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*
Department of Cell and Molecular Pharmacology and Experimental Therapeutics and
Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC 29425.
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • quercetin glucosides • flavonoids • intestinal absorption • bioavailability • humans
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), with the highest content in onions, apples and red wine
(Hertog et al. 1993
). Epidemiological studies suggest
that flavonoids are protective against coronary heart disease and
stroke (Keli et al. 1996
, Knekt et al. 1996
). Potential mechanisms include the inhibition of
15-lipoxygenase and LDL oxidation (da Silva et al. 1998
), chelation of
metal ions and scavenging of hydroxyl and peroxy radicals
(Manach et al. 1996
). Epidemiologic studies also suggest
that flavonoids are protective in certain cancers (Dorant et al. 1996
, Knekt et al. 1997
, Le Marchand et al. 2000
).
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). In 1995 Hollman et al. indirectly calculated the
absorption of quercetin aglycone and quercetin glucosides from an onion
meal in ileostomy patients. They proposed that quercetin glucosides
were actively absorbed via the intestinal glucose transporter. However,
there were no direct measurements of the quercetin glucosides in the
ileostomy fluid or plasma to support such a conclusion. In sharp
contrast, in vitro studies using human intestinal Caco-2 cell
monolayers as a model of human intestinal absorption showed a complete
lack of absorption of the glucosides, whereas quercetin itself was
easily absorbed (Walgren et al. 1998
, 2000a
, 2000b
). These contrasting observations led us to reinvestigate the fate of the quercetin glucosides and quercetin in an onion meal in ileostomy patients, with molecularly specific HPLC methodology used to measure the intake of the flavonoids and their elimination in the ileostomy fluid. Our hypothesis was that the quercetin glucosides are absorbed in the human intestine only after hydrolysis to the quercetin aglycone.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Four subjects (23–57 y) participated in the study conducted in a
Clinical Research Center. Three subjects were female and one was male;
all were Caucasian. No drugs were administered during or for 1 wk
before the study. The subjects had undergone ileostomy surgery 
1 y
previously for Crohn’s colitis (no evidence of small bowel disease) or
ulcerative colitis. They were otherwise healthy, as determined by
medical histories, physical examinations, complete blood counts,
selected blood chemistry tests (basic metabolic panel and liver panel)
and urinalysis. Written informed consent was obtained from each
subject. The study was approved by the Medical University of South
Carolina Institutional Review Board for Human Research.
The diet during and for 5 d before the study was an isocaloric
weight maintenance diet (15% protein, 50% carbohydrate, 35% fat)
formulated to be low in flavonoids, i.e., a bland diet without fruit
and fruit juices, tea, red wine and most vegetables, especially onions
and broccoli. A standardized meal of cooked onions was administered in
the morning after an overnight fast. Chopped yellow onions were
sautéed well in margarine and seasoned with ketchup and Italian
seasonings (Hollman et al. 1995
). The patients consumed
76 to 150 g of this mixture. Another aliquot of the meal was
homogenized with water in a blender and frozen for later analysis of
quercetin and its glucosides. A light meal was served 3 h later.
Heparinized blood samples were drawn immediately before the onion meal
and at 0.5, 1, 2, 4, 6, 8, 12, 24, 36 and 48 h after the start of
the meal. Blood samples were centrifuged to separate plasma. Four 12-h
ileostomy fluid collections were also made in standard ileostomy bags.
The contents of the bags were homogenized. Plasma samples and aliquots
of ileostomy fluid homogenates were immediately frozen and stored at
-20°C until analyzed.
Analytical methods.
Onion meal and ileostomy fluid homogenate samples (1 g) were
freeze-dried and extracted three times with 10 mL methanol. The
methanol extracts were dried completely with a stream of nitrogen at
40°C, reconstituted in 1 mL of methanol and 2 mL of mobile phase
(35% methanol, 5% acetic acid in water) and filtered. All samples
were analyzed for quercetin and its glucosides by HPLC, using a
Symmetry C18 column (Waters, Milford, MA) with a flow rate of 0.9
mL/min and UV detection (370 nm). HPLC peaks were identified by
comparison of retention times with standard quercetin, quercetin
4'-monoglucoside
(QMG)4
and quercetin 3,4'-diglucoside (QDG), the latter two isolated from red
onions (Walgren et al. 1998
), and also by comparison of
UV spectra obtained by in-line scanning of peaks, using photodiode
array detection. Quantitation was based on HPLC peak areas compared
with those of known amounts of injected quercetin. All values are the
mean values of duplicate analyses. Extraction recoveries were based on
standard curves obtained by spiking meal or ileostomy fluid homogenates
with known amounts of quercetin and taking them through the sample
workup procedure. Typically, the slope of the peak area versus
concentration line for ileostomy fluid (1–20 (g/g) was 93% of the
slope for direct injection of the same amounts of quercetin, i.e., the
extraction recovery was 93%. The lines were obtained by linear
regression with a least squares fit with correlation coefficients of
0.985–0.999.
Attempts to demonstrate the presence of QMG and/or QDG in plasma used
three different isolation methods. One included dilution with an equal
volume of methanol and centrifugation, a second method used the
addition of acid and centrifugation (Aziz et al. 1999
),
and a third method used lyophilization and extraction of the residue
with methanol.
To test whether the ileostomy fluid contained ß-glucosidase activity,
samples from three patients were incubated with genistin, a
commercially available 7-glucoside derivative of genistein, which
previously has been shown to be a substrate for these enzyme activities
(Day et al. 1998
, 2000
; Walle et al. 1999a
). We also tested whether the ileostomy fluid from the
same patients contained ß-glucuronidase activity. For this assay we
used chrysin 7-glucuronide as a substrate and HPLC analysis, as
previously described (Galijatovic et al. 1999
).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Methanol extracts of each meal were analyzed for their content of
quercetin, QMG and QDG. The HPLC tracing of the meal served to one of
the patients is shown in Figure 2A
. Using 370–nm UV detection, the quercetin glucosides were very
prominent, whereas there were only trace amounts of the quercetin
aglycone. Based on the HPLC analyses, the total intake of quercetin and
its glucosides in the 4 patients ranged from 10.7 to 51.6 mg (Table 1)
,
with QMG accounting for 4.7–29.9 mg and QDG for 5.9–21.8 mg. The
large variability in the content of quercetin glucosides in the onions
may be due to seasonal variations (Crozier et al. 1997
).
|
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. Only a trace of the
glucosides was detectable in a few samples. This was based on the
absence of peaks of the proper retention times with UV spectra
identical to those of the pure glucosides. However, the quercetin peak
was prominent. The peaks at retention times of 7–8 min and 12–14 min
appeared to be glucuronic acid conjugates of quercetin. These were the
retention times for the four isomeric conjugates formed when quercetin
was incubated with human liver microsomes or recombinant UGT1A9 and the
cosubstrate UDP-glucuronic acid (Walle et al. 2000
).
There were no signs of degradation products of quercetin
(Boulton et al. 1999
) in the ileostomy fluid. The total
amounts of QMG, QDG and quercetin recovered in the four 12-h
collections are shown in Table 2
. In patient 3, all of the quercetin recovered was found in the 12–24-h
ileostomy bag, whereas in the other patients more than 90% was in the
0–12-h bag. Table 2
also summarizes the recovery of quercetin and its
glucosides in the ileostomy fluids (0–48 h), expressed as a percentage
of the dose, i.e., 19.5–35.2%. We assumed that the remainder of the
dose, 64.5–80.7%, was absorbed.
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but were unsuccessful (data not shown). We also attempted to
measure unchanged quercetin and glucuronic acid and sulfate conjugates
in plasma. Only trace quantities were detected in some samples,
generally consistent with previous observations (Conquer et al. 1998
, de Vries et al. 1998
, Graefe et al. 1999
, Hollman et al. 1995
, Manach et al. 1998
, MCAnlis et al. 1999
). When ileostomy fluid from three patients was incubated with 50 (µmol/L genistin for 2 h, there was a 60–80% conversion to genistein. The same ileostomy fluids did not hydrolyze chrysin glucuronide to chrysin, even after a 4-h incubation.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 2000b
), a well-established model of human
intestinal absorption. The appearance of small amounts of quercetin
glucuronides in the ileostomy fluid is consistent with previous
experiments in rats (Crespy et al. 1999
), demonstrating
absorption of quercetin followed by glucuronidation and efflux of the
glucuronides, presumably by MRP2 (Walle et al. 1999b
).
When our HPLC method for intact QMG and QDG was applied to plasma
samples in this study, no evidence of their absorption was detected.
However, it is difficult to exclude the possibility that a small
fraction of the glucosides might have been absorbed. This issue was
addressed in several previous studies, for quercetin and for other
flavonoids (Aziz et al. 1999
, Ishii et al. 2000
, Pforte et al. 1999
, Shimoi et al. 1998
).
The exact location of the hydrolysis is not known, but several
possibilities exist. In a recent study (Day et al. 2000
), it was demonstrated that lactate phlorizin hydrolase
(LPH; EC 3.2.1.62), a family 1 ß-glucosidase, was capable of
hydrolyzing a range of flavonoid glucosides, including QMG, the latter
with a surprisingly low Km of 44 µmol/L. LPH is primarily
responsible for the hydrolysis of lactose from milk in newborns
(Semenza 1987
) and persists into adulthood in human
intestine (Flatz 1987
). LPH is a membrane-bound
enzyme present on the luminal side of the brush border and can
therefore act on flavonoid glucosides before absorption. Another
possibility is that enterocytes are constantly shed from the top of the
intestinal villi into the lumen at a very high rate (Greiner et al. 1999
). Whether these enterocytes are viable or not, they
may be capable of hydrolyzing flavonoid glucosides present in the
intestinal lumen. ß-Glucosidase activity toward QMG and other
flavonoid glucosides has been detected in intestinal tissue from rats
(Ioku et al. 1998
) and humans (Day et al. 1998
, Walgren et al. 2000b
). The finding that
ileostomy fluid had ß-glucosidase activity supports either mechanism.
It is possible that some of the hydrolysis may have occurred in the
ileostomy bag. Because bacterial contamination of the ileostomy fluid
was not directly addressed in our study, a contribution from bacterial
ß-glucosidase activity cannot be excluded. A variety of bacterial
strains have high activity of this hydrolytic enzyme
(Bokkenheuser et al. 1987
). However, the inability of
the ileostomy fluid to hydrolyze chrysin 7-glucuronide may be
considered evidence against bacterial contamination, because intestinal
ß-glucuronidase activity in general is linked to bacteria.
We conclude that quercetin is efficiently absorbed from most if not all
dietary sources of this flavonoid. We confirmed previous reports
(Conquer et al. 1998
, de Vries et al. 1998
, Graefe et al. 1999
, Hollman et al. 1995
, Manach et al. 1998
,
MCAnlis et al. 1999
) that no unchanged
quercetin aglycone could be detected in the circulating plasma.
However, hepatic metabolism of quercetin can be expected to be
efficient, leading to the formation of glucuronic acid and sulfate
conjugates and presently unknown metabolites. There is clear evidence
that some of these circulating species are biologically active
(Manach et al. 1998
, MCAnlis et al. 1999
). This should be an important area of future research.
In summary, the present investigation was a reexamination of the
absorption of quercetin and its major dietary forms, i.e., QMG and QDG,
in ileostomy patients, using molecularly specific techniques. Our
findings were different than those from a previous study
(Hollman et al. 1995
) in that both QMG and QDG were
shown to be efficiently hydrolyzed to quercetin in the small intestine
by ß-glucosidases, with most of the quercetin then absorbed. QMG and
QDG thus act as water-soluble prodrugs, yielding a favorable
absorption of quercetin.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by National Institutes of Health Grants GM55561 and RR01070.
4 Abbreviations used: QMG, quercetin 4'-monoglucoside; QDG, quercetin 3,4'-diglucoside; LPH, lactate phlorizin hydrolase.
Manuscript received May 12, 2000. Revision accepted July 19, 2000.
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