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Nutritional Sciences, University of Florida, Gainesville, FL 32611
1To whom correspondence should be addressed. E-mail: percival{at}ufl.edu.
See related article: J. Nutr. 135: 1718–1725, 2005.
Quercetin is not the most predominant flavonoid in the diet, but it is widespread and has been widely studied in a variety of models. In 1993, some years before their recent article (1), the authors published their first article on quercetin (2) and have contributed substantially to the body of literature and understanding of this ubiquitous flavonoid.
Animal studies on the tissue distribution of quercetin are rare. Most studies have focused on the mechanism of absorption or have measured levels in plasma and/or urine. One study examined the distribution of quercetin after the administration of a single-dose stable isotope but only in a few tissues (liver, plasma, and kidneys) after a short time (60 min) (3). This study by de Boer et al. (1) is the first of its kind to examine flavonoid distribution in a number of tissues after a long-term feeding trial.
Thirteen extragastrointestinal tissues were analyzed for quercetin and its 2 methylated metabolites, isorhamnetin and tamarixetin. Methylation occurs in vivo during passage through the intestinal epithelial and the liver. Quercetin has at least 18 other metabolites; hence the authors chose to look for the methylated compounds after enzymatic deglycosylation and desulfation because glucuronide and sulfur can occupy one or more of the hydroxyl groups of quercetin and make identification of the individual compounds in plasma difficult without tracers.
One of the interesting findings is that the highest level of quercetin metabolites was found in the lungs of rats. It begs the question concerning whether we know where to look for health benefits for some of these bioactive food components. Knowing where a compound accumulates would suggest where most of its benefits will likely occur. For example, rats were fed quercetin for 10 d, and although quercetin metabolites were found in the plasma, they were not detected in lipoproteins nor were the lipoproteins protected from oxidation ex vivo (4). The significance of lung accumulation is not known; however, it now provides a logical place to begin to look for biomarkers of quercetin’s benefits.
The lowest levels of quercetin were found in the spleen, white adipose tissue, and brain. Although there is evidence that a specific brain transporter exists for quercetin (5), the brain does not appear to accumulate large quantities relative to the other tissues.
Another attribute of this article is that a second species was studied. Pigs were fed a high level of quercetin in 3 meals/d for 3 d. Some differences between the 2 studies exist that make direct comparisons difficult. The duration of feeding in pigs was much shorter, a smaller number of organs were chosen for study, and pigs were administered the quercetin in 3 meals/d. Nonetheless, it was demonstrated again that multiple tissues accumulate quercetin. Accumulation in the plasma and in the heart was lower in pigs than in rats, whereas the distributions in the kidney, brain, and spleen did not differ. The pig’s liver accumulated more relative to the liver of rats. Concentrations of the 3 metabolites in rat plasma suggest that 23–100 µmol/L are physiological attainable levels from quercetin levels of 0.1 and 1% in the diet. Pig plasma reached 1.25 µmol/L after 3 d of consuming 65 g/d (500 mg/kg body weight).
Of the 3 metabolites measured, isorhamnetin was found in the highest concentration in most tissues of rats followed by quercetin, then tamarixetin; quercetin had the highest concentration in pigs. Pigs may not methylate as readily as rats, although perhaps time could play a role in the accumulation of methylated products.
Tissue distribution of quercetin (or any other flavonoid) requires further examination. Although this study was not a hypothesis-driven molecular mechanism, it was a carefully controlled, well-done investigation of the fate of a flavonoid and its metabolites. Long-term oral consumption at 2 levels of intake and a wide tissue distribution added a much needed dimension to understanding flavonoids and flavonoid metabolism. Numerous articles exist in which cultured cells are incubated with bioactive compounds without much concern about physiologic concentration or metabolism due to digestion and absorption. Usually the aglycone form is added to cultures. As this article points out, very few body tissues ever see the aglycone molecule and exposing the cultured cells to glycosylated molecule does not necessarily give the same result as the aglycone.
It is tempting now to extrapolate the results to humans because we have no knowledge of the tissue distribution of quercetin (or any other flavonoid) in people. In a review series on flavonoid intake (6,7), Manach and colleagues reviewed 24 human trials with quercetin (aglycone), onions, rutin, apples, or quercetin incorporated into a meal; these studies were designed to look the at area under the curve, turnover time, maximum concentration in the plasma, and other pharmacokinetic variables. This review series also reported 16 trials of longer-term feeding of onions, fried onions, or quercetin dietary supplements for up to 90 d, measuring end-point biomarkers of health or disease. Without knowing whether quercetin ever reaches the tissues, biomarkers of health have been maintained in a black box of assumptions. Now, after careful study, we know that it is likely that quercetin is widely distributed in human tissues.
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LITERATURE CITED |
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 TOP LITERATURE CITED |
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1. de Boer V.C.J., Dihal A. A., van der Woude H., Arts I.C.W., Wolffram S., Alink G. M., Rietjens I.M.C.M., Keijer J., Hollman P.C.H. Tissue distribution of quercetin in rats and pigs. J. Nutr. 2005;135:1718-1725.
2. Hertog M. G., Hollman P. C., Katan M. B., Kromhout D. Intake of potentially anticarcinogenic flavonoids and their determinants in adults in The Netherlands. Nutr. Cancer. 1993;20:21-29.[Medline]
3. Mullen W., Graf B. A, Caldwell S. T., Hartley R. C., Duthie G. G., Edwards C. A, Lean M. E., Crozier A. Determination of flavonol metabolites in plasma and tissues of rats by HPLC-radiocounting and tandem mass spectrometry following oral ingestion of [2-(14)C]quercetin-4'-glucoside. J. Agric. Food Chem. 2002;50:6902-6909.[Medline]
4. Benito S., Buxaderas S., Mitjavila M. T. Flavonoid metabolites and susceptibility of rat lipoproteins to oxidation. Am. J. Physiol. 2004;287:H2819-H2824.
5. Youdim K. A., Qaiser M. Z., Begley D. J., Rice-Evans C. A., Abbott N. J. Flavonoid permeability across an in situ model of the blood-brain barrier. Free Radic. Biol. Med. 2004;36:592-604.[Medline]
6. Manach C., Williamson G., Morand C., Scalbert A., Rémésy C. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am. J. Clin. Nutr. 2005;81:230S-242S.
7. Williamson G., Manach C. Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies. Am. J. Clin. Nutr. 2005;81:243S-255S.
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