)22-
InChl
15(14(21)13(12)20)6-1-2-8(17)9(18)3-6/h1-5,16-19,21H
InChl Key REFJWTPEDVJJIY-UHFFFAOYSA-N

T
Canonical SMILE C1=CC(=C(C=C1C2=C(C(=O)C3=C(C=C(C=C3O2)O)O)O)O)O

IP
CAS 117-39-5
EC Number 204-187-1
UN Number 2811

R
UNII 9IKM0I5T1E

SC
1. 3,3',4',5,7-pentahydroxyflavone
MeSH Synonyms 2. dikvertin
3. quercetin
Trivial Chemical Names Sophoretin; Xanthaurine; Meletin

NU
Molecular Weight 302.2357 g/mol
Molecular Formula C15H10O7
PROPERTIES
MA
Yellow needles or yellow powder. Converts to anhydrous form at
Physical Description
203-207 °F. Alcoholic solutions taste very bitter.
Density 1.799 g/cm3
Color Yellow needles (dilute alcohol, + 2 water)
D

Boiling Point Sublimes

Melting Point 316.5 °C
TE

In water: 60 mg/mL at 16 °C; < 1mg/mL at 70 °F

Solubility Very soluble in ether, methanol; soluble in ethanol, acetone,
pyridine, acetic acid.
P

Vapor Pressure 2.81x10-14 mm Hg at 25 °C

CE

When heated to decomposition it emits acrid smoke and irritating

Decomposition
fumes.
Dissociation Constants pKa1 = 7.17; pKa2 = 8.26; pKa3 = 10.13; pKa4 = 12.30; pKa5 =
AC

(in phenol) 13.11

Spectral Properties Max Absorption: 256 nm (log E= 4.32); 301 nm (log E= 3.89);
373 nm (log E= 4.32); Sadler Ref. Number: 594 (IR, PRISM)
1
: Adapted from U.S. National Library of Medicine [206].

46
 ACCEPTED MANUSCRIPT
Table 3. Quercetin content of selected foods1

Food source Quercetin amount (mg/100 g) edible portion

Capers, raw 233.84
Peppers, hot, yellow, raw 50.73
Onions, red, raw 39.21
Asparagus, cooked 15.16

T
Cranberries, raw 14.84

IP
Peppers, hot, green, raw 14.70
Lingonberries, raw 13.30
Blueberries, raw 7.67

R
Lettuce, red leaf, raw 7.61

SC
Onions, white, raw 6.17
Tomato, canned 4.12
Apples, Red delicious, with skin 3.86

NU
Apples, Gala, with skin 3.80
Apples, Golden delicious, with skin 3.69
Broccoli, raw 3.26
Tea, green, brewed 2.49
MA
Cherries, sweet, raw 2.29
Tea, black, brewed 2.19
Grapes, black 2.08
Grapes, white 1.12
D

Wine, red, table 1.04

TE

Wine, white, table 0.04

P
CE
AC

47
 ACCEPTED MANUSCRIPT

1
: Adapted from USDA Database for the Flavonoid Content of Selected Foods [207].

Graphical abstract

T
R IP
SC
NU
MA
D
P TE
CE
AC

48