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Food and Chemical Toxicology: Kater Ina Valentová, Jir Í Vrba, Martina Bancír Ová, Jitka Ulrichová, Vladimír KR en
Food and Chemical Toxicology: Kater Ina Valentová, Jir Í Vrba, Martina Bancír Ová, Jitka Ulrichová, Vladimír KR en
Food and Chemical Toxicology: Kater Ina Valentová, Jir Í Vrba, Martina Bancír Ová, Jitka Ulrichová, Vladimír KR en
Invited Review
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
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
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)
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
271
272
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
274
Table 2
Pharmacokinetic proles of isoquercitrin in rat plasma after oral administration of isoquercitrin containing plant extracts.
Source
Hypericum japonicum*
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
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
OR
OR2
OH
O
HO
OH
OH
O
OH
OR
OR2
O
OH
2(3,4-dihydroxyphenyl)2-oxoacetic acid
O
Obutyrate
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
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
4-hydroxyphenylacetic acid
OH
2-hydroxyphenylacetic acid
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.
276
Intended use
<150 ppm
<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
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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