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*
Division of Human Nutrition and Epidemiology, Wageningen University and Research Centre, 6700 EV, Wageningen, The Netherlands;
State Institute for Quality Control of Agricultural Products (RIKILT), 6700 AE, Wageningen, The Netherlands
**
Department of Anesthesiology, Nijmegen University Hospital, 6500 HB, Nijmegen, The Netherlands
3To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • quercetin glucosides • flavonols • bioavailability • metabolism • humans
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Quercetin is an
antioxidant in vitro because it can scavenge radicals, inhibit lipid
peroxidation and chelate metals (Rice Evans et al. 1996
). Quercetin was able to inhibit oxidation of LDL in vitro
at a concentration as low as 0.25 µmol/L, which is in the
physiological range (de Whalley et al. 1990
,
Manach et al. 1998
). Therefore quercetin might
contribute to the prevention of cardiovascular disease (Hertog et al. 1993a
). However, to induce these health effects in
humans, quercetin must enter the systemic circulation. Quercetin in
foods is bound to sugars, mainly as ß-glycosides, and the
bioavailability of these various quercetin glycosides is affected by
their sugar moiety (Hollman et al. 1995
, 1996a
and 1999
). Quercetin-3-rutinoside and quercetin-4'-glucoside are
important forms of quercetin in foods (Fig. 1
). Quercetin-3-rutinoside accounts for ~40% of quercetin in black tea
(Engelhardt et al. 1992
), and consumption of black tea
contributes about 48% to the total flavonol and flavone intake in The
Netherlands (Hertog et al. 1993b
).
Quercetin-4'-glucoside accounts for ~45% of quercetin in onions
(Kiviranta et al. 1988
), and consumption of onions
contributes another 29% to the total flavonol and flavone intake
(Hertog et al. 1993b
). Although the intake of
quercetin-3-rutinoside is twice that of quercetin-4'-glucoside, the
absorption of quercetin-3-rutinoside is only 17% of ingested dose,
whereas the absorption of quercetin-4'-glucoside is 52% of ingested
dose (Hollman et al. 1995
). Furthermore, the
bioavailability of quercetin-3-rutinoside is only 20% of that of
quercetin-4'-glucoside (Hollman et al. 1999
). Therefore
it would be interesting to attempt to increase the bioavailability of
quercetin-3-rutinoside. Rutinose is a dimer of glucose and rhamnose;
therefore quercetin-3-rutinoside can be transformed into
quercetin-3-glucoside by splitting of the rhamnose molecule with the
enzyme alpha-L-rhamnosidase (Bokkenheuser et al. 1987
, Gunata et al. 1988
, Kurosawa et al. 1973
). The resulting quercetin-3-glucoside differs only from
the highly bioavailable quercetin-4'-glucoside in the position of the
glucose moiety on the quercetin aglycone. However the bioavailability
of quercetin-3-glucoside is unknown. Therefore we tested whether the
position of the glucose moiety affected the bioavailability of
quercetin glucosides in humans.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The protocol was approved by the Ethical Committee of Nijmegen University Hospital. All subjects were fully informed about the study and signed an informed consent form. Five women and five men started with the study, but one woman was excluded because of problems with blood sampling. Mean age of the remaining nine subjects was 25 y (range 19–57 y) and mean body mass index was 21.3 kg/m2 (range 19.8–24.8 kg/m2). All subjects were healthy based on a medical questionnaire—the absence of protein and glucose in urine and normal values for blood hematocrit, hemoglobin concentration and leukocyte and platelet counts. Subjects were not allowed to use any medicine during the study, except for acetaminophen (paracetamol) and oral contraceptives.
Study design and supplements.
The subjects ingested quercetin-3-glucoside or quercetin-4'-glucoside
(Fig. 1)
on two different days in random order, and subsequently we
measured quercetin in blood over 72 h and in urine over 24 h.
Subjects consumed a low quercetin diet from d 3 to 16, having been
given a list of fruits and vegetables which contained >15 mg
quercetin/kg and of beverages with >4 mg quercetin/L (Hertog et al. 1992
and 1993c
) which they were instructed not to consume.
During the mornings of d 7 and of d 13, the subjects came to the
University Hospital Nijmegen after they had fasted overnight. Five of
the subjects ingested 325 µmol (151 mg) quercetin-3-glucoside
(#011095; Extrasynthese, Genay, France) on d 7 and 331 µmol (154 mg)
quercetin-4'-glucoside (#4564; Carl Roth, Amsterdam, The Netherlands)
on d 13. The other four subjects received the same supplements in
reverse order. Each supplement was dissolved in 10 mL ethanol plus 200
mL of hot water (5% v/v alcohol concentration). Subjects ingested
2 g of sodium chloride dissolved in 10 mL of water just before
they ingested the supplement because the sodium glucose cotransporter
might play a role in the absorption of quercetin glucosides, and sodium
is necessary for the active transport of glucose. During the first
3 h after ingestion of the supplements, subjects were allowed to
consume water only. We checked compliance with the dietary guidelines
with a 24-h recall for d 6 and 12. We calculated intakes with the Dutch
food composition table. Average energy intake was 13.4 ± 0.9
(SE) MJ, of which protein provided 14.8 ± 0.5%, fat
34.7 ± 2.8% and carbohydrates 49.8 ± 3.2%. The mean daily
quercetin intake from regular foods during the study was not different
between supplement periods and was 7.6 ± 2.3 µmol. Because this
was about 2% of the dose of the supplements, we conclude that intake
of quercetin from regular foods did not affect our results.
Collection of blood and urine samples.
We took venous blood samples (10 mL blood per blood sample) into vacuum
tubes containing EDTA once before subjects ingested the supplement, and
at 15 min, 30 min, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, 48, 60 and 72 h
after ingestion. Platelet-poor plasma was prepared by centrifuging
the blood for 10 min at 2500 x g at 4°C. The
plasma was stored at -80°C until analysis. On d 7 and 13, subjects
collected urine for 24 h in plastic bottles, one for each voiding,
with thymol (#8167; Merck, Amsterdam, The Netherlands) dissolved in
isopropanol as preservative. They stored each bottle in dry ice
immediately after voiding. At the laboratory we thawed the urine
bottles in a water bath of ~40°C, pooled and mixed urine per
subject and per supplement day, froze aliquots of urine in liquid
nitrogen and stored the urine samples at -80°C until analysis.
Subjects took 300 µmol lithium chloride dissolved in 10 mL of water
every morning from d 1 until d 14. Urinary recovery of lithium was 94.4
± 17.2% (means ± SD), which indicates that
collection of urine was complete (Sanchez-Castillo et al. 1987a
and 1987b
).
Analytical methods.
Quercetin, isorhamnetin (3'-methoxyquercetin) and their conjugates with
glycosides, glucuronic acid or sulfates in plasma or urine were
simultaneously extracted and hydrolyzed to their aglycones with 2 mol/L
HCL in aqueous methanol (Hollman et al. 1997
). We
measured the aglycones by HPLC with fluorescence detection
(Hollman et al. 1996b
). The limit of detection, i.e.,
the concentration producing a peak height three times the standard
deviation of the baseline noise was 0.007 µmol/L (2 ng/mL) for
quercetin in plasma and 0.01 µmol/L (3 ng/mL) for quercetin in urine
(Hollman et al. 1997
). The limits of detection for
isorhamnetin were one-third of those for quercetin (Hollman et al. 1996b
). Lithium was measured in undiluted, acidified
urine by atomic absorption spectrophotometry (Anonymous 1976
).
Data analysis.
We used a two-compartment model to describe the pharmacokinetics of
quercetin and isorhamnetin. We calculated peak plasma concentration,
time to reach peak plasma concentration, elimination half-life and
area under the plasma concentration vs. time curve
(AUC0
72h)4
with the MW/Pharm computer package (Proost and Meijer 1992
). We calculated the AUC072h with the linear
trapezoidal rule. Differences between results after ingestion of
quercetin-3-glucoside and after quercetin-4'-glucoside were tested for
significance by paired t test with a significance level
of P < 0.05 (SAS Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The plasma kinetic variables of the two glucosides also did not
differ, as did the bioavailability, as indicated by the similar
AUC072h (Table 1
).
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|
.
The amount of quercetin excreted in 24-h urine after intake of the
3-glucoside was not different from that after intake of the
4'-glucoside (Table 2
). Only about 3% of the ingested quercetin was excreted in urine as
quercetin aglycone or its conjugates, which indicates that quercetin is
extensively metabolized in the human liver and other organs and by the
colonic microflora. One of the metabolites of quercetin is isorhamnetin
(3'-methoxyquercetin) (Manach et al. 1998
, Morand et al. 1998
). We found isorhamnetin in plasma and urine after
ingestion of both quercetin supplements. Peak concentration of
isorhamnetin did not differ between the glucosides and was reached in
51 ± 19 min after the quercetin-3-glucoside and in 32 ± 5
min after the quercetin-4'-glucoside. Other kinetic variables of
isorhamnetin also did not differ between the quercetin glucosides (data
not shown). In urine, ~0.6% of the ingested quercetin glucosides was
recovered as isorhamnetin (Table 2)
.
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|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, who also found that the
bioavailability of quercetin-3-rutinoside was 20% of that of
quercetin-4'-glucoside. Therefore our results suggest that enzymatic
conversion of quercetin-3-rutinoside into quercetin-3-glucoside will
increase bioavailability. Quercetin-3-glucoside itself also occurs
commonly in foods such as tea, tomatoes and apples (Engelhardt et al. 1992
, Herrmann 1976
and 1988
). We may now
conclude that this naturally occurring 3-glucoside has the same high
bioavailability as the 4'-glucoside.
Quercetin glucosides are absorbed more rapidly than other quercetin
glycosides (Hollman et al. 1997
and 1999
). The mechanism
for quercetin absorption is not known. Hollman et al. (1995
and 1999
) speculated that the intestinal sodium-glucose
cotransporter is able to transport glucose attached to quercetin
through the intestinal cell wall. This idea was supported by the
results of Aziz et al. (1998)
, who found the
quercetin-4'-glucoside in human plasma after volunteers had consumed
onions. If the sodium-glucose cotransporter plays a role in the
absorption of quercetin glucosides, our results would suggest that the
absorption of glucose is not affected by its position on the attached
quercetin. However, transport of quercetin glucosides by the glucose
cotransporter has not been proven yet in vivo. For the interpretation
of the bioactivity of quercetin from foods in humans, it is important
to know in what form quercetin actually circulates in blood. From the
results in this study, it is unclear in what form quercetin circulates
in blood because we measured the concentration of quercetin after
hydrolysis to the quercetin aglycone. With regard to bioactivity of
various forms of quercetin, quercetin conjugated with glycosides,
glucuronic acid or sulfates also has antioxidant activity in vitro,
although the antioxidant activity is lower than that of the quercetin
aglycone (Manach et al. 1998
, Williamson et al. 1996
).
In addition to bioavailability data, our study also provided
information on the metabolism of quercetin into isorhamnetin
(3'-methoxyquercetin). Of the ingested quercetin glucosides, ~50% is
absorbed in the small intestine and subsequently metabolized, for
example into isorhamnetin, in the liver and in other organs. The 50%
of ingested quercetin which is not absorbed in the small intestine is
metabolized by the colonic microflora into quercetin aglycone and
phenolic acids which might be absorbed from the colon (Hollman and Katan 1998
, Hollman et al. 1995
,
Manach et al. 1998
). Only 3% of the ingested quercetin
is recovered in urine as aglycone or its conjugates. The quercetin in
urine might originate from quercetin absorbed in the small intestine
and from quercetin absorbed in the colon. Metabolites of quercetin may
also be biologically important, because they have antioxidant activity
in vitro (Manach et al. 1998
, Rice Evans et al. 1996
) and might exert antioxidant effects in humans. In this
study we measured isorhamnetin as a metabolite of quercetin.
Isorhamnetin concentration in plasma peaked shortly after the quercetin
concentration peak. This suggests that both quercetin glucosides are
methylated into isorhamnetin immediately after absorption. Methylation
of the catechol group of quercetin produces isorhamnetin, and it is
catalyzed by the enzyme catechol-O-methyltransferase in the
liver (Zhu et al. 1994
). In quercetin-4'-glucoside the
4' position is occupied by a glucose, and thus there is no catechol
group available for methylation. Deglucosylation of the 4'-glucoside is
needed to release the catechol group. Because the time to reach peak
concentrations of isorhamnetin after intake of the 3-glucoside was the
same as after intake of the 4'-glucoside, this could imply that
deglucosylation of the 4'-glucoside is not rate-limiting for
isorhamnetin formation. Furthermore, isorhamnetin is not an important
final metabolite of quercetin because only 0.6% of the ingested
quercetin glucosides was excreted in urine as isorhamnetin.
This study shows that it might be possible to increase or decrease
bioavailability of quercetin, and maybe of other components in foods
and of drugs, by attaching or detaching a glucose molecule.
Specifically, treatment of the poorly absorbed quercetin-3-rutinoside
from tea with rhamnosidase would transform it into the highly
bioavailable quercetin-3-glucoside. Recent research has reinforced the
evidence for an inverse association between the intake of flavonoids
and death from coronary heart disease (Yochum et al. 1999
). If intake of quercetin and related flavonols can indeed
be proven to reduce coronary heart disease risk, then production of
foods with a more highly bioavailable form of quercetin might become a
realistic proposition.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by the Foundation for Nutrition and
Health Research, The Netherlands.
4 Abbreviation used: AUC072h, area
under the plasma concentration vs. time curve.
Manuscript received October 28, 1999. Revision accepted January 13, 2000.
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V. Crespy, C. Morand, C. Besson, C. Manach, C. Demigne, and C. Remesy Comparison of the Intestinal Absorption of Quercetin, Phloretin and Their Glucosides in Rats J. Nutr., August 1, 2001; 131(8): 2109 - 2114. [Abstract] [Full Text] [PDF]
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A. L. A. Sesink, K. A. O'Leary, and P. C. H. Hollman Quercetin Glucuronides but Not Glucosides Are Present in Human Plasma after Consumption of Quercetin-3-Glucoside or Quercetin-4'-Glucoside J. Nutr., July 1, 2001; 131(7): 1938 - 1941. [Abstract] [Full Text] [PDF]
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