Laboratoire des Maladies Métaboliques et des Micronutriments, Institut National de la Recherche Agronomique de Clermont-Ferrand/Theix, 63122 Saint Genès Champanelle, France
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ABSTRACT |
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Rutin and quercetin absorption and metabolism were investigated in rats after in situ perfusion of jejunum plus ileum (15 nmol/min). In contrast to rutin, a high proportion of quercetin (two-thirds) disappeared during perfusion, reflecting extensive transfer into the intestinal wall. Net quercetin absorption was not complete (2.1 nmol/min), inasmuch as 52% were reexcreted in the lumen as conjugated derivatives (7.7 nmol/min). Enterohepatic recycling contribution of flavonoids was excluded by catheterization of the biliary duct before perfusion. After a 30-min perfusion period, 0.71 µM of quercetin equivalents were detected in plasma, reflecting a significant absorption from the small intestine. The differential hydrolysis of effluent samples by glucuronidase and/or sulfatase indicates that the conjugated forms released in the lumen were 1) glucuronidated derivatives of quercetin and of its methoxylated forms (64%) and 2) sulfated form of quercetin (36%). In vitro quercetin glucuronides synthetized using jejunal and ileal microsomal fractions were similar to those recovered in the effluent of perfusion. These data suggest that glucuronidation and sulfatation take place in intestinal cells, whereas no glucurono-sulfoconjugates could be detected in the effluent. The present work shows that a rapid quercetin absorption in the small intestine is very effective together with its active conjugation in intestinal cells.
conjugation; flavonal
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INTRODUCTION |
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FLAVONOIDS ARE A LARGE family of more than 4,000 secondary plant metabolites, comprising anthocyanins, flavonols,
flavones, catechines, and flavonones (10). They occur ubiquitously in fruits, vegetables, nuts, seeds, and bark, which are the main dietary
sources (14). Therefore they constitute an integral part of the human
diet, even though they are considered nonnutrients. Many studies have
been drawn toward the beneficial properties of quercetin, the most
abundant flavonol in vegetables and fruits (34), namely antibacterial,
antiviral, antioxidant, antiproliferative, anti-inflammatory, and
anticarcinogenic effects (5, 17, 23, 24). However, the metabolism of
this molecule in mammals has not been well characterized. After oral
administration of
[14C]quercetin to
rats, it has been reported that 20% was directly absorbed, 30% was
excreted unchanged in feces, and the remaining was metabolized to
various compounds such as CO2 and
phenolic acids (30). Phenolic acids, resulting from the ring fission of
quercetin by the intestinal microflora (1, 20), are extensively recovered in urine of rats after administration of quercetin or rutin
(quercetin-3-O-glucose-rhamnose) (4). Moreover, recent in vitro
studies, performed using human Caco-2 monolayer cultures, have
demonstrated an effective and rapid absorption of quercetin (32).
Moreover, many questions remain about the fate of quercetin in the
organism. In previous studies, it was found that free quercetin could
not be detected in blood plasma, whereas conjugated forms of quercetin
(glucurono-sulfated and/or methoxylated forms) were identified (15,
18). These metabolites are eliminated via the biliary and urinary
pathways (9, 28, 35). Excreted in the bile, they flow in the small
intestine and they reach the hindgut where they can be hydrolyzed by
the -glucuronidase and sulfatase activities of the microflora, which
affords possibilities of enterohepatic cycling (8, 11). The main site
for quercetin metabolism is the liver, which possesses conjugation
activities (UDP-glucuronosyltransferase, catechol
O-methyltransferase, and sulfotransferase) (7, 28).
Nevertheless, other tissues, such as kidneys and intestinal mucosa, can
also metabolize quercetin (12, 13, 19, 31).
Therefore, the aim of the present work was to investigate in the rat 1) the absorption of quercetin and rutin (one of the glysosylated forms of quercetin found in plant foods) by the small intestine (jejunal and ileal segments) in situ and 2) the metabolism of these compounds by the intestinal mucosa.
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MATERIALS AND METHODS |
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Chemicals
Diosmetin, isorhamnetin, and tamarixetin were purchased from Extrasynthese (Genay, France). Quercetin, rutin,Animals and Diets
Sixteen male Wistar rats weighing ~150 g were housed two per cage in temperature-controlled rooms (22°C), with a dark period from 0800 to 2000 and access to food from 0800 to 1600. They were fed a standard semipurified diet (73% wheat starch, 15% casein, 6% mineral mixture, 1% vitamin mixture, and 5% corn oil) for 2 wk.Animals were maintained and handled according to the recommendations of the Institut National de la Recherche Agronomique Ethics Committee, in accordance with decree no. 87-848.
Sampling Procedure
Rats were anesthetized with pentobarbital sodium (40 mg/kg body wt) 18 h after the beginning of the meal and maintained alive during the perfusion period.After cannulation of the biliary duct, a perfusion of jejunal plus ileal segment of intestine (5 cm distal from the flexura duodenojejunalis to the valvula ileocecalis) was prepared by installing cannulas (external diam 4 mm, internal diam 2.5 mm) at each extremity. This segment was continuously perfused in situ with a buffer containing (in mM) 2.5 KH2PO4, 2.5 K2HPO4, 5 NaHCO3, 50 NaCl, 50 KCl, 2 CaCl2, 2 MgCl2, 2.5 HEPES Na, 2.5 HEPES acid, pH 6.7, 8 glucose, and 1 taurocholic acid at a flow rate of 1 ml/min, at 37°C, and supplemented with 15 µM of quercetin or rutin. An aliquot of effluent was directly collected at the exit of the ileum in plastic tubes (1.5 ml) during the last 5 min of perfusion. The bile was collected all along the perfusion step.
At the end of the experiment, blood samples were withdrawn from the
abdominal aorta into heparinized tubes. Plasma, bile, and perfusate
samples were acidified with 10 mM acetic acid and then stored at
20°C.
HPLC Analysis
Samples treatment.
Plasma and bile were spiked with 3.5 µmol/l of diosmetin (final
concentration) used as an internal standard and acidified (to pH 4.9)
with 0.1 vol of acetic acid, 0.58 M. The samples were treated for 30 min at 37°C with 5 × 106
U/l -glucuronidase and 2.5 × 105 U/l sulfatase (for visualizing
the total forms). The reactions were stopped by addition of 2.85 vol of
acetone, and the resulting mixtures were centrifuged. This procedure
was sufficient to totally extract quercetin bound to plasma albumin (6,
16). After this extraction step, 20 µl of supernatant were injected
and analyzed by HPLC.
Chromatographic conditions. The HPLC system used consisted of an autosampler (Kontron 360), an ultraviolet detector (set at 370 nm), and a software system for data recording and processing. The system was fitted with a 5-µm C-18 Hypersil based deactivated silica analytical column (150 × 4.6 mm; Life Sciences International, Cergy, France). The mobile phase consisted of water and H3PO4 (99.5:0.5, solvent A) and acetonitrile (solvent B).
To separate the conjugated metabolites of flavonoids, the chromatographic conditions were as follows (flow rate 1 ml/min): 0-2 min solvent A 85%/solvent B 15%; 2-22 min solvent A 85%/solvent B 15%In Vitro Assay of Flavonoid Glucuronidation
Jejunal and ileal microsomes from rat intestine were prepared by differential ultracentrifugation at 105,000 g at 4°C for 1 h. To prepare intestinal microsomes, mucosal scraping (50 cm for jejunal and 20 cm for ileal intestine) were homogenized in ice-cold buffer containing Tris · HCl (50 mM, pH 7.2), sucrose (100 mM), EDTA (10 mM), dithiothreitol (2 mM), leupeptin (1 µM), and trypsin inhibitor (25 mg/100 ml). The final microsomal pellet was suspended in a buffer containing HEPES (100 mM), pH 7.2, sucrose (100 mM), and trypsin inhibitor (25 mg/100 ml) and kept in a frozen state atIncubations were carried out as follows. In a final volume of 750 µl,
540 µl of buffer (HEPES, 75 mM, pH 7.3, MgCl2, 10 mM), 50 µl of
UDP-glucuronic acid (4.5 mM final), and 100 µl of microsomal suspension (50 µg protein) were activated in situ by 60 µl of a
0.2% solution of Triton X-100. The reaction was started by the addition of 2 µl of quercetin (18.75 mM in DMSO). Incubations were
performed at 37°C for 3 h, and then aliquots of the reaction mixture were taken and treated [with or without -glucuronidase (and
sulfatase)] for HPLC analysis, exactly as previously decribed.
Statistics
Values are means ± SE, and the differences between values were determined by one-way ANOVA coupled with the Student-Newman-Keuls multiple-comparison test. Values of P < 0.05 were considered significant. ![]() |
RESULTS |
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Comparison of In Situ Intestinal Perfusion of Rutin and Quercetin in Rats
When the intestine was perfused at a flow rate of 1 ml/min during 30 min with a buffer containing 15 µM rutin, the concentrations of this glycoside in the effluentcollected at the extremity of the ileum were not significantly different from those initially present in the perfusate (Fig. 1). This indicates that rutin is not noticeably absorbed nor metabolized by the intestinal wall.
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By contrast, when quercetin was perfused in the jejunoileal segment (at
14.7 ± 0.6 µM, with a flow rate of 1 ml/min), the concentration
of this flavonol (free and conjugated forms) in the residual perfusate
was significantly decreased (12.6 ± 0.2 µM; Fig. 1). Thus 14.3%
of perfused quercetin was taken up by the intestinal wall. Moreover, in
plasma hydrolyzed by -glucuronidase (and sulfatase), the
concentration of quercetin was about 0.71 ± 0.06 µM (Table
1), giving additional evidence for the
absorption of quercetin through the intestinal wall. Preliminary
experiments have established that before perfusion no trace of
quercetin was present in rat plasma (data not shown).
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Differential Hydrolysis of Effluent Resulting From Intestinal Perfusion of Quercetin
The representative HPLC profile of the nonhydrolyzed effluent (Fig. 2A) is characterized by 1) a peak of quercetin at a concentration of 4.9 ± 0.4 µM (indicating that ~33% of infused quercetin was not metabolized by the intestinal cells) and 2) the presence of five unidentified peaks. Four of these peaks (1-4) totally disappeared after hydrolysis of the samples with
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When the effluent was treated with the sulfatase alone (Fig. 2C), no trace of isorhamnetin and tamarixetin was detected in this fraction, and the concentration of quercetin was estimated at 7.7 ± 0.4 µM. This indicates that the methoxylated forms of quercetin were not sulfated in the intestine and that the sulfate derivative of quercetin corresponded to 2.8 ± 0.3 µM of quercetin equivalent (calculated as the difference between the concentration of quercetin measured before and after the enzymatic treatment).
The hydrolysis of the effluent with bovine -glucuronidase led to a
complete disappearence of peaks
1-4 (Fig. 2D),
whereas peak 5 was unaffected and the
resulting concentration of quercetin was about 9.8 ± 0.6 µM. In
such conditions, the concentration in quercetin glucuronides present in
the effluent was estimated to be about 4.9 ± 0.2 µM. Moreover,
isorhamnetin (~0.2 µM) and tamarixetin (<0.1 µM) are present in
Fig. 2D, indicating that these
compounds are submitted to an intestinal glucuronidation.
The total concentration of quercetin recovered in the hydrolyzed effluent was 12.6 ± 0.2 µM, 4.9 ± 0.2 µM (namely 39%) being unconjugated forms of quercetin and 7.7 ± 0.4 µM (namely 61%) being conjugated derivatives. These conjugates are composed of 36% sulfate derivatives and 64% glucuronides; a minor part of them could be methoxylated.
Quercetin Fluxes After Intestinal Perfusion
Whereas the total flux of quercetin in the perfusion was 14.7 ± 0.6 nmol/min (flow rate 1 ml/min), only 4.9 ± 0.4 nmol/min of quercetin was recovered intact in the effluent. The secretion of conjugated derivatives from the wall into the lumen could explain why the net absorption of quercetin was low compared with its total transfer into the intestinal wall (Fig. 3). By contrast, the net flux of quercetin absorption (2.1 ± 0.4 nmol/min corresponding to 14.3% of total perfused quercetin) was markedly lower than the secretion flux of conjugates from the wall into the lumen (7.7 ± 0.4 nmol/min, namely 52.4% of total perfused quercetin) (Fig. 3). The sum of these fluxes corresponded to the net transfer of quercetin into the intestinal wall (9.8 ± 0.5 nmol/min). Therefore, 78.5% of absorbed quercetin was directly conjugated and eliminated by the intestine. In comparison to intestinal secretion, the biliary secretion flux was quite limited (Fig. 3).
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In Vitro Glucuronidation of Quercetin by Intestinal Wall
The in vitro capacity of rat jejunal and ileal fractions to transfer glucuronic acid from UDP-glucuronic acid to quercetin has been tested using microsomal preparations. It could be noted that the capacity of the jejunal wall to conjugate quercetin appeared significantly greater than that of the ileal wall (Fig. 4); the percentage of total quercetin metabolized in the jejunum microsomal fraction was 43 vs. 32% in ileal one. In both cases, the same four metabolites (referred to as a-d, according to their increasing hydrophobicity) were present on the HPLC profiles (Fig. 4). These peaks corresponded to the glucuronidated forms of quercetin.
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The HPLC profile of nonhydrolyzed effluent resulting from quercetin perfusion (Fig. 2A) has been compared with that obtained after in vitro glucuronidation of quercetin by microsomal jejunal and ileal fractions (Fig. 4). By taking into account the respective relative retention times compared with diosmetin, peaks 1, 2, and 4 (Fig. 2A) exhibited a perfect coincidence with those noted b, c, and d, obtained by the in vitro glucuronidation procedure (Fig. 4). Peak 3 could correspond to glucuronidated-methoxylated forms of quercetin (but this point was not tested). These data support the view of the existence of an UDP-glucuronyltransferase activity using quercetin as a substrate at the intestinal level.
Concentrations of Quercetin and of Its Methoxylated Forms in Various Biological Samples
At the end of the perfusion period, the concentration of quercetin in hydrolyzed plasma was about 0.71 ± 0.06 µM (Table 1). By contrast, in nonhydrolyzed plasma no trace of free quercetin could be found, indicating that the circulating forms of quercetin are glucurono-sulfoconjugates. However, these quercetin metabolites were not detected in nonhydrolyzed samples, probably because their responsiveness was too low in the present chromatographic conditions (Table 1).In all experiments a cannulation of the biliary duct was performed to test the enterohepatic cycling of quercetin. The biliary secretion was quite noticeable at the end of the perfusion; about 55 µM of quercetin and of its methoxylated forms were found in the hydrolyzed bile samples. Quercetin constituted the main form of biliary excretion (43%), the other metabolites being isorhamnetin and tamarixetin (30 and 27%, respectively) (Table 1). This high level of biliary excretion accounts for a very active hepatic metabolism of quercetin.
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DISCUSSION |
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In the present experimental pattern, rutin was not absorbed and metabolized in the small intestine. These data are in accordance with those of Manach et al. (16), which showed that the absorption of rutin was delayed compared with that of quercetin. Indeed, the hydrolysis of rutin takes place in the cecum because the microflora possesses glycosidases liable to hydrolyze glycosides with a high degree of specificity (3). Then the free quercetin produced can be absorbed, eliminated, or degraded in phenolic acids (1, 4, 30).
In contrast to rutin, the absorption of quercetin from the small intestine appears very effective, inasmuch as 66.7% of perfused quercetin is absorbed by the small intestine, although the perfusion rate is relatively high (0.9 µmol/h of quercetin, which after extrapolation represents 6.5 mg/day). A recent study dealing with the transcellular transport of quercetin in the intestine using a Caco-2 cell monolayer model (32) corroborates the present finding. The study by Walgren et al. (32) reported that the average recovery in the basolateral side was to 67% of medium quercetin with an apical loading in this molecule.
A significant part of the quercetin recovered in the effluent was conjugated. These conjugated forms of quercetin have an intestinal origin because the biliary duct was cannulated before the beginning of the perfusion (leading to a disruption of the enterohepatic cycle). The intestinal metabolism of flavonoids is still poorly known; nevertheless previous studies performed on rats have already shown that glucuronide and sulfate forms of 1-naphthol and estrogens were excreted in the lumen during in situ perfusion of the intestine (2, 26). Thus the intestinal metabolism of quercetin and that of these compounds seems quite similar. In view of this, Sfakianos et al. (27) have described an in vivo glucuronidation of an isoflavone (genistein) by the intestinal wall.
The existence of an intestinal UDP-glucuronyltransferase activity was
confirmed by the present in vitro experiments of quercetin glucuronidation from jejunal and ileal microsomal preparations. The
glucuronidation yield measured on these fractions appears lower than
that observed with liver microsomes (18); however, it was still
noticeable. Glucuronidation was not the sole conjugative activity
present in the intestine since methoxylated forms of quercetin (3- and
4-O-methylquercetin) are released after hydrolysis of the
effluents with -glucuronidase (and sulfatase). Although the activity of catechol O-methyltransferase has been reported to be maximum in the liver and kidneys (29), it is also present in the
enterocytes (21). The cells can combine processes of glucuronidation
and methylation. The glucuronidation has been described as a rapid
process (2, 22) that takes place for the high concentrations of
metabolites (12). This could explain why the percentage of
glucuronidation in the intestine (64%) appeared greater than that of
methylation (4%) (12). This result is in accordance with those of
Piskula and Terao (21), which showed that the glucuronidation of
epicatechin was more important than the methoxylation in the intestine.
Moreover, these data have been obtained in vitro, and additional
experiments could be performed to test in vivo their validity. In
keeping with a previous report (25), the present work shows the
existence of a sulfotransferase activity in intestinal cells. It is
well established that whatever its origin, the sulfotransferase
activity is inversely related to the concentration of quercetin (25,
28, 33). However, in the present conditions of perfusion, even if the
glucuronidation prevailed (64%), sulfatation was substantial (36% of
the total conjugation). At the intestinal level, quercetin was sulfated but no trace of mixed glucurono-sulfoconjugates was found. By contrast,
it has been shown (18) that in rats adapted to a quercetin diet the
major circulating forms of quercetin are constituted by
glucurono-sulfoconjugates. The absence of these compounds at the
intestinal level strongly suggests that they are preferentially synthetized in the liver.
According to the present data and to those found in the literature (11,
15, 16, 18), it could be possible to depict the major features of
quercetin absorption and the metabolism at the intestinal level (Fig.
5). Quercetin enters the cells by a still
unidentified mechanism. In these cells, quercetin is readily glucuronidated, methoxylated, and sulfated. The resulting metabolites can subsequently leave the intestinal cell possibly via a facilitated transport system, either across the apical pole (secretion of the
conjugated forms in the lumen) or across the basolateral side for their
further transfer into the portal vein. However, disposal data are not
sufficient to exclude that a part of the absorbed quercetin can
circulate in the blood as aglycone (Fig. 5).
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The liver further metabolizes the conjugated compounds arising from intestine, leading to an increase of their degree of glucuronidation, sulfatation, and methoxylation. Thus no trace of free quercetin could be detected in the plasma of rats infused with quercetin in the small intestine. This is in accordance with previous studies, in which it was reported that the circulating metabolites of quercetin recovered in the plasma are glucurono-sulfoconjugates with a high degree of methoxylation (16, 18). In vitro the rate of intestinal conjugation and of secretion of quercetin metabolites toward the lumen is quite substantial, but in vivo the intestinal secretion of conjugated derivatives could be lower. In vivo the presence of biliary quercetin conjugates in the lumen could decrease the concentration gradient between the enterocytes and the digestive content and therefore the flow of conjugates could be preferentially directed toward the basolateral side.
In the present work, both production and elimination of conjugates seen essentially occur via the intestinal pathway, rather than by the biliary route. Whatever their origin (biliary or intestinal), quercetin conjugates could be recycled after their metabolism by the microflora, in the large intestine (9). This phenomenon can contribute to extend the bioavailability of quercetin all along the light-dark cycle (9). However, bacterial degradation of quercetin into phenolic acids (4) may depress the recovery of the intestinal conjugates.
In conclusion, the intestinal secretion of quercetin conjugates constitutes an elimination pathway that should be taken into account, in addition with the urinary and biliary pathways. Nevertheless, it seems essential to characterize the transport systems for the aglycone and conjugated forms across the intestinal membrane.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: V. Crespy, Laboratoire des Maladies Métaboliques et des Micronutriments, INRA de Clermont-Ferrand/Theix, 63122 Saint Genès Champanelle, France (E-mail: crespy{at}clermont.inra.fr).
Received 25 September 1998; accepted in final form 12 April 1999.
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