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* Laboratoire de Pharmacognosie, Faculté de Pharmacie, 63001 Clermont-Ferrand, France; and
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: Severine.Talavera{at}u-clermont1.fr.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • rat • anthocyanins • berries • small intestine • absorption
Anthocyanins are a group of naturally occurring phenolic compounds responsible for the color of many flowers, fruits, and vegetables. They are glycosylated polyhydroxyl or polymethoxyl derivatives of 2-phenylbenzopyrylium (flavylium) cation (1). These natural compounds are widely present in the human diet due to their occurrence in berries and beverages, and daily anthocyanin intake has been estimated at around 200 mg/d in the United States (2). Anthocyanins are involved in a wide range of biological activities (3) including antioxidant (4–6), anti-inflammatory (7,8), and anti-carcinogenic activities (9–11); they may also have neuroprotective actions (12,13). They may be able to reduce the risk of coronary heart disease (14) through vasoprotective activities (15), effects on arterial vasomotion (16), and inhibition of platelet aggregation (17). Knowledge of anthocyanin bioavailability and metabolism is important to better understand their positive health effects. Anthocyanins are rapidly absorbed and appear in rat and human plasma as glycosides (18–20). However, the exact sites and mechanisms of absorption have not yet been determined. Recent studies showed that the stomach could be a preferential site for anthocyanin absorption (21,22). Absorption from the stomach could explain the fast appearance of anthocyanins in the bloodstream (18,20). Nevertheless, the fate of anthocyanins in the small intestine remains unknown.
Thus, the aim of this study was to investigate intestinal absorption of various anthocyanins using an in situ intestinal perfusion model in rats (23). Four purified anthocyanin glycosides (as a combination of various aglycones and glycosidic moieties) were studied. Furthermore, since berries are rich dietary sources of anthocyanins (24), intestinal absorption of blackberry anthocyanins and a commercially available bilberry extract was also evaluated.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSDISCUSSIONLITERATURE CITED |
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Animals and diets.
Male Wistar rats (n = 39; Iffa-Credo) weighing 
200 g were housed 2 per cage in temperature-controlled rooms (22°C), with a dark period from 2000 to 0800 h and access to food from 1600 to 0800 h. They were fed a semipurified control diet (755 g/kg wheat starch, 150 g/kg casein, 50 g/kg peanut oil, 35 g/kg AIN-93M mineral mixture, 10 g/kg AIN-76A vitamin mixture) during 2 wk (25).
Animals were maintained and handled according to the recommendations of the Institutional Ethics Committee of the INRA, in accordance with Decree No. 87–848.
Anthocyanin administration.
After being food deprived for 24 h, rats were anesthetized with sodium pentobarbital (40 mg/kg body wt) and kept alive throughout the perfusion period. The method for intestinal perfusion was adapted from Crespy et al. (23). After cannulation of the bile duct, perfusion of a jejunal plus ileal segment of intestine (from 5 cm distal to the flexura duodenojejunalis to the valvula ileocecalis) was prepared by installing cannulas at each extremity. This segment was continuously perfused in situ for 45 min at a flow rate of 0.75 mL/min with a physiological buffer containing KH2PO4 (5 mmol/L), K2HPO4 (2.5 mmol/L), NaHCO3 (5 mmol/L), NaCl (50 mmol/L), KCl (40 mmol/L), CaCl2 (2 mmol/L), MgSO4 (1 mmol/L), tri-potassium citrate (10 mmol/L), glucose (12 mmol/L), glutamine (2 mmol/L), and taurocholic acid (1 mmol/L), pH 6.6, at 37°C. It was supplemented with 10 µmol/L purified molecules (Cy 3-glc, Cy 3-gal, Cy 3-rut, or Mv 3-glc), blackberry extract (10 and 616 µmol/L), or bilberry extract (75.8 µmol/L). The amounts of perfused anthocyanins corresponded to those previously used in similar models (26,27). Berry anthocyanin extracts were obtained as described below. The intestine was washed of its content during the first 25 min of perfusion. 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. Effluent volume was estimated by weighing. Bile was collected in 3 fractions at 0- to 25-min, 25- to 35-min, and 35- to 45-min periods. At the end of the experiment, blood samples were withdrawn from the mesenteric vein and abdominal aorta into heparinized tubes. Urine present in the bladder was also collected. Effluent, bile, plasma, and urine samples were rapidly acidified with 240 mmol/L HCl and stored at –20°C before analysis.
Anthocyanin stability. Anthocyanins are particularly susceptible to pH variations and exist under 4 forms in equilibrium in aqueous solution (pH 1–7). Their structural transformations make them unstable at intestinal pH (28). This complex chemistry led us to determine the stability of these molecules throughout the in situ perfusion experiment (37°C, pH 6.6). Thus, an aliquot of the perfused buffer maintained at 37°C was collected at the beginning (t = 0), at t = 25 min, and at the end of the perfusion period (t = 45 min), and anthocyanins were analyzed by HPLC after acidification with 240 mmol/L HCl, as described below. The decrease in anthocyanin concentrations between 0 and 45 min allowed the overall percentage of degradation to be calculated. Moreover, anthocyanin degradation was a linear function of time. Thus, the amounts of anthocyanins perfused were determined from the mean of anthocyanin concentrations in the perfused buffer at t = 0 and t = 45 min.
Anthocyanin extracts. The major blackberry anthocyanin was Cy 3-glc (>98% of total anthocyanins) (25). Two blackberry anthocyanin extracts (low concentration, 10 µmol/L; high concentration, 616 µmol/L) were prepared from a powder obtained from frozen blackberries that were lyophilized, pulverized, and then sieved to eliminate seeds (25). Extracts were obtained from 4 g of powder treated for 30 min under agitation with 100 mL of 0.12 mol/L HCl in 10% ethanol and then centrifuged for 5 min at 12,000 x g. The supernatant was diluted 80-fold in the intestinal buffer to obtain the 10 µmol/L extract. To obtain the 616 µmol/L extract, the supernatant was evaporated to dryness using a rotary evaporator at 35°C and finally dissolved in 200 mL of the buffer.
The highly purified bilberry extract (Antho 50®, 61% anthocyanins) (22) was dissolved in 0.12 mol/L HCl in 10% ethanol and then diluted 80-fold in the intestinal buffer to obtain a final anthocyanin concentration of 75.8 µmol/L. This concentration, higher than that of purified anthocyanins (10 µmol/L), was chosen to allow quantification of each anthocyanin present in the bilberry extract. Indeed, bilberry extract was a mixture of 15 anthocyanins eluted as 13 peaks (22). Two of the peaks each contained 2 anthocyanins, due to difficulties in separating them (Fig. 1). This technical constraint prevented quantification of these peonidin and malvidin glycosides. Bilberry anthocyanin quantification was expressed as Cy 3-glc equivalents.
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Proteins from bile samples were eliminated by adding 2.8 vol of acetone, and centrifugation was performed for 5 min at 12,000 x g. Supernatants were evaporated under a nitrogen stream to the initial volume of bile. A 60-µL aliquot was immediately analyzed by HPLC, as described below.
Anthocyanins present in plasma samples were extracted with a solid-phase extraction cartridge (Sep-Pak C18 Plus, Waters) using Cy 3,5-diglc as internal standard (22) and then analyzed by HPLC (60 µL).
Urine samples were centrifuged for 5 min at 12,000 x g and the supernatant (20 µL) was analyzed by HPLC, as described below.
HPLC analysis. Analysis of anthocyanins was performed by HPLC using a photodiode array detector (DAD200, Perkin-Elmer) and an UV-visible detector (785A, Perkin-Elmer) at 524 nm, as previously described (22). Identification of the compounds present in samples was made by comparison with the authentic compounds based on retention time and the UV-visible spectrum and by the addition of an overload of individual compounds.
Identification of anthocyanin metabolites was carried out by HPLC-electrospray ionization (ESI)-MS-MS analysis. These analyses were performed on a Hewlett-Packard HPLC system equipped with MS-MS detection (API 2000, Applied Biosystem), as previously described (29). The MS data were collected in multiple reaction monitoring mode by monitoring the transition of parent and product ions specific for each compound at a dwell time of 0.5 s. Anthocyanin metabolites were detected according to the respective m/z values of their parent and product ions: cyanidin-3-glucoside (449/287), cyanidin monoglucuronide (463/287), peonidin-3-glucoside (463/301), and peonidin monoglucuronide (477/301). An m/z value of 176 for the substitution group indicated a glucuronide residue. However, the exact site of glucuronidation could not be specified.
Glucose measurements. Glucose concentrations were determined by an enzymatic method (30). Determination of intestinal glucose absorption allowed us to ensure that intestinal mucosa integrity was maintained.
Data analysis. Values are given as means ± SEM, and when appropriate, significance of differences between values was determined by one-way analysis of variance followed by the Student-Newman-Keuls test (GraphPad, Instat). Values of P < 0.05 were considered significant.
RESULTS
Stability. Anthocyanin stability was dependent on structure. In the experiment conducted with purified molecules, the overall percentage of degradation during the 45 min of perfusion was 2.32 ± 0.67% for Cy 3-glc (n = 7), 3.63 ± 0.20% for Mv 3-glc (n = 5), 4.13 ± 0.67% for Cy 3-gal (n = 7), and 5.15 ± 0.91% for Cy 3-rut (n = 6). Cy 3-glc was the major anthocyanin in blackberry extract (>98% of total anthocyanins) (Fig. 2A) and its percentage of degradation throughout the experiment was 0.69 ± 0.15% (n = 6). Bilberry anthocyanin stability was also related to aglycone chemical structure. The delphinidin glycosides were the least stable; their percentage of degradation reached 9.31 ± 0.25% (n = 5). This high degradation of delphinidin glycosides precluded accurate evaluation of their intestinal absorption. Thus, we have only determined the intestinal absorption of more stable bilberry anthocyanins such as cyanidin derivatives (degradation of 2.29 ± 0.25%), petunidin derivatives (degradation of 5.66 ± 0.57%), and peonidin + malvidin derivatives (degradation of 2.13 ± 0.47%).
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45 nmol/5 min) showed that Cy 3-glc (pure compound or from blackberry extract) was more absorbed (P < 0.05) from the intestinal lumen than other anthocyanins (Table 1). Perfusion of bilberry extract brought various amounts of the different anthocyanins (Table 2). The percentage of absorption was evaluated for each stable anthocyanin and it varied between anthocyanins from 8.1% (Pn 3-ara + Mv 3-glc) to 19.1% (Cy 3-glc) (Table 2). The mean percentage of absorption was 15.3 ± 2.0 and 12.7 ± 0.6% for cyanidin and petunidin glycosides, respectively (n = 5). The mean absorption of peonidin + malvidin glycosides was lower (9.05 ± 0.53%, P < 0.01) than that of cyanidin derivatives. The percentage of absorption of Cy 3-glc was not significantly affected by its origin (purified component or blackberry or bilberry extract) (Tables 1, and 2). Cy 3-gal also presented the same percentage of absorption, whatever the perfused solution (pure molecule or bilberry extract).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSDISCUSSIONLITERATURE CITED |
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Since cyanidin is the main anthocyanin aglycone encountered in plants (3), we compared the absorption of three 3-glycosides of cyanidin (glucoside, galactoside, and rutinoside) and of the 3-glucoside of a highly methylated aglycone, malvidin. We assumed that a decrease of anthocyanin amounts in the effluents reflected their intestinal absorption, although anthocyanin uptake through the intestinal epithelium was not demonstrated in experiments conducted with low doses. Anthocyanins were efficiently absorbed from the small intestine (from 10.7 to 22.4% of the perfused dose). Intestinal absorption was influenced by the glycosidic moiety. Indeed, Cy 3-glc was significantly more absorbed than Cy 3-gal or Cy 3-rut. Absorption of quercetin glucosides across the intestinal brush border membrane involves an interaction with the intestinal sodium-dependent glucose transporter SGLT1 (35,36). Hence, anthocyanin glucosides, which have a similar basic flavonoid structure, could also interact with this transporter. Aglycone structure also had an impact on anthocyanin intestinal absorption, since the presence of methylated groups reduced intestinal absorption. Indeed, absorption of Mv 3-glc was about 50% lower than that of Cy 3-glc (P < 0.05). Moreover, intestinal absorption of anthocyanins is quite different from that of other flavonoids. Quercetin 3-rutinoside was not absorbed through the intestinal wall after similar in situ perfusion (23), whereas cyanidin rutinoside was. This discrepancy could be related to the cationic structure of anthocyanins.
Among dietary sources of anthocyanins, bilberry (V. myrtillus L.) is one of the richest (24,37). Therefore, we studied intestinal absorption of a bilberry anthocyanin extract (Antho 50®) that contained 15 different anthocyanins derived from combinations of 5 aglycones (Dp, Cy, Pt, Pn, Mv) and 3 sugars (galactose, glucose, arabinose). The delphinidin derivatives proved unstable under experimental conditions (37°C, pH 6.6), and therefore we could not establish total absorption of bilberry anthocyanins. However, we previously showed that delphinidin glycosides from bilberry extract were absorbed in high proportions from the stomach, which constitutes a favorable environment for their stability (22). When each bilberry component was considered separately (except the Dp glycosides) a high variability of absorption was observed, as was previously described at the gastric level (22). Moreover, anthocyanin intestinal absorption was similar whatever the anthocyanin source (pure molecule or berry extracts). Thus, taken as a whole, these results indicated that anthocyanin glycosides were absorbed through the intestinal wall.
Only anthocyanin glycosides were present in effluents, and neither metabolized derivatives nor aglycones were detected. Intestinal ß-glycosidases were reported to play an important role in flavonoid absorption (32,38,39), but their impact on anthocyanin hydrolysis is yet to be determined. If anthocyanin glycosides were hydrolyzed by these enzymes, the aglycones produced could be rapidly cleaved into phenolic acids due to their instability at physiological pH. However, no such phenolic acids were detected in our effluents (data not shown). It could therefore be suggested that the presence of the cation group in anthocyanins would influence their intestinal metabolism. Moreover, anthocyanins absorbed through the intestinal barrier were not excreted back under conjugated forms in the intestinal lumen, as was reported for some flavonoids (23,27,33). Thus, these results again highlighted that the metabolism of anthocyanins is quite different from that of other flavonoids.
Analysis of biological fluids gave information about circulating forms and possible mechanisms of anthocyanin metabolism. After perfusion of a high dose of blackberry anthocyanins, native Cy 3-glc as well as its methylated derivative (Pn 3-glc), a monoglucuroconjugate of Pn, and a monoglucuroconjugate of Cy were all identified in urine and plasma. Methylation of Cy 3-glc was previously mentioned in rat (18,20,25) and human (40) studies. Detection of anthocyanidin glucuroconjugates was reported in some recent human studies (29,40), but not in rat models. The exact pathway that led to the formation of anthocyanidin monoglucuronides is still unknown. However, some hypotheses can be put forward. One possible pathway is that Cy 3-glc was absorbed intact and then partly methylated to form Pn 3-glc in the liver. Afterwards, either Cy 3-glc or Pn 3-glc could serve as a substrate for UDP-glucose dehydrogenase to form the corresponding glucuronide from the glucose form (40). Another possible pathway is that Cy 3-glc was hydrolyzed to aglycone in the intestine. Cyanidin could then be rapidly glucuronidated here or absorbed and then methylated or glucuronidated in the liver. However, no aglycone was detected in plasma. The major anthocyanin recovered in bile was the methylated derivative, Pn 3-glc. As was already suggested (22), this methylated form was probably mainly formed in the liver and preferentially eliminated by bile. Some studies reported the presence of methylated anthocyanins in rat liver (18,20). Furthermore, a glucuronide of Pn was also identified in bile. The presence of Cy 3-glc and its metabolites in the first collected fraction of bile (0–25 min) highlighted that intestinal absorption of anthocyanins and their further metabolism occurred very quickly.
After perfusion of a high amount of blackberry anthocyanins around 15% of anthocyanins were absorbed, whereas only low concentrations of anthocyanins were detected in plasma. We previously reported similar results after in situ gastric administration of anthocyanins (22). In addition, various studies reported a low bioavailability for these compounds (19,25,40). Taken as a whole, these results raise the question of anthocyanin tissue distribution and their possible transformation after absorption. Anthocyanin chemistry is complex, and a large part of the absorbed anthocyanins could thus be metabolized to noncolored forms, thereby escaping detection under normal conditions.
Thus these results, taken together with our previous studies (22), indicated that significant amounts of anthocyanins could be quickly absorbed from both stomach and small intestine. In a study carried out with the same molecules, we previously reported that a high proportion (25%) of anthocyanin monoglycosides was absorbed from the stomach (22). Therefore, contrary to what was observed for other flavonoids (41,42), the stomach could constitute a site of anthocyanin absorption that is just as important as the small intestine. This is all the more interesting when we consider that the stomach constitutes a favorable environment for anthocyanins. Future research will be aimed at investigating anthocyanin distribution to various tissues and evaluating the potent antioxidative activity of their metabolites.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Manuscript received 2 April 2004. Initial review completed 2 May 2004. Revision accepted 14 June 2004.
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TOPABSTRACTMATERIALS AND METHODSDISCUSSIONLITERATURE CITED |
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