Isoqercetin

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Food and Chemical Toxicology 68 (2014) 267282
Contents lists available at ScienceDirect
Food and Chemical Toxicology

journal homepage: www.elsevier.com/locate/foodchemtox
Invited Review
Isoquercitrin: Pharmacology, toxicology, and metabolism

Katerina Valentov a,b,c,, Jir Vrba a, Martina Bancrov a, Jitka Ulrichov a,c, Vladimr Kren b
a
University, Hnevotnsk 3, CZ-775 15 Olomouc, Czech Republic

Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacky
Laboratory of Biotransformation, Institute of Microbiology, Academy of Sciences of the Czech Republic, Vdensk 1083, Prague 4 CZ-142 20, Czech Republic
c
University, Hnevotnsk 3, CZ-775 15 Olomouc, Czech Republic
Centre of Drug-Dietary Supplements Interactions and Nutrigenetics, Faculty of Medicine and Dentistry, Palacky
b
a r t i c l e
i n f o
Article history:
Received 20 January 2014
Accepted 14 March 2014
Available online 27 March 2014
Keywords:
Quercetin-3-glucoside
Quercetin-3-O-b-D-glucopyranoside
Enzymatically modied isoquercitrin
Bioavailability
Safety
Biological activity
a b s t r a c t
The avonoid isoquercitrin (quercetin-3-O-b-D-glucopyranoside) is commonly found in medicinal herbs,
fruits, vegetables and plant-derived foods and beverages. This article reviews the occurrence, preparation,
bioavailability, pharmacokinetics, toxicology and biological activity of isoquercitrin and enzymatically
modied (a-glucosylated) isoquercitrin (EMIQ). Pure isoquercitrin can now be obtained on a large scale
by enzymatic rutin hydrolysis with a-L-rhamnosidase. Isoquercitrin has higher bioavailability than
quercetin and displays a number of chemoprotective effects both in vitro and in vivo, against oxidative
stress, cancer, cardiovascular disorders, diabetes and allergic reactions. Although small amounts of intact
isoquercitrin can be found in plasma and tissues after oral application, it is extensively metabolized in the
intestine and the liver. Biotransformation of isoquercitrin includes deglycosylation, followed by formation of conjugated and methylated derivatives of quercetin or degradation to phenolic acids and carbon
dioxide. The acceptable daily intake of (95%) isoquercitrin and of EMIQ was estimated to be 5.4 and
4.9 mg/kg/day, respectively. Adverse effects of higher doses in rats included mostly (benign) chromaturia; nevertheless some drug interactions may occur due to the modulation of the activity and/or expression of drug metabolizing/transporting systems. With respect to the safety, affordability and benecial
pharmacological activities, highly pure isoquercitrin is a prospective substance for food supplementation.
2014 Elsevier Ltd. All rights reserved.
Contents
1.
2.
3.
4.
5.
6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.
Occurrence and production/preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Physico-chemical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Chemical structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Solubility, hydro-/lipophilicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.
Spectral properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Biological activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Molecular targets of isoquercitrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Animal and clinical studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Bioavailability and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.
Absorption and bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.
Biotransformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4.
Biodistribution and excretion of metabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Data related to the safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.
Safety/potential toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.
Potential interactions with drug metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
268
268
269
269
270
270
270
270
271
272
273
273
274
276
276
276
277
278
Corresponding author at: Laboratory of Biotransformation, Institute of Microbiology, Academy of Sciences of the Czech Republic, Vdensk 1083, Prague 4 CZ-142 20,
Czech Republic. Tel.: +420 296 442 766.
E-mail address: kata.valentova@email.cz (K. Valentov).
http://dx.doi.org/10.1016/j.fct.2014.03.018
0278-6915/ 2014 Elsevier Ltd. All rights reserved.
268
K. Valentov et al. / Food and Chemical Toxicology 68 (2014) 267282
Conflict of Interest . . . . .
Transparency Document .
Acknowledgments . . . . . .
References . . . . . . . . . . . .
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1. Introduction
Isoquercitrin (quercetin-3-O-b-D-glucopyranoside; Fig. 1,
Table 1) is, together with rutin (quercetin-3-O-rutinoside), one of
the major glycosidic forms of the natural avonol quercetin
(3,5,7,30 ,40 -pentahydroxyavone; Fig. 1). In recent decades, quercetin has been the subject of a large number of biological studies
(Boots et al., 2008; Dajas, 2012; Gibellini et al., 2011; Harwood
et al., 2007; Okamoto, 2005; Russo et al., 2012). In contrast, the
biological activity of quercetin glycosides has been studied to a lesser extent. For instance, in 2012, the Web of Science database
shows 1489 records on quercetin, 482 records on rutin and only
49 records on isoquercitrin. However, isoquercitrin has been
attracting increasing research attention (Fig. 2) due to its presence
in plant-derived food and a growing array of its biological activities. Moreover, our recently developed biocatalytic method for
the production of pure isoquercitrin from rutin (Gerstorferov
et al., 2012; Kren et al., 2010; Weignerov et al., 2012) attracts
the interest of the food and pharmaceutical industry. While pharmacological reviews of rutin have been published recently (Chua,
2013; Sharma et al., 2013), no survey on isoquercitrin is available
to date. In this review we summarize the current knowledge of
the biochemical and pharmacological activities of isoquercitrin,
and also its safety and/or possible adverse effects with respect to
its potential use in food supplementation.
Searches in several scientic literature databases, including
PubMed, Web of Science and Scopus, were conducted through
MarchDecember 2013 and papers related to isoquercitrin
occurrence, production, physicochemical properties, bioavailability, metabolism, potential toxicity and pharmacological activity
were selected. Articles dealing with enzymatically modied
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278
278
278
278
isoquercitrin (EMIQ, a quercetin-glycoside mixture consisting of

isoquercitrin and its a-glucosylated derivatives (Salim et al.,
2004)), called sometimes a-glucosyl isoquercitrin, and enzymatically decomposed rutin (consisting partly of isoquercitrin
and quercetin (Hasumura et al., 2004)) were also included in this
review.
1.1. Occurrence and production/preparation
It is reasonable to assume that isoquercitrin, being the monoglucoside of the most abundant natural avonoid quercetin, is ubiquitously distributed in the plant kingdom. For instance,
isoquercitrin is one of the bioactive components of the medicinal
plant St. Johns wort (Hypericum perforatum L.; Paulke et al.,
2006) and it is commonly found in fruits, vegetables, cereals and
various plant-derived beverages such as tea and wine (Hasumura
et al., 2004). The rst isolation of isoquercitrin was accomplished
from the seed pods of Cercis canadensis L. (eastern redbud;
Douglass et al., 1949). Recently, the occurrence of isoquercitrin has
been reported e.g. in Rosa soulieana Crpin owers (Yang et al.,
2013), Eucommia ulmoides Oliv. leaves (Dai et al., 2013), Crataegus
pinnatida Bge. (Chinese hawberry) fruits (Jurkov et al., 2012),
Crataegus azarolus L. (azarole) leaves (Belkhir et al., 2013), owering shoots of Caragana arborescens Lam. (Siberian peashrub;
Olennikov et al., 2013), leaves of Arbutus unedo L. (strawberry tree;
Males et al., 2013), in various Allium species (Vlase et al., 2013b,
2013a), in extracts from amaranth leaves, owers, stems and seeds
(Kraujalis et al., 2013), and in pistachio nuts (Pistacia vera var.
Kerman; Fabani et al., 2013). Phenol-Explorer, the rst comprehensive database on polyphenol content in foods (Neveu et al., 2010),
lists 36 items containing between 0.0067 (kiwi juice) and 41.95
Fig. 1. Structures of selected quercetin derivatives and other avonoids related to isoquercitrin and its metabolism.
269
Table 1
Isoquercitrin summary.
Name
Isoquercitrin
Structure
OH
OH
O
HO
HO
O
OH
Synonyms
IUPAC name
CAS No.
Molecular formula
Molar mass
Physical state
Spectral data
Solubility in water
Water/octanol
partition
Specic rotation
Melting point
HO
OH
O
CH2OH
Quercetin-3-glucoside, quercetin-3-O-glucoside, quercetin 3-O-b-D-glucopyranoside, isoquercitroside, isoquercitin, hirsutrin, 3glucosylquercetin, glucosyl 3-quercetin, isotrifolin, isohyperoside, and isotrifoliin
2-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxychromen-4-one
482-35-9
C21H20O12
464.38 g/mol
Yellow powder
UV/Vis absorption maxima at 257 and 352 (Slimestad, 2003) or 353 nm (Pudzianowska et al., 2012)
95 mg/l (Makino et al., 2009)
log P = 0.76 (Rothwell et al., 2005)
a27
589 58:0 (c = 0.1 mol /l, in MeOH) (Kwon et al., 2010)
198 C (Chebil et al., 2007), 188189 C (Calzada and Alanis, 2007)
(fresh black chokeberries fruits of the shrub Aronia melanocarpa

(Michx.) Elliott) mg isoquercitrin/100 g (mean 2.38, median
0.59 mg/100 g). Based on these data and considering the recommended daily dose of 5 100 g of fruits and vegetables, average
daily intake can be estimated at ca 312 mg.
Although isoquercitrin is widely distributed, it is difcult to obtain sufcient amounts in a pure state for the food and pharmaceutical industry, since its content in plant material is extremely low
(Lu et al., 2013c). A more convenient way to produce isoquercitrin
is, therefore, selective removal of rhamnose from rutin molecule,
which may be extracted e.g. from buckwheat or red beans.
Chemical hydrolysis of rutin is not possible since only (unwanted)
aglycone quercetin is produced. Enzymatic cleavage of rutin using
naringinase/hesperinase/rhamnosidase reactions followed by purication provides so-called enzymatically decomposed rutin
(Hasumura et al., 2004), which is typically a mixture of isoquercitrin and quercetin. We have recently developed an efcient method (Fig. 3) for the biocatalytic production of highly pure
isoquercitrin (ca 99.5%) from rutin using the alkali-tolerant a-Lrhamnosidase from Aspergillus terreus heterologously expressed
in Pichia pastoris (Gerstorferov et al., 2012; Kren et al., 2010;
Weignerov et al., 2012). On the other hand, EMIQ is manufactured
from rutin by transglycosylation with cyclodextrin glucotransferase, in which 07 (mean = 2) glucose units are a-coupled to the original glucose moiety (Akiyama et al., 2000).
2. Physico-chemical properties
2.1. Chemical structure
Flavonoids are benzo-c-pyrone derivatives composed of
phenolic and pyran rings and are classied according to the substitutions in the basic skeleton. In nature, avonoids exist primarily
as 3-O-glycosides and polymers (Heim et al., 2002). In the isoquercitrin molecule the glucose is attached to the C-3 of quercetin;
in rutin, L-a-rhamnopyranosyl-(1,6)-b-D-glucopyranose (rutinose)
Fig. 2. Distribution of records on isoquercitrin (topic = isoquercitrin) in Web of Science (507 records) and Scopus (1409 records) from the year 1950 to September 18, 2013.
270
OH
OH
OH
OH
-L-rhamnosidase
HO
HO
O
OH
OH
CH2O
O
H3C
HO
HO
O
OH
HO
O
OH
CH2OH
O
HO
Rutin
HO
HO
OH
Isoquercitrin
Fig. 3. Schematic representation of derhamnosylation of rutin to isoquercitrin.
subtitutes at the same position (Fig. 1). The following structural

elements of avonoids are important for their radical scavenging
activity: the o-dihydroxy (catechol) structure in the B-ring has a
pronounced antiradical activity; the 2,3-double bond in conjugation with a 4-oxo group in the C-ring has a capacity to delocalize
p-electrons and stabilize avonoid radicals after H-abstraction;
the C-3 (C-ring), C-5 and C-7 (A-ring) hydroxyl groups act as scavengers of free radicals (Heim et al., 2002; Makris and Rossiter,
2002). Quercetin is a planar molecule with torsion angle s of
180, in which electron delocalization between the B- and C-ring
is favoured. Bond dissociation enthalpies for the OH-groups
increase in the order 40 -OH < 30 -OH < 3-OH < 7-OH < 5-OH and Habstraction is, therefore, easier from the B-ring than from the Aring. The presence of the 2,3-double bond and the possibility of
keto-enol tautomerism allows H-abstraction from the quercetin
3-OH group forming a radical with high spin density at the C-2,
thus allowing C-ring opening during quercetin metabolism
(Trouillas et al., 2006).
2.2. Solubility, hydro-/lipophilicity
Flavonoids are weak acids and their solubility therefore
increases with rising pH (Weignerov et al., 2012). Flavonols generally exhibit poor solubility in water, and in aqueous solutions
they undergo spontaneous oxidation resulting in the formation of
insoluble matter (Emura et al., 2010). The glycosylation of avonols increases their solubility in water. The water solubility of
quercetin, isoquercitrin and rutin was estimated to be 50, 206
and 196 lmol/l (equivalent to 15, 95 and 120 mg/l, respectively),
compared to the free solubility of EMIQ (Makino et al., 2009).
In contrast, isoquercitrin and rutin were less soluble than quercetin
in polar organic solvents (Chebil et al., 2013, 2007). For experiments performed in aqueous buffers, stock solutions (up to
1000 concentrated) are usually prepared in dimethyl sulfoxide
(van der Woude et al., 2003; Vrba et al., 2012); suspensions in
water were used in vivo (Makino et al., 2009; Paulke et al., 2006).
The in vivo bioavailability and biological activity of a compound
depends not only on its mere solubility, but also on the interphase
partitioning. Lipophilicity and hydrophilicity controls protein and
membrane interactions, transport and binding activity, inuencing
absorption and excretion of the compound. The octanolwater
(buffer) partition coefcient of isoquercitrin (logP) was determined
to be 0.760.77 compared to 1.82 for quercetin, (0.25) for EMIQ
and (0.45)(0.64) for rutin (Murota et al., 2010; Rothwell
et al., 2005). The positioning of quercetin and its metabolites in
the membranes was investigated recently using molecular
dynamics simulations. Regardless of its initial position and
orientation, quercetin systematically incorporated into the lipid
membrane close to the polar head groups of the bilayer and was
almost parallel to the surface. No analogous data are available for
isoquercitrin to date, but both the sulfation and glucuronidation

of quercetin strongly increased the afnity of the molecules to
the aqueous phase (Koinov et al., 2012).
2.3. Spectral properties
One of the main biological functions of avonoids in plants is in
their pigmentation; quercetin is one of the main chromophores in
many of the avonoid-based dyes, used since the 15th century
(Rameov et al., 2012; Sokolov et al., 2011). This property is also
exploited in food products, together with their ability to protect
colours from degradation (FDA, 2007; Yan et al., 2013; Yokohira
et al., 2008).
The absorption spectra of avonoids consist of two distinctive
bands in the broad range of 240400 nm. Band I, appearing
between 300 and 380 nm, is ascribed to the B-ring (with kmax at
around 350370 nm), while band II covering the range of 240
280 nm (with kmax at ca 260270 nm) is attributed to the AC benzoyl system. A weak band with a maximum at around 300 nm was
ascribed to the C-ring alone (Cvetkovic et al., 2011). For isoquercitrin in methanol, bands were observed with kmax at 257 and 352
(Slimestad, 2003) or 353 nm (Pudzianowska et al., 2012).
The popularity of natural colorants in food products increased
after the discovery of probable association between the consumption of some articial dyes and child hyperactivity (McCann et al.,
2007). Natural pigments (e.g., anthocyanins) are not sufciently
stable, but their properties can be improved when a copigment
is added. The stabilization of grape skin anthocyanins by copigmentation with EMIQ was recently investigated. In ratios of 2:1,
1:1, and 1:2 (w/w, anthocyanin/EMIQ), the kmax value for anthocyanin increased signicantly. The copigmentation was also pHdependent, EMIQ inhibited the production of the colourless
carbinol pseudobase at pH 4 and 5 (Yan et al., 2013).
3. Biological activity
3.1. Molecular targets of isoquercitrin
The benecial effects of avonoids on human health are primarily attributed to their antioxidant and anti-inammatory activities.
Their antioxidant and/or antiradical action may be mediated
through the direct scavenging of reactive oxygen/nitrogen species
(ROS/RNS), inhibition of prooxidant enzymes or induction of antioxidant enzymes (Prochzkov et al., 2011). An investigation of
its antiradical activity in purely chemical systems revealed the
ability of isoquercitrin to scavenge ROS and RNS, including
superoxide anion radicals (Kim et al., 2013b), hydroxyl radicals
(Kong et al., 2008; Li et al., 2011), peroxyl radicals (Salucci et al.,
2002) and peroxynitrite (Nugroho et al., 2014). Isoquercitrin was
also found to scavenge superoxide radicals produced by a
xanthine/xanthine oxidase system and to inhibit xanthine oxidase

activity itself (Salem et al., 2010). Using murine macrophage
RAW264.7 cells, isoquercitrin was shown to attenuate superoxide
production stimulated with zymosan or phorbol 12-myristate 13acetate (PMA). In zymosan-activated RAW264.7 cells, isoquercitrin
inhibited the phosphorylation of the p47phox protein, a crucial
event in the assembly of the active phagocyte NADPH oxidase complex, which is responsible for superoxide production in a process
called oxidative or respiratory burst (Kim et al., 2013b). Isoquercitrin was also recognized as an inhibitor of myeloperoxidase, which
generates hypochlorous acid from H2O2 and Cl during respiratory
burst (Regasini et al., 2008). In rat peritoneal macrophages, isoquercitrin was found to attenuate lipopolysaccharide (LPS)-induced
expression of inducible nitric oxide synthase (iNOS) (Lee et al.,
2008). Although isoquercitrin did not suppress the expression of
iNOS stimulated by zymosan in RAW264.7 cells, cell treatment
with isoquercitrin reduced the levels of nitrite and protein-bound
3-nitrotyrosine, stable metabolites of nitric oxide and peroxynitrite, respectively (Kim et al., 2013b). As for antioxidant activity,
isoquercitrin was consistently demonstrated to attenuate oxidative
stress-induced cell death in vitro. For instance, isoquercitrin diminished H2O2-induced DNA damage in isolated human lymphocytes
(Boligon et al., 2012) and decreased intracellular ROS levels, glutathione depletion and lipid peroxidation in H2O2-treated rat retinal
ganglion RGC-5 cells (Jung et al., 2010). It should be mentioned
that isoquercitrin, like other avonoids, may also display pro-oxidant behaviour resulting from the formation of reactive avonoid
phenoxyl radicals through the autooxidation of avonoids or their
oxidation by ROS or peroxidases (Prochzkov et al., 2011). For instance, isoquercitrin was shown to induce a rapid NADPH oxidation in an NADPH/peroxidase/H2O2 system, even though it
caused neither DNA cleavage nor production of hydroxyl radicals
in vitro (Liu et al., 2010; Yang et al., 2012).
It is commonly believed that the antioxidant action of avonoids may play a positive role in various oxidative stress-related
diseases such as inammation, atherosclerosis and cancer (Reuter
et al., 2010). Nonetheless, in addition to relatively non-specic
antioxidant effects, a number of specic molecular targets of avonoids have been identied to date. Flavonoids are known to interact with other biomolecules, particularly with proteins, and hence
they may modulate the function of enzymes, cell receptors or transcription factors (Quideau et al., 2011). It was shown that the binding of isoquercitrin to human and bovine serum albumins used as
model proteins is markedly weaker than that of quercetin (Dangles
et al., 2001). However, isoquercitrin was reported to inhibit several
enzymes in vitro, such as rat liver microsomal 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Kwon et al., 2010), rat intestinal
a-glucosidase (Shibano et al., 2008), the a-glucosidase from Saccharomyces cerevisiae (Li et al., 2009b) and human a-amylase (Li
et al., 2009a). Similarly, isoquercitrin was shown to inhibit sugar
transport mediated by the glucose transporter GLUT2 (Kwon
et al., 2007).
Investigation of possible anti-inammatory activity showed
that isoquercitrin may decrease the levels of prostaglandin E2
produced by LPS-stimulated RAW264.7 cells (Hammer et al.,
2007), presumably via inhibiting the activity of cyclooxygenase-2
(Soberon et al., 2010). Isoquercitrin was also found to reduce the
production of interleukin-6 in human osteosarcoma MG-63 cells
stimulated by tumour necrosis factor a (Kim et al., 2013a). This
aside, isoquercitrin appeared to suppress the PMA-induced transcriptional activity of activation protein-1 (AP-1) and upregulation
of matrix metalloproteinase-9 in human brosarcoma HT1080
cells (Kong et al., 2008). Due to the anticancer potential of avonoids, their possible anti-angiogenic activity is receiving increasing
attention. Tumour growth and metastasis depends on angiogenesis, forming new vessels from pre-existing ones (Matsubara et al.,
271
2004) and inhibition of this process is a promising target in cancer

pharmacotherapy. Isoquercitrin was reported to inhibit angiogenesis in vitro and ex vivo; it was found to inhibit the outgrowth of
microvessels in a rat aortic ring assay and to reduce the proliferation, migration and tube formation of human umbilical vein
endothelial cells (Matsubara et al., 2004).
Other in vitro biological activities identied for isoquercitrin
include, for instance, its inhibitory activity on the formation of
advanced glycation end products (Jang et al., 2008). Isoquercitrin
was also found to promote the elongation of neurites in mouse
neuroblastoma/rat glioma hybrid NG108-15 cells through the
modulation of the expression, activity and intracellular localization
of Rho A GTPase (Palazzolo et al., 2012). Under oxidative stress
conditions, isoquercitrin was shown to induce the expression and
activity of sterol regulatory element-binding protein-2 (SREBP-2)
in human neuroblastoma SH-SY5Y cells. This effect resulted in
the stimulation of SREBP-2-mediated sterol synthesis and cytoprotection against H2O2-induced oxidative stress, presumably via
maintaining membrane integrity (Soundararajan et al., 2008). Isoquercitrin was found to activate the Wnt/b-catenin pathway in
mouse 3T3-L1 preadipocytes and inhibited their differentiation
(Lee et al., 2011). Isoquercitrin was also shown to downregulate
the protein levels of tyrosinase in mouse melanoma B16 cells, thus
inhibiting melanogenesis (Ohguchi et al., 2010). Chemopreventive
activity of isoquercitrin might also be related to the modulation of
xenobiotic-metabolizing enzymes (Section 5.2), generally thought
to have adverse consequences for drug metabolism (Kang et al.,
2004). For instance, the inhibition of CYP1A1 and CYP1B1 by
isoquercitrin may play a positive role since these enzymes activate
various procarcinogens such as polycyclic aromatic hydrocarbons
(Chaudhary and Willett, 2006). In vitro studies also show that certain avonoids, including quercetin, may cause a mild cellular
stress, which is associated with the activation of the cytoprotective
transcription factor Nrf2 that regulates the expression of antioxidant and phase II enzymes, thus leading to overall cytoprotection
(Prochzkov et al., 2011; Tanigawa et al., 2007).
It should be mentioned that isoquercitrin is usually effective in
cellular models at concentrations of about 10 lM and above. Such
high concentrations of isoquercitrin were not found in plasma of
experimental animals (see Section 4.2), but it cannot be ruled out
that these concentrations may be reached, for instance, in the
intestine or in the liver. In vitro studies also show that the biological activity of isoquercitrin is not as broad as that of quercetin. For
instance, isoquercitrin, unlike quercetin, does not induce the
expression of heme oxygenase-1, which produces the antioxidant
biliverdin and anti-inammatory agent carbon monoxide (Vrba
et al., 2013). It may be nevertheless presumed that many molecular
targets of isoquercitrin will be discovered in the future.
3.2. Animal and clinical studies

Most of the in vivo studies with isoquercitrin, besides those
devoted to its bioavailability, metabolism and safety (Section 5),
are focused on its potential antioxidant, anti-inammatory, anticarcinogenic, cardioprotective, antidiabetic, anti-allergic, and neuropharmacological activities.
Protective effects of isoquercitrin (single dose 0.12512.5 lmol/
kg, i.p.) against cadmium-induced lipid peroxidation and protein
oxidative damage were investigated in mice treated with CdCl2.
Isoquercitrin was shown to chelate Cd2+ and to attenuate its toxic
effects, including the decrease in superoxide dismutase (SOD) and
catalase activities, elevated lipid peroxidation (determined as thiobarbituric acid reacting substances, TBARS), and production of nitric oxide, protein carbonyls and DNAprotein crosslinks (Li
et al., 2011). Locally applied isoquercitrin (10 mg/kg) displayed
272
preventive effects against carrageenan-induced inammation in

rats (Morikawa et al., 2003).
Both isoquercitrin and EMIQ at a dose of 1% in a basal diet
(equivalent to 500 mg/kg/day) in rats for one week exhibited
in vivo antioxidant power measured in the serum and compared
to rats fed the basal diet. In rats, isoquercitrin and EMIQ administered at doses of 0.01%, 0.1% and 1% for six weeks caused a dosedependent but non-signicant decrease in the number and area
of GST-P positive preneoplastic liver lesions induced by N-diethylnitrosamine (Yokohira et al., 2008). EMIQ administration at a
dose of 2000 ppm in distilled water for 10, 8 and 6 weeks to male
F344/N Slc rats two weeks after i.p. N-diethylnitrosamine injection
and fed a diet containing oxfendazole, phenobarbital, b-naphtoflavone or thiocetamide signicantly reduced the number of GSTP-positive foci (Fujii et al., 2013; Kuwata et al., 2011; Morita
et al., 2011; Nishimura et al., 2010; Shimada et al., 2010). EMIQ decreased CYP2B2 and malic enzyme expression and inhibited ex vivo
NADPH-dependent ROS production in microsomes from rats treated with oxfendazole (Nishimura et al., 2010). With phenobarbital,
EMIQ attenuated the proliferative cell nuclear antigen (PCNA) ratio
and constitutive active/androstane receptor (CAR) nuclear positivity with no effect on liver microsomal ROS production, 8-hydroxydeoxyguanosine or TBARS content (Morita et al., 2011). EMIQ
inhibited the b-naphtoavone-induced increase of TBARS levels,
content of heme oxygenase-1 positive macrophages and induction
of antioxidant-, apoptosis- and inammation-related genes in the
liver (Kuwata et al., 2011). In contrast, when tumour promotion
was achieved with thiocetamide, co-administration with EMIQ increased the hepatic TBARS and 8-hydroxydeoxyguanosine levels,
the number of apoptotic and death receptor-5 (DR5)-positive cells,
and the content of 4-hydroxy-2-nonenal within the GST-P positive
foci. Outside the foci, EMIQ decreased the number of apoptotic and
DR5-positive cells. These results suggest a mainly anti-inammatory and pro-apoptotic activity of EMIQ in this model (Fujii et al.,
2013). In contrast, EMIQ co-treatment failed to supress the effects
of ochratoxin A, a renal carcinogen (Taniai et al., 2013).
Recently, quercetin glucosides (identical to EMIQ, 100 mg/kg/
day, p.o.) reduced tumour size in mice inoculated with murine syngeneic colon cancer cells. On the other hand, EMIQ promoted ischemia-induced angiogenesis and blood ow recovery in a murine
hindlimb ischemia model by a mechanism dependent on endothelial NO synthase. Moreover, the treatment resulted in an increased
plasma glutathione level. Taken together, these results suggest that
quercetin glucosides may suppress pathological angiogenesis and
stimulate physiological angiogenesis (Sumi et al., 2013).
Signicant effects of isoquercitrin and EMIQ on the cardiovascular system were also observed. After 22 days of oral administration
(3 and 26 mg/kg), EMIQ dose-dependently suppressed the increase
in mean blood pressure and heart rate in spontaneously hypertensive rats (Emura et al., 2007). In the same model, isoquercitrin
(0.54 mg/kg, i.v.) exhibited an antihypertensive effect involving
the inhibition of the angiotensin-converting enzyme and a diuretic
effect comparable with that of standard diuretics (Gasparotto
Junior et al., 2012). In atherogenic apoE-decient mice fed a
high-fat diet, EMIQ supplementation (0.026%) of the high fat diet
for 14 weeks signicantly suppressed the aortic atherosclerotic
lesion area as well as the macrophage and 4-hydroxy-2-nonenal
content in the plaques (Motoyama et al., 2009).
The potential antidiabetic activity of isoquercitrin was investigated several times in rats. Isoquercitrin (15 mg/kg/day, p.o. for
10 days) inhibited aloxan-induced hyperglycemia, hepatic and renal lipid peroxidation and the activity of hepatic glucose-6-phosphatase, while the activities of catalase and SOD, and the content
of glutathione were increased (Panda and Kar, 2007). Isoquercitrin
(single dose 100 mg/kg, p.o.) also delayed the glycaemic peak
by 30 min in oral glucose tolerance tests and thus exhibited a
time-dependent anti-hyperglycemic activity. On the other hand,

50 and 200 mg/kg were not active in this model (Paulo et al.,
2008) and no signicant effect on fasting plasma glucose level
was found in rats treated with isoquercitrin (3 or 9 mg/kg, p.o.)
for 11 days (Hunyadi et al., 2012).
A series of studies were devoted to the anti-allergic activity of
isoquercitrin and EMIQ. Isoquercitrin was identied as one of the
active components of Argemone platyceras Link & Otto (prickly
poppy) with anti-asthmatic properties. Isoquercitrin (>6.4 lM)
inhibited the ovalbumin antigenic response and leukotriene-induced response in guinea pigs airways ex vivo (Fernandez et al.,
2005). In a murine model of asthma, isoquercitrin (15 mg/kg/day,
p.o. for 5 days) supressed ovalbumin induced eosinophil counts
in bronchoalveolar lavage uid, blood and lung parenchyma, acting
as effective anti-inammatory agents with a potential for treating
allergies (Rogerio et al., 2007). EMIQ and, to a lesser extent, isoquercitrin, signicantly suppressed the allergic reaction in the murine
ear passive cutaneous anaphylaxis reaction using ovalbumin
(Makino et al., 2009). In human subjects, 100 mg/day EMIQ for
8 weeks was shown to effectively relieve ocular symptoms of
Japanese cedar pollinosis when administered preventively (Hirano
et al., 2009) or therapeutically (Kawai et al., 2009).
Isoquercitrin is present in many tranquillizing plants and probably is, together with other avonoids, responsible for part of their
neuropharmacological properties (Loscalzo et al., 2009). Isoquercitrin (0.6 mg/kg, p.o.) was one of the pure compounds from Hypericum perforatum found to be active in the forced swimming test
in rats (Butterweck et al., 2000). In mice, isoquercitrin (30 mg/kg,
i.p.) signicantly reduced the number of rearings in the hole board
test, which measures sedative behaviour (Loscalzo et al., 2009).
Among other biological activities, isoquercitrin (ID50 19.2 lmol/
kg) exhibited a moderate ability to reduce intestinal uid secretion
following Vibrio cholerae enterotoxin administration to rats
(Velazquez et al., 2009) and antiprotozoal effects against Entamoeba histolytica (IC50 14.7 lg/ml) and Giargia lamblia (IC50
47.5 lg/ml) (Calzada and Alanis, 2007).
4. Bioavailability and metabolism

A complete overview of the absorption, bioavailability and metabolic prole of isoquercitrin is not easy to obtain. Various metabolites can be formed before and after absorption and identication
of the metabolites strongly depends on the analytical procedure
used. In many older studies, detection using HPLC with UVVis
(Day et al., 2003; Spencer et al., 1999) or uorescence after chelation with Al3+ (Al(NO3)3) (Ader et al., 2000) was used with relatively low sensitivity. Often, detection was carried out in samples
after enzymatic or acid hydrolysis (Cermak et al., 2003; Day
et al., 2003; Paulke et al., 2012; Spencer et al., 1999), which did
not allow precise identication of some metabolites (conjugates).
Moreover, both enzymatic and acid hydrolytic treatment also
cleaves the b-glycosidic bond in isoquercitrin (Wang et al., 2011;
Wolffram et al., 2002).
There are only a few studies that have been done using pure
isoquercitrin and comparing its metabolism with that of quercetin
(Paulke et al., 2012) and/or EMIQ and rutin (Cermak et al., 2003;
Makino et al., 2009; Murota et al., 2010; Reinboth et al., 2010).
Other metabolic studies used enzymatically modied rutin or food
containing isoquercitrin together with a mixture of other structurally similar compounds (He et al., 2013; Lu et al., 2013a; Zhou
et al., 2011). Most of the researchers were only looking for metabolites with an intact avonol structure and limited data are
available about (microbial) degradation (C-ring ssion) products
that can be absorbed. Similarly, information about metabolites in
faeces is scarce. Last but not least, various polyphenols, including
quercetin, were shown to be able to adsorb to the surface of erythrocytes and other cells, thus playing a pivotal role in the distribution and bioavailability of circulating phenolics (Ginsburg et al.,
2011; Koren et al., 2010). To our knowledge, no information about
this phenomenon is available for isoquercitrin or its metabolites
in vivo.
4.1. Absorption and bioavailability
Despite many in vitro and in vivo studies, the absorption of
avonoids in the gastrointestinal tract remains unclear (Crozier
et al., 2010). Data from animal and human studies (Ader et al.,
2000; Erlund et al., 2000; Graefe et al., 2001) provide good
evidence for some, but not all avonoids being primarily absorbed
in the small intestine. It was originally thought that only deglycosylated quercetin can be absorbed at the intestinal level due to its
hydrophobic nature (Kuhnau, 1976). However, later studies demonstrated that quercetin glycosides exhibit higher bioavailability
than the aglycone (Hollman et al., 1995, 1997, 1996) while quercetin glucosides are absorbed more rapidly than other types of glycosides such as rutin (Arts et al., 2004; Cermak et al., 2003; Reinboth
et al., 2010; Russo et al., 2012). The bioavailability of isoquercitrin
(and quercetin) in pigs and rats can be increased when administred
together with a high fat (17%) diet (Lesser et al., 2004), alcohol
(Dragoni et al., 2006) or nondigestible oligosaccharides
(Matsukawa et al., 2009).
Isoquercitrin, in contrast to quercetin, was shown to be not
absorbed in the stomach (Crespy et al., 2002). The intestinal
absorption of isoquercitrin is thought to be associated with its
deglycosylation (see Section 4.3) mostly by lactase-phlorizin
hydrolase (LPH, known also as lactase), responsible for the hydrolysis of the disaccharide lactose and able to hydrolyse a broad
range of avonoid glucosides. The free quercetin released can enter
epithelial cells by passive diffusion due to higher lipophilicity and
proximity to the cell membrane (Day et al., 2000; Gee et al., 2000).
Indeed, in human colon adenocarcinoma Caco-2 cells (having very
low levels of LPH) the uptake of isoquercitrin was lower than that
of quercetin (Boyer et al., 2004) and hyperoside (quercetin-3-Ogalactoside) (Zuo et al., 2006). Alternatively, the Na+-dependent
glucose transporter SGLT1 was thought to mediate the transport
of intact glycosidic forms of avonoids into epithelial cells,
followed by intracellular cleavage by cytosolic b-glucosidase
(Wolffram et al., 2002). However, the experimental arrangement
(SGLT1 inhibition by Na+ restriction and phlorizin) used in this
study did not enable to discriminate between inhibition of SGLT1
and competition for LPH active sites (Arts et al., 2002). Isoquercitrin was found to be absorbed into rat everted-jejunal sacs only
after hydrolysis by LPH (Day et al., 2003). Moreover, a study using
SGLT1 expressed in Xenopus laevis oocytes indicated that SLGT1
neither transports isoquercitrin nor other tested avonoids (Kottra
and Daniel, 2007). However, other recent studies analysing nonhydrolysed samples found considerable amounts of intact isoquercitrin in rat plasma after the administration of isoquercitrin-rich
plant extracts (He et al., 2013; Li et al., 2008; Zhou et al., 2011). The
mechanism of the absorption of intact isoquercitrin remains
unknown.
A study in rats showed that isoquercitrin was absorbed better
than quercetin, rutin and quercitrin (quercetin-3-O-rhamnoside)
(Morand et al., 2000). In healthy humans, isoquercitrin (151 mg,
p.o.) had similar bioavailability as spiraeoside (Olthof et al.,
2000). In pigs equipped with a permanent jugular (and portal)
catheter, the bioavailability of a single oral dose equivalent to
148 lmol/kg increased in the order rutin (23 relative %) < quercetin (100%) < isoquercitrin (148%). The relative bioavailability of
isoquercitrin increased signicantly using a smaller dose of
29.6 lmol/kg (167% compared to quercetin) and when mixed with
273
ground beef compared to a standard diet (240%) (Cermak et al.,

2003). Similar results were also found in dogs fed with quercetin,
isoquercitrin or rutin at a dose of 30 lmol/kg orally. The plasma
concentration of quercetin metabolites (glucuronidated and/or sulfated conjugates of quercetin and isorhamnetin) was higher after
the administration of isoquercitrin compared to the aglycone.
The absolute bioavailability of quercetin was 4%; the relative
bioavailability was 92% for rutin, 100% for quercetin and 235% for
isoquercitrin (Reinboth et al., 2010).
Conjugated quercetin, isorhamnetin and tamarixetin were
found in portal and peripheral blood plasma and in the bile of rats
after in situ intestinal perfusion with isoquercitrin (Arts et al.,
2004). The same metabolites were also detected in the plasma
and brains of rats 4 h after a single dose of St. Johns wort
(H. perforatum) extract (1600 mg/kg) or isoquercitrin (100 mg/kg,
p.o.; Paulke et al., 2006). After oral administration of isoquercitrin
(50 lmol/kg) in rats under anaesthesia, a rapid (15 min after ingestion) increase in the plasma concentration of quercetin and tamarixetin (conjugates) was observed. EMIQ was absorbed even more
easily and to a greater extent (Makino et al., 2009). The maximal
plasma level of quercetin metabolites in human subjects was
achieved at 1.5 h for EMIQ, indicating absorption in the upper
intestine. After consumption of isoquercitrin, the plasma level of
metabolites was almost constant over 6 h. In contrast, very low
levels of metabolites were found after consumption of rutin. The
area under the curve was apparently increased in the order
rutin < isoquercitrin < EMIQ (Murota et al., 2010). A very recent
comparison of quercetin (12 mg/kg/day) and isoquercitrin
(18 mg/kg/day) bioavailability was performed in rats fed by intragastric gavage for 8 days. Consistently higher levels of metabolites
in samples of the liver, lung, heart, kidney, brain and plasma (25fold) were found in rats fed with isoquercitrin compared to those
supplemented with quercetin. These ndings show that the bioavailability of quercetin can be enhanced using isoquercitrin as
its source. Furthermore, the authors proposed to enrich quercetin-containing herbal extracts with isoquercitrin and standardise
them according their isoquercitrin content (Paulke et al., 2012).
On the other hand, enhanced bioavailability might lead to more
pronounced adverse effects, especially those related to the modulation of drug metabolism (Section 5.2).
4.2. Pharmacokinetics
Pharmacokinetic studies in various models using plasma pretreated by deconjugating enzymes (Cermak et al., 2003; Reinboth
et al., 2010) have consistently shown the rst concentration peak
of quercetin conjugates appearing about 6090 min after isoquercitrin consumption followed by the second, higher peak at 2.5
4 h, indicating intensive enterohepatic circulation. For instance,
in dogs administered with isoquercitrin (30 lmol/kg p.o.), cmax1
(for quercetin) of 667 nM was found at 0.8 h and cmax2 of
88.3 nM appeared at 4.1 h. Mean residence time was determined
to be 6.4 h, AUC for quercetin and isorhamnetin conjugates were
353 and 45 min lmol/l, respectively (Reinboth et al., 2010).
Only three studies using various isoquercitrin-containing plant
extracts in rats focused on determination of intact isoquercitrin in
plasma and its pharmacokinetics. Only one peak was consistently
found in the plasma with elimination half-life 0.82.7 h and peak
concentration 1234309 ng/ml (equivalent to 0.39.3 lM; for detailed pharmacokinetic data, see Table 2). On the other hand, no
metabolites were reported in these studies (He et al., 2013; Li
et al., 2008; Zhou et al., 2011). From these data it can be concluded
that amounts of isoquercitrin close to those usually found active
in vitro (ca 10 lM, see Section 3.1) can be absorbed intact and that
it is quickly eliminated and/or biotransformed to quercetin and
isorhamnetin conjugates.
274
Table 2
Pharmacokinetic proles of isoquercitrin in rat plasma after oral administration of isoquercitrin containing plant extracts.
Source
Hypericum japonicum*
Apocynum venetum** (leaves)
Morus alba*** (leaves)
n
Dose (extract)
Extract composition (mg/g)
5
23.0 g/kg
Quercitrin (2.1), isoquercitrin (2.7)
6
0.48 g/ml
Not provided
Dose (isoquercitrin)
t1/2 (h)
cmax (ng/ml)
tmax (h)
Ke (h1)
AUC(0t) (ng h/ml)
AUC(01) (ng h/ml)
Ref.
62.1 mg/kg
2.16 0.50
4309 332
1.17 0.24
0.34 0.09
7689 2006
7875 2074
Li et al., 2008
Not provided
2.71 1.99
147.7 9.2
0.5 0.0
n.d.
317.4 330.5
330.5 7.9
Zhou et al., 2011
8
1 g/kg
Rutin (29.7), isoquercitrin (38.1),
astragalin (24.9), quercetin (4.0)
38.1 mg/kg
0.88 0.61
122.66 70.32
0.23 0.12
1.20 0.78
99.51 22.04
106.38 21.71
He et al., 2013
t1/2,
*
elimination half-life; cmax, peak plasma concentration; tmax, time to reach cmax; Ke, apparent elimination rate constant; AUC, area under the curve.
Matted St. Johns worth.
European dogbane.
***
White mulberry.
**
4.3. Biotransformation
Originally, no hydrolysis of avonoid glycosides seemed to occur in the oral cavity. Some data suggest however that at least
some glycosides, probably glucosides, can be efciently hydrolysed
there (Browning et al., 2005; Walle, 2004). To date, no enzymes involved in the biotransformation of avonoid glycosides were identied in the stomach. Accordingly, isoquercitrin was stable during
incubation with gastric content preparations (Chang et al., 2005;
Zuo et al., 2006). On the other hand, isoquercitrin may undergo
deglycosylation by microbial enzymes or by LPH present on the
outer surface of the intestinal brush border (Day et al., 2000). Indeed, the hydrolysis of isoquercitrin to quercetin by small intestinal content preparation was inhibited by the presence of phlorizin
(Zuo et al., 2006). If absorbed intact, isoquercitrin can be hydrolysed in enterocytes by cytosolic b-glucosidases. The liberated
quercetin is then glucuronidated, sulfated and/or methylated by
UDP-glucuronyltransferases (UGTs), sulfotransferases (SULTs) and
catechol-O-methyl transferases, all of which were found in human
and rat intestine. Among the conjugated derivatives in plasma, 78
79% was as quercetin, 8.511% as isorhamnetin and 1013% as
tamarixetin conjugates (Cermak et al., 2003; Lesser et al., 2004).
A signicant amount of conjugated avonoids is re-secreted by
enterocytes via multidrug resistance-associated protein 2 (MRP2)
or breast cancer resistance protein (BCRP) into the intestinal lumen
(Cermak and Wolffram, 2006). Glucuronides could serve as a more
stable quercetin transport form; they can be deconjugated e.g. in
vascular smooth muscle cells (Galindo et al., 2012; Menendez
et al., 2011). On the other hand, methylated and/or conjugated
metabolites also exhibit biological activity, which can be either
similar to or different from that of the parent compound (Araujo
et al., 2013; Beekmann et al., 2012; Lodi et al., 2008; Tribolo
et al., 2008; Williamson et al., 2005).
It has been shown that isolated rat intestine hydrolyses isoquercitrin and glucuronidates the released aglycone; quercetin and
quercetin glucuronides were found in the serosal uid in the ratio
of 1:3 (Spencer et al., 1999). After isoquercitrin transport into rat
everted intestinal sacs, quercetin and its 3- and 7-glucuronides
were detected in the serosal compartment (Gee et al., 2000). Isoquercitrin was found to be relatively unstable in the small intestine
and colon contents in vitro. After 30 min of incubation, 36%, 70%,
96% and 100% of the isoquercitrin was degraded by the content
of the duodenum, jejunum, ileum and colon, respectively (Chang
et al., 2005). In Caco-2 cells, which lack various biotransformation
enzymes, including UGTs, no metabolites of isoquercitrin were
produced. Using a rat in situ intestinal perfusion model, quercetin
glucuronides appeared mainly in mesenteric blood (Zuo et al.,
2006). When incubated with a homogenate from the rat intestinal
epithelium, isoquercitrin was rapidly deglycosylated to quercetin.

In the same model, the degradation of EMIQ to quercetin was associated with a transient increase in the concentration of isoquercitrin, indicating that isoquercitrin is an intermediate of EMIQ
digestion (Makino et al., 2009).
Intestinal bacteria also play an important role in isoquercitrin
metabolism. Isoquercitrin can be hydrolysed by Enterococcus casseliavus and the released aglycone can be degraded to 3,4-dihydroxyphenylacetic acid and phloroglucinol, which is further
metabolized to acetate and butyrate e.g. by Eubacterium ramulus
and Clostridium orbiscindens isolated from human faeces (Schneider
et al., 1999; Schoefer et al., 2003). Quercetin was also reported to
be metabolized to various phenolic (3-hydroxybenzoic, 3,4-dihydroxybenzoic and 3,4-dihydroxyphenylacetic) acids by certain
strains of Pediococcus spp., Streptococcus spp., Lactobacillus spp.,
Bidobacterium spp. and Bacteroides spp. (discussed in Cermak
and Breves, 2006). In acidied faeces and urine of germ-free gnotobiotic rats fed with isoquercitrin, only quercetin and isorhamnetin
were found. Samples from rats associated with the human intestinal bacteria E. ramulus and E. casseliavus contained signicant
amounts of 3,4-dihydroxyphenylacetic acid (Schneider et al.,
2000). Quercetin, isoquercitrin and rutin were all degraded
in vitro by porcine hindgut content (Cermak and Breves, 2006). Isoquercitrin metabolites produced by bacteria isolated from human
faeces were recently analysed using an LC/MS technique. Quercetin, acetylated or dehydroxylated isoquercitrin, and hydroxylated
or hydroxymethylated quercetin were found to be the major
metabolites (Lu et al., 2013b). However, avonoids in general, are
further degraded into numerous phenolic and carboxylic acid
products (Heinrich et al., 2013), as well as to carbon dioxide
(Walle, 2004; Walle et al., 2001).
After in vitro colonic fermentation of quercetin and some of its
glycosides (but not isoquercitrin) with rat faecal material for 48 h,
the main fermentation product was protocatechuic acid, followed
by phenylacetic, homovanilic and p-hydroxybenzoic acids (Serra
et al., 2012). Similar compounds were found after exhaustive
electrochemical hydrolysis of quercetin (Rameov et al., 2012;
Sokolov et al., 2011, 2012). The proposed metabolic pathway for
quercetin degradation by rat colonic ora includes C-ring ssion
and the formation of 3-(3,4-dihydroxyphenyl)propionic acid, further degraded into 3,4-dihydroxyphenylacetic acid. Subsequent
degradation leads to protocatechuic acid and then to 4-hydroxybenzoic acid. 3,4-Dihydroxyphenylacetic acid may also be dehydroxylated to m- or p-hydroxyphenylacetic and phenylacetic acids
(Serra et al., 2012).
The biotransformation of both isoquercitrin and the aglycone
quercetin may also proceed in the liver. LC/MS analyses of metabolites produced by isolated human or rat hepatocytes showed that
275
OH
C2H5O
OH
OH
OH
OH
HO
OH
HO
OH
OH
HO
EMIQ
O H
n=0-7
OH
HO
OH
O
OH
HO
OH
OH
acetylated isoquercitrin
OH
OH
O
OH
OH
HO
HO
O
O
OR1
OR2
OH
O
HO
OH
OH
O
OH
OR
OR2
O
OH
2(3,4-dihydroxyphenyl)2-oxoacetic acid
O
Obutyrate
methylated and conjugated

isoquercitrin derivatives
HO
OH
O
OH
OH
OR3
CO2
HO
Oacetate
OH
phloroglucinol
OH
OH
OH O
methylated and conjugated
quercetin derivatives
O
OH
Quercetin
HO
OH
HO
O
HO
OH
OH
OH
OH
OH
O
HO
OH
OH
OH O
dehydroxylated isoquercitrin
OH
OH
O
O Isoquercitrin
OH
HO
OH
HO
OH
HO
OH
OH
O
3-(3,4-dihydroxyphenyl)propionic acid
HO
HO
OH
2,4,6-trihydroxybenzoic acid
HO
OH
OH
OH
O
3-hydroxyphenylacetic acid
O
phenylacetic acid
HO
OH
OH
HO
OH
OH
3,4-dihydroxyphenylacetic acid
3,4-dihydroxybenzoic
(protocatechuic) acid
O
OH
OH
O
OH
OH
OMe
HO
OH
3-methoxy-4-hydroxy-phenylacetic acid
OH
p-hydroxybenzoic acid
Fig. 4. Schematic representation of isoquercitrin metabolism in mammals (according to (Harwood et al., 2007; Lu et al., 2013b; Rameov et al., 2012; Serra et al., 2012;
Schneider et al., 1999; Vacek et al., 2012; Walle, 2004); speculative intermediate is in grey). R1, R2, and R3 represent b-D-glucuronopyranosyl-, sulfate- or methyl- moieties.
the predominant biotransformation processes for quercetin and its

glycosides, isoquercitrin and rutin, were methylation and glucuronidation. After the incubation of hepatocytes with isoquercitrin,
the metabolites included two mono-methylated derivatives, two
mono-glucuronides and three mono-methylated glucuronides. Isoquercitrin was, however, metabolized somewhat less extensively
in hepatocytes than the aglycone (Vacek et al., 2012). An overview
of potential isoquercitrin metabolites is given in Fig. 4.
In some studies (Ader et al., 2000; Reinboth et al., 2010),
kaempferol (3,5,7,40 -tetrahydroxyavone) was reported to be an
isoquercitrin metabolite. Nonetheless, the enzyme mixture from
Helix pomatia, used for the hydrolysis of conjugated metabolites,
was identied to be responsible for the appearance of kaempferol
and/or quercetin in treated samples. After correcting for this contamination, the authors concluded that kaempferol is neither a
metabolite of quercetin nor isoquercitrin (Cermak et al., 2003).
In animal studies where plasma samples were hydrolysed

either by b-glucuronidase/arylsulfatase from H. pomatia or
under acidic conditions, quercetin, isorhamnetin (30 -methylquercetin) and sometimes tamarixetin (40 -methylquercetin) were
consistently found to be main metabolites of both isoquercitrin
and EMIQ (Cermak et al., 2003; Makino et al., 2009; Morand
et al., 2000; Paulke et al., 2012; Reinboth et al., 2010). In pigs
tted with a permanent jugular and portal catheter, only conjugated quercetin metabolites were found in not only jugular but
also portal blood plasma after the administration of quercetin,
isoquercitrin or rutin, indicating that avonols are extensively
metabolized in intestinal mucosa (Cermak et al., 2003). In rats
with cannulated jugular veins administered a single oral dose
of isoquercitrin (4.5 mg/kg), quercetin glucuronide and a trace
amount of intact glucoside were found in plasma (Chang
et al., 2005).
276
In human subjects, neither aglycone nor glucosides, in contrast

to glucuronides, were detected in plasma after supplementation
with isoquercitrin or spiraeoside (Sesink et al., 2001). In a later
study, metabolic proles of isoquercitrin and EMIQ in plasma did
not differ, with the glucuronides of quercetin and isorhamnetin,
and 30 -sulfate of quercetin being observed as major metabolites
(Murota et al., 2010).
In contrast to all the ndings above, some recent studies found
substantial amounts of intact isoquercitrin in rat plasma (He et al.,
2013; Li et al., 2008; Xue et al., 2011a; Zhou et al., 2011) and mouse
brains (Guo et al., 2011) after administration of isoquercitrin rich
plant extracts (He et al., 2013; Li et al., 2008; Xue et al., 2011; Zhou
et al., 2011). A common feature of these experiments was effective
plasma extraction without the hydrolysis of samples and sensitive
HPLC or LC/MS analyses. On the other hand, these studies were
done using complex mixtures containing non-dened compounds
that can affect the metabolism of isoquercitrin (Zuo et al., 2006).
Moreover, no conjugates were reported in these studies. These
results, however provide evidence for the absorption of intact avonoid isoquercitrin very shortly after their application followed
by release of the aglycone at the intestinal level (He et al., 2013).
Nevertheless, further research is required to elucidate the fate of
isoquercitrin and its metabolites in human body uids and organs.
4.4. Biodistribution and excretion of metabolites
Quantitative data about the biodistribution and excretion of isoquercitrin metabolites are scarce in the literature. Only two studies
(Makino et al., 2009; Reinboth et al., 2010) evaluated absolute bioavailability of isoquercitrin in rats and dogs compared to equimolar dose of quercetin i.v. and found 912% (n/n) of isoquercitrin
(compared to 23.8% of quercetin and 35% for EMIQ) in plasma
as conjugated quercetin metabolites.
From other studies, a rough estimate can be made using (maximal) plasma or organ concentration and approximate total plasma
volume (ca 3752 ml/kg) (Berson, 1954; Fox et al., 1984; Hansard
et al., 1953; Lee and Blaufox, 1985) and organ weights (Okamura
et al., 2011). Using this approach, maximum plasma content of intact isoquercitrin in rats (He et al., 2013; Li et al., 2008) was calculated to be 0.061.38% of the dose administered, compared to
0.043.2% as conjugated quercetin in rats, pigs and dogs (Lesser
et al., 2004; Makino et al., 2009; Murota et al., 2010; Olthof
et al., 2000; Reinboth et al., 2010) and 1.510 times higher compared to the same dose of the aglycone (Lesser et al., 2004; Makino
et al., 2009; Reinboth et al., 2010). Urine content in rats and human
subjects in the rst 24 h was 1.25.6% of the dose as quercetin and
isorhamnetin conjugates (Olthof et al., 2000; Schneider et al.,
2000). In rat faeces, trace amount of quercetin was found and ca
9% of the dose was recovered as 3,4-dihydroxyphenylacetic acid
(Schneider et al., 2000). Concerning the content in various tissues
in rats, 0.027% of the dose was found in the brain, 0.403% in the
liver, 0.025% in the heart, 0.085% in kidneys, 0.084% in the lung
and 3.2% in plasma (Paulke et al., 2012).
Considering the maximum values from the above mentioned
studies, all these represent only 19% (or 29% using the absolute bioavailability) of the dose administered. Moreover, considering the
nding of (Walle et al., 2001) that 2381% of the C4@O moiety of
the quercetin molecule is excreted as CO2, lead us to the conclusion
that the fate of isoquercitrin metabolites is far from being known. A
robust study on the biodistribution and excretion of isoquercitrin
and its metabolites is needed, including in the same model (i) oral
and intravenous application; (ii) determination of intact isoquercitrin (without enzymatic or acid hydrolysis) and all possible metabolites (including phenolic acids and related compounds as
suggested in Fig. 4), and (iii) analysis of all relevant organs, body
uids and excrements.
5. Data related to the safety

As a naturally occurring compound, small amounts of isoquercitrin are a common component of a normal human diet. However,
based on its benecial properties, interest in food supplementation
with this avonol has been increasing. Prior to the common use of
isoquercitrin in doses that would increase its uptake beyond that
from natural sources, the safety of isoquercitrin needs to be established and/or conrmed. Basically no toxicological studies were
performed and no evaluation of pure isoquercitrin has been conducted so far. On the other hand, the safety of quercetin has been
evaluated in a variety of genotoxicity assays and a full range of
acute, subchronic, chronic and reproductive toxicity studies that
have been critically reviewed recently (Harwood et al., 2007;
Okamoto, 2005) and high-purity quercetin was Generally Recognized As Safe (GRAS) in 2010 (FDA, 2010).The issue of quercetin
safety is relevant to isoquercitrin since quercetin may be a metabolite as well as an unwanted admixture of both isoquercitrin and
EMIQ preparations (FDA, 2007).
5.1. Safety/potential toxicity

According to unpublished results from the Japanese Ministry of
Health, Labour and Welfare cited by Hasumura et al. (2004) and
Tamura et al. (2010), isoquercitrin was mutagenic in the Ames test
using Salmonella typhimurium TA 98 and TA1537 strains but no
genotoxicity was found using the chromosome aberration test in
cultured mammalian cells or the micronucleus test in mice.
Isoquercitrin enhanced the mutagenic response of S. typhimurium
to 2-acetamidouorene, but exhibited a protective effect against
mutagenicity induced by aatoxin B1 (Snijman et al., 2007), tertbutylhydroperoxide and cumene hydroperoxide (Edenharder and
Grunhage, 2003).
The general toxicity of enzymatically decomposed rutin
containing 95% isoquercitrin was evaluated with a dietary administration at concentrations of 0%, 0.2%, 1% and 5% to Wistar rats for
13 weeks. Neither mortality, obvious clinical signs, macroscopic
nor histopathological ndings (except for yellowish urine in
animals from the 5% group) were observed throughout the experiment. Males receiving 5% exhibited a slight reduction in body
weight, signicant decrease in triacylglycerol, total bilirubin, inorganic phosphorus, haemoglobin and haematocrit and slightly
increased relative lungs and testes weights. Females with the same
treatment had a decreased monocyte ratio. Based on these results,
the no-observed-adverse-effect level (NOAEL) and the no-observed-effect level (NOEL) of enzymatically decomposed rutin
in Wistar rats were estimated to be 1% (539 mg/kg/day, i.e. 38 g
for a 70 kg individual) in males and 5% (3227 mg/kg/day, i.e.
225 g/70 kg/day), respectively (Hasumura et al., 2004).
A subsequent evaluation of chronic (52 weeks) toxicity on Wistar rats was performed with the same product at 0%, 0.04%, 0.2%,
1% or 5% in the daily diet. No toxicological ndings were found
in the mortality, clinical biochemistry or organ weights. Chromaturia, increased urinary calcium excretion in both sexes and incidence of mineralization, inammatory cell debris, inammatory
cell inltration and/or transitional cell hyperplasia in the renal pelvis in males were noted in the 5% group. The NOAEL was therefore
estimated to be 1%, corresponding to 542.4 mg/kg/day (Tamura
et al., 2010). Using a 100-fold safety factor, the NOAEL converts
to an acceptable daily intake (ADI) of 5.4 mg/kg/day, or 378 mg/
person/day (70 kg/person).
Toxicological data available for EMIQ were examined in 2006
2007 by an Expert Panel of independent scientists to determine
whether EMIQ, under the conditions of intended use as an
antioxidant to protect avours and colours in food products

Table 3
Foods and beverages intended for EMIQ use to protect avours and colours.
Dose
Intended use
<150 ppm
Non-alcoholic beverages, avoured milk products, wine coolers,

shochu-based avoured beverages, frozen dairy products,
gelatines and puddings, jams and jellies, soft candy, cakes,
cookies, pastries, pies, powdered or canned soups
Chewing gums
<1500 ppm
(Table 3), is safe and would be GRAS. In 2007, following independent, critical evaluation of all data and information, the Panel
unanimously concluded that, . . . EMIQ meeting appropriate
food-grade specications and manufactured and used consistent
with current Good Manufacturing Practice is safe and GRAS based
on scientic procedures (FDA, 2007).
GRAS notication is supported among others by some unpublished or hardly accessible data from Japanese journals, including
the following: EMIQ was tested negative for mutagenic activity
in the bacterial reverse mutation assay using six S. typhimurium
strains and one E. coli. The oral LD50 in SpragueDawley rats was
>25 g/kg. No clinical signs or mortality related to treatment were
found during a range-nding test in F344DuCrj rats received EMIQ
at 0%, 0.625%, 1.25%, 2.5%, or 5.0% in the diet for 4-weeks. Organ
weights did not differ signicantly from those of the controls,
but a tendency for lower mean body weights was observed in
the 2.5% and 5% groups. Yellow discoloration of the cranium and
fore- and hind-limb bones without any histopathological changes
was found in both sexes receiving P1.25% of the yellow to yellow-orange substance. Subsequently, a 13-week toxicity study
was performed in ten F344DuCj rats per sex, per group receiving
0%, 0.3%, 0.625%, 1.25% or 2.5% EMIQ in the diet. Yellow discoloration of the cranium and femoral bone was seen in females in
the 1.25% and 2.5% groups and in males in the P0.625% groups,
observed even after a 4-week recovery period, and yellow or yellowbrown urine in all treated groups. Decreased body weight gain
in both sexes was observed in the 2.5% group (Tamano et al., 2001,
cited in (FDA, 2007; Salim et al., 2004)). After the study was published, the authors revised the NOAEL from 0.3% to 1.25%, due to
conclusions from an external peer reviewer concluding that,
although the observed bone discoloration was treatment related,
the absence of any histopathological correlations indicates that
the effect was not toxicologically signicant. A NOAEL of 1.25% corresponds to a dietary intake of about 800 mg/kg/day (FDA, 2007).
Chronic toxicity/carcinogenicity was evaluated on 50 male and
50 female (total 300 rats) F344/DuCrj rats receiving 0%, 0.5% or
1.5% EMIQ in the diet for 104 weeks. There were no treatment-related clinical signs of toxicity; body weights, feed consumption,
survival rates, and blood and clinical chemistry did not differ from
controls. There was a slight but signicant decrease in relative
spleen weights in all treated groups with no histopathological correlation. A non-signicant tendency of an increase in the incidence
of pituitary adenomas was observed in the high-dose females.
There were no apparent effects of the test substance on the
development of kidney neoplasms, hyperplasias, or chronic
nephropathy. Bone discoloration was not reported (Salim et al.,
2004).
Based on the decrease in spleen weights, Salim et al. (2004) concluded that the lowest non-effective dose level was less than 0.5%
in the diet, but the decrease in spleen weights was subsequently
found to be toxicologically non-signicant due to the absence of
accompanying microscopic lesions (FDA, 2007). Based on this conclusion, the NOAEL for EMIQ set to at least 1.5% in the diet (the
highest dose level), corresponding to 598 mg/kg/day for females
and 489 mg/kg/day for males. The lower NOAEL converts to ADI
of 4.89 mg/kg/day, or 293 mg/p/d, (60 kg/p) (FDA, 2007). Finally,
277
the consumption of EMIQ at a dose of 100 mg/day for 8 weeks

was shown to be safe in human subjects nding no side effects,
such as gastrointestinal symptoms, allergic reactions, cardiovascular symptoms during the entire period (Hirano et al., 2009; Kawai
et al., 2009).
To conclude this section, it is necessary to state that the doses
used to study the biological activity in vivo (see Section 3.2) were
usually above the ADI and below the NOAEL of both enzymatically
decomposed rutin and EMIQ (Emura et al., 2007; Fujii et al., 2013;
Hunyadi et al., 2012; Kuwata et al., 2011; Loscalzo et al., 2009;
Morita et al., 2011; Nishimura et al., 2010; Panda and Kar, 2007;
Paulo et al., 2008; Rogerio et al., 2007; Shimada et al., 2010; Sumi
et al., 2013; Yokohira et al., 2008). On the other hand, only preparations of quite low purity (max. 95%) were tested to date and the
safety of pure isoquercitrin remains to be evaluated.
5.2. Potential interactions with drug metabolism
Another often neglected aspect of the safety evaluation of natural products includes the investigation of potential drugdrug,
herbdrug or fooddrug interactions that could have signicant
pharmacological and toxicological consequences (Bouov and
Sklov, 2012; Cermak, 2008; Cermak and Wolffram, 2006; Moon
et al., 2006; Rodeiro et al., 2008).
The phenomenon of drugdrug interactions generally arises
from the inhibition or induction of drug metabolizing/transporting
systems that include phase I oxidative enzymes, phase II conjugation enzymes and phase III efux transporters (Xu et al., 2005).
Isoquercitrin as well as quercetin inhibited the activities of recombinant human cytochrome P450 (CYP) 1A1 and CYP1B1
(Chaudhary and Willett, 2006). Quercetin was also found to inhibit
other recombinant human phase I enzymes, namely, CYP1A2,
CYP2C8, CYP2C9, CYP2D6 and CYP3A4 (Obach, 2000; Rahman
et al., 1994). On the other hand, quercetin was shown in vitro to increase the activity of NADPH-CYP reductase in microsomes from
human liver, lung and heart (Dudka et al., 2005).
No effects of isoquercitrin on phase II enzymes have been reported to date, but quercetin in vitro inhibited human placental
glutathione S-transferase (GST-P) 1-1 (van Zanden et al., 2003), human liver SULT1A1 (De Santi et al., 2002) and recombinant human
SULT1E1. The activity of SULT1E1, which is also known as estrogen
sulfotransferase was also inhibited by quercetin in primary human
mammary epithelial cells (Otake et al., 2000). Similarly, no published data are available on the effect of isoquercitrin on P-glycoprotein. In contrast, quercetin was found to cause either the
stimulation (Phang et al., 1993) or inhibition of P-glycoprotein
in vitro (Shapiro and Ling, 1997). Pharmacokinetic interactions of
quercetin with P-glycoprotein substrates were also observed
in vivo. The co-administration of quercetin decreased the oral bioavailability of cyclosporin in pigs and rats (Hsiu et al., 2002) but
elevated the plasma levels of digoxin in pigs (Wang et al., 2004).
Pre-treatment with quercetin, in contrast to co-administration,
also increased the bioavailability of diltiazem in rabbits (Choi
and Li, 2005). Using Caco-2 cells, isoquercitrin was found to inhibit
drug efux mediated by organic cation transporter-2 (Ofer et al.,
2005).
In addition to the modulation of enzyme activity, both isoquercitrin and quercetin alter the expression of drug-metabolizing
enzymes. In Caco-2 cells, quercetin was found to suppress 1,25vitamin D3-induced CYP3A4 activity (Sergent et al., 2009). In the
same model, quercetin upregulated the protein levels of UGT1A6
and two efux transporters, MRP2 (Bock et al., 2000) and BCRP
(Ebert et al., 2007). Quercetin was also recognized as a low afnity
ligand of the aryl hydrocarbon receptor (AhR) that regulates the
expression of CYP1A1, CYP1A2 and CYP1B1 (Ciolino et al., 1999).
However, it was recently shown that quercetin activates AhR
278
indirectly via inhibiting the metabolic turnover of 6-formylindolo[3,2-b]carbazole, an endogenous AhR ligand (MohammadiBardbori et al., 2012). The ability of quercetin to induce CYP1A1
expression was documented in several in vitro cell models, including human hepatoma HepG2 cells (Vrba et al., 2012), human breast
cancer MCF-7 cells (Ciolino et al., 1999), and immortalized human
HaCaT keratinocytes (Mohammadi-Bardbori et al., 2012). Quercetin applied repeatedly (3 80 mg/kg, i.p.) to rats was found to
increase the activities of CYP1A and CYP2B in liver microsomes
(Rahden-Staron et al., 2001). The administration of quercetin
(60 mg/kg in rats) p.o. by gastric gavage for 5 consecutive days also
upregulated the activity of CYP1A1 in the small intestine, while
the activity of CYP2B1/2 was elevated in the small intestine and
in the liver. The same treatment of rats with isoquercitrin resulted
in the upregulation of CYP1A1, CYP1A2 and CYP2B1/2 activities in
the liver with the activity of CYP1A1 increased in the small
intestine as well (Krzkov et al., 2009). Despite these ndings,
isoquercitrin was unable to activate the AhR-CYP1A1 pathway in
HepG2 cells (Vrba et al., 2012). The discrepancy between the
in vitro and in vivo effects suggests that the in vivo activity of
isoquercitrin may be associated with its metabolic biotransformation
to the aglycone quercetin and/or other metabolites, and hence
possible drug interactions caused by quercetin should be taken
into account when evaluating the safety of isoquercitrin.
6. Conclusion
Isoquercitrin has been attracting increasing commercial interest, since it can be now easily obtained by the selective enzymatic
hydrolysis of rutin. A water-soluble form of isoquercitrin, so-called
enzymatically modied (a-glucosylated) isoquercitrin (EMIQ)
has been registered by the FDA for use in foods. Isoquercitrin
exhibits a broad range of positive biological effects both in vitro
and in vivo, especially chemoprotective activities against oxidative
stress, cancer, cardiovascular disorders, diabetes and allergic reactions. Existing research on isoquercitrin indicates that this quercetin glucoside is more water-soluble and more bioavailable than the
aglyconequercetin. Isoquercitrin can be found intact in plasma
and tissues after oral application, nevertheless it is mostly deglycosylated before absorption, and hence it may serve as a source of
quercetin in humans. On the other hand, little is known about
the biodistribution and fate of the degradation products in vivo.
The acceptable daily intake of 95% isoquercitrin (enzymatically
decomposed rutin) and EMIQ can be estimated to be 5.4 and
4.9 mg/kg/day, respectively. Adverse effects of higher doses in rats
included mostly (benign) chromaturia, but possible drug interactions should be taken into consideration due to the inuence on
phase I and phase II enzymes and/or drug transporters such as Pglycoprotein. It may be concluded that the considerable pharmacological potential of isoquercitrin deserves further research using
the newly available pure isoquercitrin.
Conict of Interest
The authors declare that there are no conicts of interest
Transparency Document
The Transparency document associated with this article can be
found in the online version.
Acknowledgments
Financial support from the Czech Science Foundation, project
P303/12/G163 (KV, JU) and 301/11/0767 (JV, JU, MB, VK), COST
chemistry action CM1001 (VK), EU FP7 project NOVOSIDES FP7KBBE-2010-4-265854 co-funded by MSM 7E11011 (VK, KV) and
by research concept of the Institute of Microbiology
AV0Z50200510 are gratefully acknowledged.
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Food and Chemical Toxicology 68 (2014) 267282

Contents lists available at ScienceDirect

Food and Chemical Toxicology

Isoquercitrin: Pharmacology, toxicology, and metabolism

University, Hnevotnsk 3, CZ-775 15 Olomouc, Czech Republic

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K. Valentov et al. / Food and Chemical Toxicology 68 (2014) 267282

isoquercitrin (EMIQ, a quercetin-glycoside mixture consisting of

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K. Valentov et al. / Food and Chemical Toxicology 68 (2014) 267282

(fresh black chokeberries fruits of the shrub Aronia melanocarpa

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Fig. 3. Schematic representation of derhamnosylation of rutin to isoquercitrin.

subtitutes at the same position (Fig. 1). The following structural

isoquercitrin to date, but both the sulfation and glucuronidation

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K. Valentov et al. / Food and Chemical Toxicology 68 (2014) 267282

xanthine/xanthine oxidase system and to inhibit xanthine oxidase

2004) and inhibition of this process is a promising target in cancer

3.2. Animal and clinical studies

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K. Valentov et al. / Food and Chemical Toxicology 68 (2014) 267282

preventive effects against carrageenan-induced inammation in

time-dependent anti-hyperglycemic activity. On the other hand,

4. Bioavailability and metabolism

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ground beef compared to a standard diet (240%) (Cermak et al.,

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K. Valentov et al. / Food and Chemical Toxicology 68 (2014) 267282

Apocynum venetum** (leaves)

Morus alba*** (leaves)

epithelium, isoquercitrin was rapidly deglycosylated to quercetin.

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K. Valentov et al. / Food and Chemical Toxicology 68 (2014) 267282

methylated and conjugated

the predominant biotransformation processes for quercetin and its

In animal studies where plasma samples were hydrolysed

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In human subjects, neither aglycone nor glucosides, in contrast

5. Data related to the safety

5.1. Safety/potential toxicity

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Non-alcoholic beverages, avoured milk products, wine coolers,

the consumption of EMIQ at a dose of 100 mg/day for 8 weeks

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a-glycosyl isoquercitrin. <http://

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chromatography. J. Anal. Methods Chem., UNSP 385473, http://dx.doi.org/

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