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Department of Pharmacology and Toxicology, Nijmegen Center for Molecular Life Sciences, 6500 HB, Nijmegen, The Netherlands;
*
RIKILT, Wageningen University and Research Centre, 6700 AE, Wageningen, The Netherlands; and
Small Animal Research Center, Wageningen University, 6700 HB, Wageningen, The Netherlands
2To whom correspondence should be addressed. E-mail: a.sesink{at}ncmls.kun.nl.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • flavonoids • quercetin-3-glucoside • lactase phlorizin hydrolase • intestinal uptake • rats
Epidemiologic studies have shown an inverse association between fruit and vegetable intake and the incidence of cardiovascular diseases and several types of cancer (1 –3 ). Several components of plant foods, such as the flavonoids, are now being screened for possible positive health effects. Flavonoids are polyphenolic compounds that have antioxidant (4 ) and antiproliferative activity (5 ), in addition to protective effects in models of cardiovascular diseases (6 ,7 ) or colon carcinogenesis (5 ,8 ,9 ). Before flavonoids can exert systemic effects, these compounds must be absorbed from the intestinal lumen. Studies on bioavailability have shown that orally ingested flavonoids can indeed be absorbed into the bloodstream (10 ). Flavonoids in plant foods occur mainly as ß-glycosides. On the basis of studies showing that quercetin glucosides were preferentially absorbed from the intestinal lumen of humans compared with quercetin aglycone or rutin, Hollman postulated that the sodium dependent glucose transporter (SGLT1) (3 ) might be involved (11 ,12 ). Several experimental studies have shown direct interaction of quercetin glucosides with SGLT1 (13 –15 ). Evidence for SGLT1-mediated cellular uptake is, however, very limited. It has been shown that intact quercetin glucosides are not present in human peripheral (16 ,17 ) or rat mesenteric blood (18 ), implying that the quercetin glucosides very likely are hydrolyzed before entering the bloodstream. In small intestinal cells, two ß-glycosidases are present. Cytosolic ß-glucosidase (CBG) has hydrolytic activity toward several flavonoid glucosides, although quercetin-3-glucoside (Q3G) is not a substrate (19 ). Lactase phlorizin hydrolase (LPH), an extracellular enzyme located at the brush border membrane of intestinal cells, can also hydrolyze flavonoid glucosides, including Q3G (20 ). It has not been established which glycosidase is responsible for the initial hydrolytic step in vivo. The aim of this study was to assess the role of LPH in the small intestinal absorption of flavonoid glucosides, using Q3G as a model compound. For this, we used an in situ rat small intestinal perfusion model, in which disappearance of Q3G from the perfusion fluid and appearance in plasma of quercetin and its metabolite, isorhamnetin, were indicative of intestinal uptake of Q3G. In our model, LPH could effectively be inhibited by N-(N-butyl)deoxygalactonojirimycin (NB-DGJ). NB-DGJ is normally used as an inhibitor of ceramide glucosyltransferase (21 ), used in the treatment of Gaucher’s disease. This drug appears to be a potent and selective inhibitor of LPH as well (21 ).
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Quercetin-3-glucoside and isorhamnetin were purchased from Roth (Karlsruhe, Germany). Quercetin, phlorizin, glucose, lactose and ß-glucuronidase/sulfatase (Helix pomatia, G1512) were obtained from Sigma (St. Louis, MO). NB-DGJ was purchased from TRC (Toronto, Canada). Radiochemicals ([14C]-glucose and [14C-glucose]lactose) were obtained from Amersham Biosciences (Buckinghamshire, UK). All other chemicals used were of analytical grade. A mix of quercetin glucuronides used in this study was kindly provided by Karen O’Leary (Institute of Food Research, Norwich, UK).
Animals and diets.
The experimental protocol was approved by the animal welfare committee of Wageningen University, Wageningen, The Netherlands. Male outbred Wistar rats (Harlan/Wu Horst, The Netherlands, specific pathogen–free, n = 20), mean body weight 233 g (SD 6.9) were housed individually in metabolic cages in a room with controlled temperature (22–24°C), relative humidity (50–60%) and light:dark cycle (lights on from 0600 to 1800 h). For three consecutive days before the experiment, all rats were fed a commercially available soy-free semipurified diet (g/kg): dextrose 540, cellulose 50, cornstarch 100, casein 200, corn oil 50, standard AIN-76 vitamin and mineral mixtures (Hope Farms, Woerden, The Netherlands).
In situ perfusion studies.
After overnight food deprivation, rats (n = 5/group) were anesthetized by inhalation of isoflurane, using nitrous oxide and oxygen (1:1) as carrier. First the vena jugularis was cannulated. Then the abdominal cavity was opened and two cannulas (i.d. 1.52 mm) were inserted into the small intestine (jejunum and ileum). The contents of the cannulated segment were removed by flushing gently with 60 mL saline (37°C). Perfusion was started by injecting 10 mL of the test solution (37°C) in the cannulated segment, and connecting the intestine immediately to a single-pass perfusion system. Constant perfusion took place at a flow rate of 1 mL/min at 37°C, using a potassium phosphate buffer (5 mmol/L, pH 6.7) containing (mmol/L) 100 NaCl, 20 KCl, 2 CaCl2, 2 MgCl2 and 0.5 Na-taurocholate. The perfusion buffer was supplemented with 50 µmol/L Q3G and increasing concentrations of NB-DGJ (0, 0.5, 2 and 10 mmol/L). In control experiments in which Q3G was incubated in the perfusion fluid at 37°C for 60 min, there was no disappearance of Q3G and no free aglycone formed, indicating that the glycoside was stable under the experimental conditions. Perfusion was stopped after 20 min, and in the last minute, samples were taken from the perfusion fluid at the end of the cannulated segment and at the inlet of the perfused segment (for the t = 0 min sample). Effluent samples were acidified with sodium acetate (10 mmol/L, pH 4.9)/ascorbic acid (1 g/L, final concentrations). Before the experiment and at 20 min, blood was drawn from the cannulated vena jugularis, collected in EDTA-tubes and plasma was subsequently prepared by centrifuging for 10 min at 2000 x g (4°C). All samples were stored at -20°C before analysis.
The efficacy of NB-DGJ as an inhibitor of LPH in this model was tested by measuring the amount of [14C]-label in plasma after a 30-min perfusion of lactose (10 mmol/L, spiked with 0.46 MBq [14C-glucose]lactose) in the absence or presence of 0.4 mmol/L NB-DGJ. The appearance of [14C]-label in plasma was quantified using a scintillation counter (Wallac 1409, Perkin Elmer, Boston, MA). Selectivity of NB-DGJ for LPH was tested in intact rats by studying the appearance of radioactive label in plasma after oral ingestion of 1 mL lactose (50 mmol/L, spiked with 1.85 MBq/kg body [14C-glucose]lactose) or 1 mL glucose (50 mmol/L, spiked with 1.85 MBq/kg body [14C-glucose]) in the presence of 10 and 20 mmol/L NB-DGJ. In these experiments, the appearance of lactose-derived 14C-label in plasma 30 min postingestion was inhibited by 95 and 97% in the 10 and 20 mmol/L NB-DGJ groups, respectively (P < 0.01 vs. controls, data not shown). The amount of 14C-label in plasma of rats orally given 14C-glucose, indicative of intestinal SGLT1-activity, was not affected by 10 or 20 mmol/L NB-DGJ (data not shown). These data indicate that NB-DGJ selectively inhibits LPH.
Preparation of samples.
Plasma (100 µL) was incubated with 0.5 mg ß-glucuronidase/sulfatase (H. pomatia, 300 U ß-glucuronidase and 20 U sulfatase) in 40 µL of 0.6 mol/L sodium acetate buffer (pH 4.9) with 6 g/L ascorbic acid. After incubation for 2 h at 37°C in a shaking water bath, samples were deproteinized with 2 volumes acetonitrile and thoroughly mixed. Then, one volume 20% o-phosphoric acid (containing 3 g/L ascorbic acid) was added. Samples were centrifuged for 10 min at 10,000 x g and analyzed by HPLC. Effluents were analyzed without prior treatment with ß-glucuronidase/sulfatase.
HPLC.
A Merck Hitachi L-6000A pump (Hitachi, Tokyo, Japan), equipped with a Gilson 234 auto sampler (Gilson, Villagers-le-Bel, France) and a coulometric detector (CoulArray detector model 5600, ESA, Chelmsford, MA), set at 250, 300 and 500 mV, was used (Pd as reference). Separation of a 20 µL sample was performed on a Chromolith RP-18e column (100 mm x 4.6 mm, Merck, Darmstadt, Germany) protected by a New Guard RP18 guard column (15 mm x 3.2 mm, 7 µm, Perkin Elmer, Norwalk CT). The columns were maintained at 30°C with an ESA column heater (ESA, Chelmsford, MA). The solvents for the gradient elution were 5% acetonitrile (v/v) (solvent A) and 70% acetonitrile (v/v) (solvent B) in citrate buffer (25 mmol/L, pH 3.7). The following gradient, at a flow rate of 2.5 mL/min, was used: 0–12 min, linear gradient to 60% B; 12–12.5 min, linear gradient to 100% B; 12.5–14.5 min, 100% B; 14.5–15 min, linear gradient to 0% B. Total run time was 16 min.
Statistics.
Results are presented as means ± SEM. A commercially available package (GraphPad Prism version 3.00) was used for all statistics. One-way ANOVA followed by Dunnett’s multiple comparison test when appropriate was used to test for significant differences between the control group and any of the other treatment groups. Differences with P < 0.05 were considered be significant in all experiments.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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After perfusion of rat jejunum and ileum for 30 min with 10 mmol/L lactose spiked with [14C-glucose]-lactose, the concentration of 14C-label in the peripheral circulation was almost 19.2 ± 0.1 MBq/L plasma. When 0.4 mmol/L NB-DGJ was added to the perfusion fluid, the concentration of 14C-label in plasma was 4.8 ± 0.1 MBq/L, an inhibition of 75% (P < 0.001 compared with controls). This indicates that NB-DGJ was a potent inhibitor of lactase activity of LPH.
Intestinal hydrolysis of quercetin-3-glucoside.
The initial concentration of quercetin-3-glucoside in the perfusion fluid at the inlet of the cannulated intestinal segment was similar in all groups. In the control group, the concentration of quercetin-3-glucoside declined from 48.2 ± 1.1 to 34.3 ± 1.3 µmol/L after intestinal passage. Thus, 29% of quercetin-3-glucoside (13.8 ± 0.7 µmol/L) disappeared from the perfusion fluid during passage through the small intestine (Fig. 1 ). In the effluent, quercetin aglycone was present at 2.1 ± 0.3 µmol/L. Several small peaks could be detected in the effluent with retention times similar to those of standard quercetin glucuronides (not shown), but these were not quantified. Intestinal hydrolysis of quercetin-3-glucoside was inhibited 38% (P < 0.05), 50% (P < 0.01) and 67% (P < 0.01) by 0.5, 2.0 and 10 mmol/L NB-DGJ, respectively (Fig. 1 ). The amount of free aglycone present in the effluent was also decreased by NB-DGJ (Fig. 1 ). At 10 mmol/L NB-DGJ, 0.3 ± 0.1 µmol/L quercetin was present in the effluent (inhibition of 86%, P < 0.01).
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Intact quercetin-3-glucoside, quercetin aglycone and isorhamnetin were not detected in plasma before the experiment (limit of detection: 22 nmol/L). After intestinal perfusion, several peaks that had retention times similar to those of standard quercetin glucuronides were seen in the chromatogram (not shown). These peaks disappeared after treatment with ß-glucuronidase/sulfatase and the formation of quercetin and a small amount of isorhamnetin. Concentrations of quercetin and isorhamnetin in plasma of control rats after enzymatic hydrolysis were 1.23 ± 0.22 and 0.17 ± 0.03 µmol/L, respectively (Fig. 2 ). NB-DGJ decreased the total concentration of both metabolites in plasma 37, 55 (P < 0.11) and 75% (P < 0.01) less than controls for the 0.5, 2.0 and 10.0 mmol/L NB-DGJ groups, respectively.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Recently, transport of quercetin-3-glucoside across the brush border membrane of rat small intestine was attributed to the SGLT1 (22 ). In that study, paradoxically, no transport of the intact glucoside, free quercetin or any metabolite was shown. Instead, only disappearance of Q3G from the apical solution with formation of free quercetin was shown (a result also observed in the present study), which could be inhibited by glucose and phlorizin. We argue that this drop in extracellular Q3G concentration more likely indicates extracellular hydrolysis rather than transport across the intestinal mucosa. Moreover, in addition to inhibiting SGLT1-activity, both glucose and phlorizin have been shown to inhibit LPH (29 ,30 ). More indicative of the involvement of SGLT1 in that study was the 25% inhibition of Q3G disappearance by a Na+-free buffer. Interestingly, in our study, a similar percentage of Q3G absorption could not be explained by inhibition of LPH, suggesting that direct absorption of intact Q3G by SGLT1 should not be excluded. In fact, Walgren et al. (31 ,32 ) showed SGLT1-dependent apical-to-basolateral transport of intact Q4'G in Caco-2 cells. However, this could be achieved only by applying very high, nonphysiologic concentrations of quercetin-4'-glucoside (Q4'G) (250 µmol/L) to the apical compartment, together with inhibition of apical efflux by multidrug-resistance proteins. A similar phenomenon was reported for the "nontransportable" SGLT1-inhibitor phlorizin, which can be transported by SGLT1 (at a low rate) when applied at high but not physiologic concentrations (33 ). When Q4'G concentration was high, transport of the glucoside (31 ) was still very low compared with quercetin aglycone (34 ) (the apparent permeability coefficient = 0.032 ± 0.008 x 10-6 and 5.8 ± 1.1 x 10-6 cm/s for the glucoside and aglycone, respectively). This is in sharp contrast to the observation that in vivo, the glucoside is absorbed preferentially over its aglycone (11 ,14 ,18 ,35 ).
In conclusion, using an in situ intestinal perfusion system, we showed that after specific inhibition of LPH, hydrolysis of Q3G decreased by 67% and plasma concentration of quercetin was 75% lower. Because Q3G likely can be hydrolyzed only by LPH, our results suggest that hydrolysis by LPH is a major step in the intestinal absorption of quercetin-glucosides.
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FOOTNOTES |
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3 Abbreviations used: CBG, cytosolic ß-glucosidase; LPH, lactase phlorizin hydrolase; NB-DGJ, N-(N-butyl)deoxygalactonojirimycin; Q3G, quercetin-3-glucoside; Q4'G, quercetin-4'-glucoside; SGLT1, sodium dependent glucose transporter.
Manuscript received 30 August 2002. Initial review completed 7 October 2002. Revision accepted 12 December 2002.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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