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© 2008 American Society for Nutrition J. Nutr. 138:1417-1420, August 2008

Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Tissue Distribution of Quercetin in Pigs after Long-Term Dietary Supplementation1,2

Juliane Bieger3, Rainer Cermak4,*, Ralf Blank3, Vincent C. J. de Boer5, Peter C. H. Hollman5, Joseph Kamphues6 and Siegfried Wolffram3

3 Institute of Animal Nutrition and Physiology, University of Kiel, 24098 Kiel, Germany; 4 Institute of Veterinary Physiology, University of Leipzig, 04103 Leipzig, Germany; 5 RIKILT-Institute of Food Safety, Wageningen University and Research Centre, 6708 Wageningen, The Netherlands; and 6 Institute of Animal Nutrition, University of Veterinary Medicine Hannover, Foundation, 30173 Hannover, Germany

* To whom correspondence should be addressed. E-mail: cermak{at}vetmed.uni-leipzig.de.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Although the flavonol quercetin is intensively investigated, our knowledge about its bioavailability and possible target organs is far from being complete. The aim of this study was to check the potential of quercetin to accumulate in various tissues after long-term dietary treatment compared with a single treatment with flavonol. Pigs ingested either a single dose of quercetin aglycone (25 mg/kg body weight; Expt. 1) or received the flavonol twice a day at the same dose mixed into their regular meals (i.e 50 mg·kg–1·d–1) for 4 wk (Expt. 2). In both experiments, we took plasma and tissue samples 90 min after the final meal and analyzed them using HPLC. Additionally, the specific activity of the enzyme β-glucuronidase was measured in selected tissues. Higher flavonol concentrations than in plasma were found in only the liver (Expt. 1) or the intestinal wall and kidneys (Expt. 2). All tissues except blood plasma contained a variable amount of deconjugated quercetin in the range of 30–100% of total flavonols. However, the specific β-glucuronidase activity was not correlated with the proportions of deconjugated flavonols in the various tissues. Long-term dietary intake of the flavonol did not lead to a greater accumulation in any tissue compared with the single treatment. Flavonol concentrations only exceeded the plasma concentration within organs involved in its metabolism and excretion, including liver, small intestine, and kidneys.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Flavonoids such as the flavonol quercetin are polyphenols that are present as secondary metabolites in plants and occur in most plant-derived foodstuffs at various concentrations (1). Several studies have shown a correlation between the consumption of polyphenol-rich foods and the prevention of chronic diseases, such as coronary heart disease (2–4). Knowledge of the distribution of flavonoids within the body is crucial for a proper understanding of their biological effects.

In a previous study, we described the tissue distribution in rats of quercetin and its 2 methylated derivatives, isorhamnetin and tamarixetin, after long-term feeding of 2 diets containing either 0.1 or 1% quercetin (~50 or 500 mg/kg body weight, respectively) (5). The highest tissue concentrations of quercetin, isorhamnetin, and tamarixetin were detected in the lungs, testes, and kidneys. The lowest concentrations were found in the brain and white adipose tissue. Whereas blood plasma contained nearly exclusively conjugated flavonols, several tissues, including lung, liver, kidney, and testes, contained a rather high proportion of free quercetin and isorhamnetin (4–40% of total flavonoids) (5). Conjugated flavonols may have different biological activities compared with the aglycones (6–8).

In the same study, data from 3 pigs that had received a quercetin-containing diet (500 mg·kg–1·d–1) for 3 d were also presented (5). Tissue and plasma flavonol concentrations were much lower compared with the rats with a similar daily quercetin intake (1% diet). However, the length of the feeding period was much shorter in the pig experiment. Moreover, pigs were deprived of food for 8 h before slaughtering, whereas the rats were killed in a postprandial state (5). Thus, it remains unclear whether a longer feeding period leads to a considerably higher tissue accumulation of flavonols in pigs, which are considered a much better model for humans than rats (9).

Therefore, one aim of the present study was to investigate whether quercetin accumulates in pigs in a tissue-specific manner after chronic administration of the flavonol compared with a single quercetin dose. Furthermore, β-glucuronidase activity was determined in several tissues. Similar to humans and rats, blood plasma of pigs contains almost exclusively glucuronidated and sulfated metabolites after oral intake of quercetin (10,11). Therefore, any flavonol aglycones present in tissues most likely are liberated by deconjugating enzymes. The hydrolysis of glucuronides, the main quercetin metabolites (12,13), is catalyzed by β-glucuronidase, an acid hydrolase expressed in many tissues and body fluids (14). We wanted to compare the concentrations of quercetin aglycone and the specific β-glucuronidase activity in various body tissues and to determine whether these variables are correlated.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
Chemicals

Flavonols and bovine serum albumin were obtained from Carl Roth. β-Glucuronidase/sulfatase (crude enzyme extract from Helix pomatia) was purchased from Sigma-Aldrich. Dye reagent concentrate for protein assay was obtained from Bio-Rad-Laboratories.

Animals and diets

All experiments were performed with cross-bred male castrated pigs obtained from the Institute of Animal Breeding of the University of Kiel. Experiments were performed in accordance with the German animal welfare law.

    Expt. 1 (short-term feeding). Three pigs (body weight ~70 kg) were individually housed and adapted to a commercial diet for fattening pigs mainly composed of wheat, barley, rye, and defatted soybean meal (diet no. 4300, Plambeck) containing (per kg diet) 165 g crude protein, 21 g crude fat, 53 g crude fiber, 12.6 MJ metabolizable energy, and 897 g dry matter. Vitamins and minerals were supplemented according to the recommendations of the German Society of Nutritional Physiology (15). Tap water was consumed ad libitum by nipple drinkers. On the experimental day, pigs consumed 1 meal consisting of the basal diet supplemented with a dose of 25 mg quercetin/kg body weight. Then 90 min later, pigs were killed and samples (various body tissues, blood) were taken.

    Expt. 2 (long-term feeding). Seven pigs (initial body weight 33–37 kg) were kept under similar conditions and fed restrictively (80% of voluntary feed intake) twice daily over a period of 4 wk with the same diet as in Expt. 1 (final body weight 48–56 kg). Quercetin aglycone was added to each meal at a dosage of 25 mg/kg body weight, resulting in a total daily intake of 50 mg/kg. At the end of the feeding period, pigs were killed by exsanguination after anesthesia (ketamine and azaperone) 60–90 min after the last morning feeding.

Experimental procedures

    Preparation of samples. During exsanguination, blood samples (2 times 10 mL) from each pig were immediately collected into heparinized tubes. Tissue samples (~10 g each) were obtained from kidneys, liver, mid-jejunum, skeletal muscle (diaphragm and longissimus dorsi muscle), and lung tissue (Expt. 1 and 2) as well as from proximal colon, white adipose tissue, mesentery, intestinal lymph nodes, and brain (only in Expt. 2). Samples were immediately frozen on dry ice and stored at –70°C until further preparation. Plasma was separated from 1 of the 2 blood samples and stored as described above. The 2nd blood sample and tissue samples were lyophilized, frozen in liquid nitrogen, and ground under constant cooling using a mill (Jahnke and Kunkel Analysenmühle, IKA Labortechnik) or a mortar. All tissue samples were weighed before and after lyophilization and stored in airtight containers at –70°C until analysis.

    Tissue extractions and HPLC analyses. Two aliquots of plasma (980 µL) or tissue [100 mg suspended in 980 µL of saline (150 mmol/L NaCl)] were spiked with 20 µL of internal standard (50 mg rhamnetin/L methanol) and acidified with acetic acid (0.583 mol/L) to a final pH of 5. To determine the fraction of conjugated and free compounds, 1 of the 2 plasma and tissue samples were treated with β-glucuronidase/sulfatase. All samples were incubated for 60 min at 37°C. Further treatment of samples and analysis by HPLC were performed according to previously published methods (11,16,17).

    Correction for residual blood. As previously described (5), hemoglobin was determined in the supernatant of homogenized tissue and in full blood samples with a spectrophotometer at a wave length of 540 nm (UV-1602, Shimadzu Europe). The fraction of residual blood in tissues was calculated by dividing the peak maximum of hemoglobin in tissues with the peak maximum of the respective full blood sample. Flavonol concentrations determined in the respective plasma sample were then multiplied with the fraction of residual blood in tissues and subtracted from the value obtained for the tissue (5).

    Assay for β-glucuronidase activity. According to a previously published method (18), we determined activity of β-glucuronidase in cell-free extracts prepared from liver, kidney, skeletal muscle (diaphragm and longissimus dorsi muscle), and lung tissue obtained from 3 pigs of Expt. 2 by measuring the release of p-nitrophenol from p-nitrophenol glucuronide (10 mmol/L) after a 5-min lag-phase during a period of 25 min at 37°C at 400 nm (UV-1602, Shimadzu Europe). One activity unit (U) is defined as the amount of enzyme releasing 1 nmol p-nitrophenol·min–1 at 37°C and pH 7.2.

Statistics

Flavonol concentrations and tissue-specific activities of β-glucuronidase are presented as means ± SEM. For data evaluation and analyses, we used GraphPad Prism 4 (GraphPad Software). Differences between concentrations of total flavonols (sum of quercetin, isorhamnetin, and tamarixetin from enzymatically treated samples) were evaluated using ANOVA with subsequent pairwise comparisons of group means with Dunnett's multiple comparison test. Because plasma is considered as the central compartment from which distribution into tissues occurs, tissue concentrations were compared with plasma concentrations. The relationship between concentration of aglycone in organs and tissue specific β-glucuronidase activity was investigated with Pearson correlation analysis. We used the Tukey-Kramer test for unbalanced data for analysis of differences between Expt. 1 and Expt. 2. The level of significance was set at P < 0.05.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
At 90 min after ingestion of a single quercetin-containing meal (Expt. 1), the total flavonol concentration in liver was higher than in plasma (Table 1). In all samples analyzed, quercetin was the main metabolite (Table 1). The proportions of aglycones were not determined in this experiment.


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  		TABLE 1 Quercetin, isorhamnetin, and tamarixetin concentrations in tissues of pigs fed a single quercetin dose (25 mg kg–1) (Expt. 1)12

 
After feeding a quercetin-containing diet (50 mg·kg–1·d–1) over a period of 4 wk (Expt. 2), colon, kidney, and jejunum contained higher total flavonol concentration than plasma (Table 2). Flavonol concentrations in all other investigated tissues, including liver, did not differ from plasma. Lungs, white adipose tissue, muscles, and brain did not accumulate flavonols after the 4-wk treatment. In all tissues, quercetin accounted for 67–98% of total flavonols (Table 2). The difference in total flavonol concentration between Expt. 1 and Expt. 2 was significant for only liver with a higher value after a single quercetin-containing meal.


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  		TABLE 2 Quercetin, isorhamnetin, and tamarixetin concentrations in tissues of pigs fed 50 mg quercetin kg–1·d–1 for 4 wk (Expt. 2)12

 
All tissues investigated in Expt. 2 contained a variable fraction of free quercetin, isorhamnetin, and tamarixetin (Table 2). Colon, mesentery, diaphragm, lungs, and brain contained only deconjugated quercetin (100%); in liver and jejunum, the fraction of free quercetin accounted for ~90%. The fraction of free quercetin in the other tissues was between 30 and 60%. In contrast, plasma contained hardly any nonconjugated quercetin. Fractions of free and conjugated forms of isorhamnetin and tamarixetin roughly followed the distribution pattern of quercetin (Table 2).

Tissue-specific β-glucuronidase activity was determined in tissue samples obtained from lung, liver (high proportion of aglycones), kidneys (low proportion of aglycones), and muscles from 3 pigs in Expt. 2. The variation between pigs was considerable. β-Glucuronidase activity in kidneys, lungs, and liver were (mean value, n = 3): 144 ± 31.2, 125 ± 21.2, and 96.9 ± 11.7 U/mg protein, respectively. In the muscle samples, specific activity was 38.6 ± 7.3 U/mg protein (diaphragm) and 33.9 ± 4.6 U/mg protein (longissimus dorsi muscle), respectively. The proportion of aglycones was not correlated with the specific β-glucuronidase activity in the various tissues.


   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
After oral intake of quercetin or quercetin glycosides, quercetin and its methylated metabolites isorhamnetin and tamarixetin appear in the circulation of rats and humans almost exclusively in their conjugated form, i.e. as glucuronides and/or sulfates (10). This was also shown for pigs (11). Even portal plasma did not contain any detectable amounts of free quercetin after oral administration of the flavonol (17). Thus, quercetin is more or less completely conjugated during its absorption. In contrast to rats, in which nearly one-half of the absorbed amount of quercetin is methylated to isorhamnetin, the proportion of isorhamnetin in pig and human plasma is rather low (11,17). This was confirmed in the present study, where isorhamnetin and tamarixetin represented <20% of total plasma flavonols.

In Expt. 1 and 2, plasma concentrations of total flavonols never exceeded 2 µmol/L (Tables 1 and 2). At the time point of sampling (90 min after ingestion of the quercetin-enriched meal), plasma concentrations in the range of peak levels can be expected (11,17). In comparison, the plasma levels in rats with a similar dietary intake of quercetin (0.1% quercetin diet, corresponding to ~50 mg·kg–1 body weight·d–1) exceeded 20 µmol/L (5). Similarly, we observed the same discrepancy in plasma concentrations between rats and pigs after a 10-fold higher intake of quercetin (~500 mg·kg–1 body weight·d–1) in a previous study (5). Thus, the differences in plasma concentrations between pigs and rats seem to be due to species differences and not to the different sampling points in the previous study.

Most interestingly, plasma concentrations after long-term feeding (Expt. 2) were not higher than after intake of a single quercetin-containing meal (Expt. 1). Although comparisons between treatments should be interpreted with care, this finding indicates that quercetin does not accumulate in plasma after dietary administration over several weeks. This is in accordance with the short plasma half-life of quercetin of ~4 h in pigs (11), because the quercetin administrations in the long-term feeding experiments were separated by a period of ~3 times the elimination half-life.

Liver (Expt. 1), kidneys, and intestinal tissues (Expt. 2) contained higher flavonol levels than plasma. Although data from intestinal tissues have to be interpreted with caution due to a possible contamination with ingesta (despite intensive rinsing), the mucosa of the gut is centrally involved in the metabolism and excretion of quercetin (12,19). Similarly, the liver and kidneys are involved in flavonol metabolism and excretion.

Concentrations of flavonols in skeletal muscle were not higher after long-term feeding in comparison to short-term feeding. Thus, muscles did not accumulate quercetin even after several weeks but rather appeared to reflect intake of quercetin with the last meal. With regard to the discussion of any direct antioxidant effect of flavonols in meat, relevant for post mortem storage and stability, the very low concentrations in muscle and fat must be considered. Furthermore, the previously high flavonol concentrations in lungs of rats (5) was not confirmed in the present study with pigs.

Among the various organs investigated, the brain had the lowest flavonol concentration. This is in agreement with other studies and shows that the blood brain barrier efficiently limits flavonol uptake into the central nervous system (5).

The occurrence of flavonols in mesenterial lymph nodes as found in Expt. 2 might suggest a possible transport of these substances via the lymph as previously discussed (20).

Except for blood plasma, all investigated organs contained a considerable proportion of deconjugated quercetin, ranging from ~30–100% of the total quercetin concentration after enzymatic treatment. In rats, the major fraction of quercetin conjugates are glucuronides, whereas sulfate conjugates appear in lower amounts (12,13). A similar metabolite pattern was also shown in pigs, at least after oral intake of isoflavones (21). Thus, the tissue-specific amount of quercetin aglycones could be due to different activities of β-glucuronidase, the enzyme responsible for deconjugation of the major metabolites (i.e. glucuronides). In human hepatoma cells, it was demonstrated that quercetin-3- and -7-glucuronide were subjected to deglucuronidation by β-glucuronidase followed by sulfation to quercetin-3'-sulfate (22). Thus, we checked in a preliminary experiment a possible correlation between the concentration of aglycones in selected tissues and the tissue-specific β-glucuronidase activity. There was, however, no correlation between these 2 variables. The kidneys, for example, had the lowest proportion of aglycones but had the highest enzyme activity. However, deglucuronidation may be followed by instantaneous sulfatation (22) or reglucuronidation by UDP-glucuronosyltransferases. This would hamper our ability to detect an association between β-glucuronidase activity and the amount of aglycones present in tissues. The crude enzyme extract used in this study did not allow differentiation between glucuronides and sulfates, because it contained both β-glucuronidase as well as sulfatase activities. In addition, deconjugation of flavonol metabolites can take place during the extraction procedure (5). Thus, the concentrations determined in our tissue samples may not necessarily reflect the in vivo situation. Taken together, in vivo tissue concentrations of flavonol aglycones could be smaller than reported.

In conclusion, this study demonstrated that pigs did not accumulate quercetin in most tissues after a long-term and high-dose dietary intake of the flavonol. Only organs involved in flavonol metabolism and excretion, including small intestine, liver, and kidneys, contained significantly higher flavonol concentrations than plasma. Thus, the latter organs should be considered as primary targets of potential beneficial effects. The different tissues contained variable amounts of deconjugated quercetin. However, the concentration of the aglycone in several organs did not correlate to the tissue-specific activity of β-glucuronidase, at least under the conditions of this study.


   ACKNOWLEDGMENTS
 
We thank Petra Schulz and Maike Jürgensen for their valuable technical assistance.


   FOOTNOTES
 
1 Supported by grant WO 763/2-3 from the German Research Foundation. Back

2 Author disclosures: J. Bieger, R. Cermak, R. Blank, V. C. J. de Boer, P. C. H. Hollman, J. Kamphues, and S. Wolffram, no conflicts of interest. Back

Manuscript received 11 February 2008. Initial review completed 26 March 2008. Revision accepted 9 May 2008.


   LITERATURE CITED
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 

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