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Laboratoire des Maladies Métaboliques et des Micronutriments, Institut National de la Recherche Agronomique, de Clermont-Ferrand/Theix, 63122 Saint Genès Champanelle, France
1To whom correspondence should be addressed. E-mail: crespy{at}clermont.inra.fr
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSHPLC analysisRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • quercetin • phloretin • flavonoid glucosides • rats • in situ perfusion
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSHPLC analysisRESULTSDISCUSSIONREFERENCES |
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and
constitute an integral part of the human diet. The most important
groups are anthocyanidins, catechins, flavones, flavanones and
flavonols (2)
. Nevertheless, some minor classes of
flavonoids, such as chalcone and dihydroxychalcone, must also be taken
into account.
In the flavonol category, quercetin is the most abundant compound
in vegetables and fruits and many biological properties are associated
to this compound: antibacterial, antiviral, antioxidant,
antiproliferative, antiinflammatory and anticarcinogenic effects
(3
,4)
. In food, quercetin is present as glycosylated
forms, mainly as ß-glycosides (5)
, and the nature of
glycosylation markedly influence the efficiency of quercetin
absorption. In vivo, it has been shown that absorption and metabolism
of quercetin or of quercetin glucosides took place in the small
intestine (6
,7)
, whereas rutin
(quercetin-3-O-glucose-rhamnose) cannot be absorbed at this
level (8
9
10)
. Before its absorption, rutin must be
hydrolyzed by the cecal microflora and then released quercetin can be
directly absorbed or degraded as phenolic acids (11
12
13)
.
It appears that the hydrolysis of the glucoside moiety constitutes the
first step of the intestinal metabolism of the glucosylated forms.
Therefore, using a Caco-2 cells line model, quercetin glucosides were
first deglycosylated in the process of intestinal digestion
(14)
. A cytosolic ß-glucosidase, located in the small
intestine, exhibited activity toward flavonoid glucosides
(15
,16)
. Another ß-glucosidase presents on the brush
border of the intestine, lactase phloridzin hydrolase
(LPH)2
is characterized by its substrate specificity toward phloridzin (a
dihydroxychalcon) (17
,18)
. This compound is a classic
competitive inhibitor of the intestinal sugar carrier:
Na+/glucose cotransporter (SGLT1)
(19)
and is considered to be an antidiabetic agent
(20
,21)
. It is of interest to determine whether flavonol
glucosides, which have a structure quite similar to phloridzin
(Fig. 1
), may also be good substrates for the ß-glucosidase site of LPH.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSHPLC analysisRESULTSDISCUSSIONREFERENCES |
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Diosmetin, isoquercitrin and hesperetin were purchased from Extrasynthese (Genay, France). Quercetin, phloridzin, phloretin and ß-glucuronidase/sulfatase from Helix Pomatia were purchased from Sigma (L’Isle D’Abeau, Chesnes, France).
Animals and diets.
Wistar rats, born at the Institute (Institut National de la Recherche
Agronomique), weighing 
150 g, were housed, two per cage, in
temperature-controlled rooms (22°C), with a dark period from 8:00
to 20:00 h and with access to food from 8:00 to 16:00 h. They were fed
a standard semipurified diet (730 g/kg wheat starch, 150 g/kg casein,
60 g/kg mineral mixture, 10 g/kg vitamin mixture and 50 g/kg 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 87-848.
Sampling procedure.
Rats were anesthetized with sodium pentobarbital (40 mg/kg body) 18 h after the beginning of the meal and were kept alive during the perfusion period. After cannulation of the biliary duct, a perfusion of jejunal + ileal segments of intestine (from 5 cm distal from the flexura duodenojejununalis to the valvula ileocoecalis) was prepared by installing cannulas at each extremity. This segment was continuously perfused in situ at a flow rate of 1 mL/min, for 30 min, with a buffer containing: KH2PO4 (5 mmol/L), K2HPO4 (2.5 mmol/L), NaHCO3 (5 mmol/L), NaCl (50 mmol/L), KCl (50 mmol/L), CaCl2 (2 mmol/L), MgCl2 (2 mmol/L), pH 6.7, glucose (8 mmol/L) and taurocholic acid (1 mmol/L), at 37°C and supplemented with 15 µmol/L of quercetin with or without 150 µmol/L of phloretin, 15 µmol/L of isoquercitrin with or without 150 µmol/L of phloridzin or with 15 µmol/L of phloretin or phloridzin. The intestine was washed of its content during the first 15 min. All the molecules used were stable in the buffer throughout the perfusion period. Aliquots of effluent were directly collected at the exit of the ileum in plastic tubes (1.5 mL) during the last 5 min of perfusion.
At the end of the experiment, blood samples were withdrawn from the mesenteric vein (corresponding to the perfusate segment of the intestine) and abdominal aorta into heparinized tubes. Plasma and perfusate samples were acidified with 10 mmol/L acetic acid and stored at -20°C.
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HPLC analysis |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSHPLC analysisRESULTSDISCUSSIONREFERENCES |
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Plasma and perfusate samples were spiked with internal standard namely:
diosmetin (14 µmol/L) in quercetin and isoquercitrin experiments or
hesperetin (3.5 µmol/L) for phloretin and phloridzin experiments.
They were acidified (to pH 4.9) with 0.1 volume of acetic acid (0.58
mol/L). The samples were treated for 30 min at 37°C in the absence
(unconjugated forms) or in the presence (total forms) of 5 x 106 U/L ß-glucuronidase and 2.5 x 105
U/L sulfatase. The reactions were stopped by adding of 2.85 volumes of
acetone and the resulting mixtures were centrifuged for 4 min at 14 000
x g. Supernatant (20 µL) was injected and
analyzed by HPLC. The concentrations of conjugated derivatives were
estimated as the difference between the concentrations of quercetin
measured before and after the enzymatic treatment. For the effluent,
all the concentrations measured have been corrected by taking into
account the intestinal absorption of water as previously described
(10)
.
Chromatographic conditions.
The HPLC system used consisted of an autosampler (Kontron 360), an ultraviolet detector (set at 370 nm for flavonols and at 280 nm for dihydroxychalcones) and a software system for data recording and processing. The system was fitted with a 5-µm C-18 Hypersil BDS analytical column (150 x 4.6 mm; Life Sciences International, Cergy, France). The mobile phase consisted of water/H3PO4 (99.5: 0.5; solvent A) and acetonitrile (solvent B).
To visualize and 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: linear gradient from solvent A 85%/solvent B 15% to solvent A 60%/solvent B 40%; 22–24 min: solvent A 60%/solvent B 40%; 24–27 min: return to initial mobile phase conditions, then equilibration for 8 min.
Glucose measurements.
The glucose concentration was determined by an enzymatic method
(22)
.
Statistics.
Values are means ± SEM, and the differences were determined by one-way ANOVA coupled with the Student-Newman-Keuls multiple comparison test. Differences with P < 0.05 were considered significant. The statistical analysis of the glucose absorption was realized by one-way ANOVA coupled with the Tukey post-hoc test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSHPLC analysisRESULTSDISCUSSIONREFERENCES |
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When quercetin was perfused for 30 min (at 14.70 ± 0.60 nmol/min)
in the intestinal lumen, this flavonol was recovered in the intestinal
effluent as the native form (4.90 ± 0.40 nmol/min) and as
conjugated forms (7.70 ± 0.40 nmol/min; Fig. 2
). When the effluent was hydrolyzed by a ß-glucuronidase/sulfatase,
86% of perfused dose was recovered in the effluent at the end of
perfusion. Thus, the remaining of perfused quercetin (14%)
corresponded to the net absorption of this compound by the intestinal
wall.
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. This result suggests that the transport through the brush
border was more efficient for isoquercitrin than for its aglycone. The
HPLC profile corresponding to the effluent of isoquercitrin perfusion
(Fig. 3
) was characterized by a peak of isoquercitrin, one of free quercetin
(1.85 ± 0.50 µmol/L) and four unidentified peaks (noted 1–4).
Isoquercitrin was stable in the buffer (data not shown); thus,
quercetin recovered in the effluent originates from the partial
hydrolysis of the glucoside at the level of the intestinal wall. The
four unidentified peaks completely disappeared after enzymatic
treatment by a ß-glucuronidase/sulfatase, indicating that they
corresponded to conjugated derivatives. These peaks had retention time
similar to those of the conjugated forms of quercetin found in
experiments in which quercetin was perfused (Fig. 3)
. This similarity
suggests that the conjugated forms recovered after isoquercitrin
perfusion could correspond to the conjugated forms of quercetin and
that isoquercitrin was first hydrolyzed into quercetin before its
conjugation by the intestinal enzymes. Taking into account the
respective retention times, compared with diosmetin (internal
standard), it may be noted that one of the quercetin conjugates (peak
1; Fig. 3
) presents a chromatographic behavior close to that of
isoquercitrin. In fact, it is difficult to distinguish between
glucoside and endogenous conjugated derivatives.
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). In
parallel, the net absorption of isoquercitrin perfusion was higher than
that observed after quercetin perfusion (P < 0.05;
25% vs. 14%, respectively). These data suggest that the
3-O-glucosylation of quercetin improved its net absorption
by the intestinal wall. After quercetin or isoquercitrin perfusion, no
native forms were present in nonhydrolyzed plasma from mesenteric vein
(data not shown). After enzymatic hydrolysis, quercetin appeared in the
plasma, indicating that the circulating forms of quercetin were
conjugated metabolites. After a quercetin or an isoquercitrin
perfusion, the arterioveinous difference found in quercetin
concentration was 1 µmol/L. Nevertheless, because the blood flow
was not measured, we did not quantify the flavonol absorption. Intestinal metabolism of phloretin and phloridzin.
When phloretin was perfused into the intestinal lumen at a rate of
14.40 ± 0.49 nmol/min, a portion of the aglycone was directly
excreted in the effluent at the end of perfusion (6.06 ± 0.62
nmol/min; Fig. 4
). In parallel to this excretion, the dihydroxychalcon was recovered as
conjugated forms (4.73 ± 0.38 nmol/min), as shown by their
disappearance in the presence of ß-glucuronidase/sulfatase. As
quercetin, phloretin was metabolized by intestinal conjugative enzymes,
and some of these conjugated forms (glucuronides and/or sulfates) were
secreted into the mucosal side. At the end of the perfusion, the 3.61
± 0.20 nmol/min of perfused phloretin not recovered in the
effluent corresponds to the net absorption of this compound by the
intestinal wall.
|
). This result suggests that hydrolysis of
phloridzin to phloretin is not a limiting step for its absorption,
because 80% of this glucoside was hydrolyzed. After a phloridzin or
phloretin perfusion, the secretion of aglycone was not different (0.05
< P < 0.1; Fig. 4
). Moreover, the analysis of
HLPC profiles indicated that the conjugated forms of phloridzin found
in the effluent corresponded to those recovered after phloretin
perfusion (data not shown). This strongly suggests that the hydrolysis
of phloridzin preceded its metabolism by the intestinal conjugative
enzymes. When phloridzin was perfused, its absorption by the intestinal
wall was markedly lower than that measured when the aglycone was
perfused (1.11 ± 0.50 nmol/min vs. 3.60 ± 0.20 nmol/min;
P < 0.05, respectively). Moreover, the flux of the
secretion of conjugated metabolites was significantly reduced
(P < 0.05) when phloridzin was perfused instead of
phloretin (2.87 ± 0.89 nmol/min and 4.73 ± 0.38 nmol/min,
respectively).
When phloridzin (phloretin 2'-O-glucose) was present in the
perfusion medium, the glucose absorption, measured at the end of
perfusion period, was markedly decreased (-42% compared with control;
Table 1
). By contrast, glucose absorption was not modified in the presence of
phloretin (0.05 < P < 0.1).
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Comparison of intestinal metabolism of isoquercitrin and phloridzin.
After an isoquercitrin or phloridzin perfusion, the levels of the
glucosylated forms recovered in the effluent were not different (0.05
< P < 0.1; Figs. 2
and 4
). This indicates that
the intestinal wall hydrolyzed the two glucosides to the same extent.
When phloridzin was perfused, the excretion of the aglycone form was
markedly higher than that observed after isoquercitrin perfusion (6.77
± 0.50 nmol/min vs. 1.85 ± 0.50 nmol/min, respectively;
P < 0.05). Moreover, the secretion of conjugated forms
and the net absorption of isoquercitrin were more important than were
those of phloridzin (P < 0.05; Figs. 2
and 4
). This
result shows that the net transfer of quercetin from isoquercitrin into
the intestinal wall is more efficient than that of phloretin from
phloridzin. It should be noted that, in contrast to phloridzin, glucose
absorption was not modified by isoquercitrin (Table 1)
.
Comparison of intestinal metabolism of quercetin and phloretin.
At the end of perfusion period, the amount of phloretin recovered in
the effluent was greater than that of quercetin (6.06 ± 0.62
nmol/min vs. 4.90 ± 0.40 nmol/min, respectively; P
< 0.05; Figs. 2
and 4
). The secretion flux of the conjugated
forms was greater after perfusion of quercetin than phloretin (7.70
± 0.40 nmol/min vs. 4.73 ± 0.38 nmol/min, respectively;
P < 0.05). These results suggest that the capacity of
quercetin to enter the intestinal cells is higher than that of
phloretin and/or that the intestinal conjugative enzymes are more
effective toward quercetin than toward phloretin. Nevertheless, the net
absorption of quercetin (2.10 ± 0.40 nmol/min) was markedly lower
(P < 0.05) than that of phloretin (3.60 ± 0.20
nmol/min).
Intestinal metabolism of isoquercitrin in presence of phloridzin.
When perfused at 146.40 ± 3.50 nmol/min, phloridzin markedly
inhibited glucose absorption (-83%; Table 1
). When phloridzin and
isoquercitrin were perfused together, the concentration of
isoquercitrin recovered in the effluent was not different (0.05 < P < 0.1) from that observed with isoquercitrin alone
(3.74 ± 0.30 nmol/min vs. 3.13 ± 0.50 nmol/min,
respectively; Fig. 5
). This indicates that the presence of phloridzin did not affect the
capacity of isoquercitrin to enter the intestinal cells and its
hydrolysis. Moreover, as shown in the Figure 5
, the excretion of
quercetin consecutive to isoquercitrin perfusion was not modified by
phloridzin (0.05 < P < 0.1). By contrast,
phloridzin markedly decreased the secretion of conjugated forms of
quercetin (3.33 ± 0.30 nmol/min vs. 5.55 ± 0.40 nmol/min
for isoquercitrin alone; P < 0.05). This phenomenon
led to a 61% increase in the net absorption of isoquercitrin (5.81
± 0.26 nmol/min vs. 3.61 ± 0.13 nmol/min for isoquercitrin
alone; P < 0.05).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSHPLC analysisRESULTSDISCUSSIONREFERENCES |
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After intestinal infusion of quercetin or phloretin, some conjugated
forms were recovered in the effluent. Because the biliary duct was
cannulated at the beginning of the perfusion, these conjugated forms
were necessarily of intestinal origin. Conjugative enzymes are present
in the enterocytes (23
,24)
and this enzymatic equipment
allows intestinal cells to glucuronidate, sulfate and methylate
flavonoids (14
,25
,26)
. Moreover, using Caco-2 cells, Plumb
et al. (27)
have shown that when quercetin was added in
the apical side, some conjugated quercetin were recovered on this side,
indicating that quercetin had been absorbed and metabolized in the
cells and then transported back to the apical side. These data are
consistent with our results and confirm that enterocytes constitute an
effective site for flavonoids conjugation.
After an isoquercitrin or phloridzin infusion, the conjugated forms
recovered in the effluent were similar to those found after perfusion
of the corresponding aglycone. This result is corroborated by a
previous study (28)
, performed with everted intestine, and
showing that the conjugated derivative recovered on the mucosal side
was identical in experiments using phloretin or phloridzin.
Nevertheless, it could not be excluded that microflora present into the
intestinal lumen contribute to glucoside hydrolysis and to conjugation
of the aglycones (29
,30)
. In our experiments, because the
rats were deprived of food and because the first 20 min of the
perfusion step washed the intestinal contents, the contribution of the
intestinal microflora to the metabolism of flavonoids should be quite
limited.
Some studies have reported that quercetin glucosides are present in
human plasma without metabolic conversion (31
,32)
.
Howeover, in the present study, we did not detect any intact aglycone
or glucosylated forms in the mesenteric vein, showing that all the
glucosides were necessarily hydrolyzed and conjugated before their
transfer on the serosal side. Indeed, recently, using a multielectrode
coulometric detection, together with suitable chromatographic
conditions, we have shown that the circulating metabolites present in
the plasma of rats fed an isoquercitrin meal or a quercetin meal were
identical and corresponded to conjugated derivatives of quercetin, such
as glucuronided, sulfated and methoxylated forms (7
,33)
.
The present study clearly demonstrated that the hydrolysis of the
glucosyl moiety constitutes a crucial step in the intestinal metabolism
of flavonol and dihydroxychalcon glucosides. When glucosides were
perfused, the corresponding aglycone form was recovered in large amount
in the effluent. The hydrolysis of phloridzin to phloretin is performed
by the ß-glucosidase site of LPH, present on the brush border of the
enterocytes (18)
. Phloridzin is considered to be a
competitive inhibitor of the
glucose/Na+-dependant carrier
(19
,34)
, but the dihydroxychalcone moiety is not
transported by SGLT1 (35)
. Furthermore, our data show that
a large proportion of the phloretin released from phloridzin hydrolysis
diffused directly into the effluent, and we observed that the magnitude
of the secretion of quercetin from isoquercitrin was considerably
lower. The high secretion of phloretin into the lumen could be related
to the extracellular hydrolysis of the glucoside and/or to differences
between the activities of intestinal conjugation of each compound.
When isoquercitrin was perfused, the magnitude of its hydrolysis into
quercetin was of the same order of magnitude as that of the
dihydroxychalcon glucoside. In the presence of a high flux of
phloridzin (150 nmol/min), the excretion of isoquercitrin and the
secretion of quercetin from isoquercitrin were not affected. These
results suggest that the hydrolysis of isoquercitrin by LPH did not
constitute a limiting step for its intestinal metabolism and support
the hypothesis that isoquercitrin could be hydrolyzed by a cytosolic
ß-glucosidase (15
,16)
. Such a process could contribute
to decrease the secretion of the aglycone into the lumen as observed in
our study. Phloridzin did not influence the hydrolysis of isoquercitrin
and it is not excluded that the lactase site of LPH could participate
in its hydrolysis. Recently, it has been shown in vitro that the
lactase site of LPH was responsible for the hydrolysis of different
glucosides and particularly, that of quercetin glucosides
(36)
.
It has been previously suggested that SGLT1 was involved in the
transport of flavonol glucosides into the intestinal cells
(6)
. Using the technique of the everted intestine, it has
been shown that quercetin glucosides are able to interact with the
sodium-dependant glucose transport (37)
. However, no
evidence for an active transport of these compounds was found in
experiments performed on human intestinal epithelial Caco-2 cells
(38)
. In our study, when phloridzin was perfused, the
activity of SGLT1 was affected, as reflected by the marked inhibition
of glucose absorption. However, the absorption of isoquercitrin was not
significantly modified by the presence of phloridzin. These whole data
do not account for the involvement of SGLT1 in the intestinal transport
of isoquercitrin and raise questions about the nature of the
transporter responsible for isoquercitrin entry into intestinal cells
in vivo.
After a quercetin infusion, the secretion of conjugated forms was
higher than after an isoquercitrin infusion. By contrast, the net
absorption increased when isoquercitrin was perfused instead of its the
aglycone form. This result, obtained in situ, is in accordance with the
in vivo studies reporting that, in humans, glucosylated forms of
quercetin were more efficiently absorbed than quercetin itself
(6
,39)
. In our experiments, the direct perfusion of
quercetin could result in a high concentration of this compound in the
enterocyte, leading to an enhancement in the rates of conjugation and
transfer of conjugated forms across the brush border into the
intestinal lumen. For isoquercitrin, this phenomenon could be limited
by the prerequisite step of hydrolysis to quercetin. In the same way,
the secretion of conjugated metabolites seems to be more important for
phloretin than for phloridzin. Thus, the O-glucosylation of
quercetin and phloretin improved the secretion of conjugated
metabolites in the lumen.
We did not detect any trace of perfused compounds in intestinal mucosa extract (data not shown), indicating the absence of binding to the enterocytes. In such conditions, the difference between the concentrations measured in the original perfusate and in the remaining perfusate corresponded to the real net absorption.
The comparison of the net absorption of quercetin and phloretin indicated that the absorption of the flavonol was better, whereas the secretion of conjugated metabolites was lower for phloretin than for quercetin. This suggests that quercetin enters the cells more readily than phloretin, possibly because of the planarity of the quercetin molecule. The higher net absorption of isoquercitrin, compared with that of phloridzin, may be due to differences in the hydrolysis step. The extracellular hydrolysis of phloridzin may have elicited a production of the aglycone directly in the lumen, leading to a decrease of its net absorption. By contrast, the intracellular hydrolysis of isoquercitrin could limit the excretion of quercetin on the mucosal side and favor its net absorption.
The presence of phloridzin decreased the intestinal conjugation of
isoquercitrin. The decreased secretion of quercetin conjugation in the
lumen led to an improvement in the net absorption of isoquercitrin.
This result could be explained by a saturation of the intestinal
capacity of conjugation and/or to a limitation of the secretion into
the mucosal side when the two flavonoid glucosides are simultaneously
present in the lumen. In a previous study of the interactions between
phloridzin and p-nitrophenol at the intestinal level, it was
shown that the inhibition of the glucuronidation process improved
intestinal absorption of the drug (40)
. Thus, the
intestine could limit the net absorption by an extensive secretion of
conjugates.
In conclusion, the present study clearly shows that the absorption of flavonoid glucosides was highly dependent on the mechanisms involved in their hydrolysis and on the activity of their intestinal conjugation. However, additional investigations should be performed to determine the nature of the carrier involved in flavonol glucoside transport at the intestinal level.
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FOOTNOTES |
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Manuscript received February 15, 2001. Initial review completed March 14, 2001. Revision accepted April 30, 2001.
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