Quercetin Explained

Quercetin is a plant flavonol from the flavonoid group of polyphenols. It is found in many fruits, vegetables, leaves, seeds, and grains; capers, red onions, and kale are common foods containing appreciable amounts of it.[1] It has a bitter flavor and is used as an ingredient in dietary supplements, beverages, and foods.

Occurrence

Quercetin is a flavonoid widely distributed in nature.[1] The name has been used since 1857, and is derived from quercetum (oak forest), after the oak genus Quercus.[2] [3] It is a naturally occurring polar auxin transport inhibitor.[4]

Quercetin is one of the most abundant dietary flavonoids,[1] [5] with an average daily consumption of 25–50 mg.[6]

Foods data-sort-type="number" Quercetin,
mg / 100 g
capers, raw 234
capers, canned 173
lovage leaves, raw 170
86
radish leaves 70
carob fiber 58
dill weed, fresh 55
53
yellow wax pepper, raw 51
fennel leaves 49
32
32
30
23
19
18
buckwheat seeds 15
15
13
12
In red onions, higher concentrations of quercetin occur in the outermost rings and in the part closest to the root, the latter being the part of the plant with the highest concentration.[7] One study found that organically grown tomatoes had 79% more quercetin than non-organically grown fruit.[8] Quercetin is present in various kinds of honey from different plant sources.[9]

Biosynthesis

In plants, phenylalanine is converted to 4-coumaroyl-CoA in a series of steps known as the general phenylpropanoid pathway using phenylalanine ammonia-lyase, cinnamate-4-hydroxylase, and 4-coumaroyl-CoA-ligase.[10] One molecule of 4-coumaroyl-CoA is added to three molecules of malonyl-CoA to form tetrahydroxychalcone using 7,2′-dihydroxy-4′-methoxyisoflavanol synthase. Tetrahydroxychalcone is then converted into naringenin using chalcone isomerase.

Naringenin is converted into eriodictyol using flavanoid 3′-hydroxylase. Eriodictyol is then converted into dihydroquercetin with flavanone 3-hydroxylase, which is then converted into quercetin using flavonol synthase.[10]

Glycosides

Quercetin is the aglycone form of a number of other flavonoid glycosides, such as rutin (also known as quercetin-3-O-rutinoside) and quercitrin, found in citrus fruit, buckwheat, and onions.[1] Quercetin forms the glycosides quercitrin and rutin together with rhamnose and rutinose, respectively. Likewise guaijaverin is the 3-O-arabinoside, hyperoside is the 3-O-galactoside, isoquercitin is the 3-O-glucoside and spiraeoside is the 4′-O-glucoside. CTN-986 is a quercetin derivative found in cottonseeds and cottonseed oil. Miquelianin is the quercetin 3-O-β-D-glucuronopyranoside.[11]

Several taxifolin (also known as dihydroquercetin) glycosides also exist. Isoquercetin is the 3-O-glucoside of quercetin.

Rutin degradation pathway

The enzyme quercitrinase can be found in Aspergillus flavus.[12] This enzyme hydrolyzes the glycoside quercitrin to release quercetin and L-rhamnose. It is an enzyme in the rutin catabolic pathway.[13]

Pharmacology

Pharmacokinetics

The bioavailability of quercetin in humans after oral intake is very low, with one study concluding it must be less than 1%.[14] Intravenous injection of quercetin shows a rapid decay in concentration described by a two-compartment model (initial half-life of 8.8 minutes, terminal half-life of 2.4 hours).[14] Because it undergoes rapid and extensive metabolism, the biological effects presumed from in vitro studies are unlikely to apply in vivo.[1] [15] [16] [17] Quercetin supplements in the aglycone form are less bioavailable than the quercetin glycoside often found in foods, especially red onions.[1] [18] Ingestion with high-fat foods may increase bioavailability compared to ingestion with low-fat foods, and carbohydrate-rich foods may increase absorption of quercetin by stimulating gastrointestinal motility and colonic fermentation.[1] Whereas quercetin has been shown to be a potent anti-inflammatory compound in a variety of in vitro and in vivo bioassay models, oral quercetin in human subjects has not exhibited the desired effects.[19] Because of low solubility and poor bioavailability of quercetin, derivatives have been synthesized to overcome these challenges and enhance its biological activity, leading to compounds with improved properties for possible therapeutic applications.[20]

Metabolism

Quercetin is rapidly metabolized (via glucuronidation) after the ingestion of quercetin foods or supplements.[21] Five metabolites (quercetin glucuronides) have been found in human plasma after quercetin ingestion.[22] [21] Taken together, the quercetin glucuronides have a half-life around 11–12 hours.[21]

In rats, quercetin did not undergo any significant phase I metabolism. In contrast, quercetin did undergo extensive phase II (conjugation) to produce metabolites that are more polar than the parent substance, hence are more rapidly excreted from the body. In vitro, the meta-hydroxyl group of catechol is methylated by catechol-O-methyltransferase. Four of the five hydroxyl groups of quercetin are glucuronidated by UDP-glucuronosyltransferase. The exception is the 5-hydroxyl group of the flavonoid ring, which generally does not undergo glucuronidation. The major metabolites of orally absorbed quercetin are quercetin-3-glucuronide, 3'-methylquercetin-3-glucuronide, and quercetin-3'-sulfate.[23] A methyl metabolite of quercetin has been shown in vitro to be more effective than quercetin at inhibiting lipopolysaccharide-activated macrophages.

Compared to other flavonoids, quercetin is one of the most effective inducers of the phase II detoxification enzymes.[24]

In vitro studies show that quercetin is a strong inhibitor of the cytochrome P450 enzymes CYP3A4 and CYP2C19 and a moderate inhibitor of CYP2D6.[25] [26] Drugs that are metabolized by these pathways may have increased effect. An in vivo study found that quercetin supplementation slows the metabolism of caffeine to a statistically significant extent in a particular genetic subpopulation, but in absolute terms the effect was almost negligible.[27]

Food safety

In 2010, the U. S. Food and Drug Administration acknowledged high-purity quercetin as generally recognized as safe for use as an ingredient in various specified food categories at levels up to 500 mg per serving.[28]

Health claims

Quercetin has been studied in basic research and small clinical trials.[1] [29] [30] While supplements have been promoted for the treatment of cancer and various other diseases,[1] [31] there is no high-quality evidence that quercetin (via supplements or in food) is useful to treat cancer[32] or any other disease.[1] [33]

The US Food and Drug Administration has issued warning letters to several manufacturers advertising on their product labels and websites that quercetin product(s) can be used to treat diseases.[34] [35] The FDA regards such quercetin advertising and products as unapproved  - with unauthorized health claims concerning the anti-disease products  - as defined by "sections 201(g)(1)(B) and/or 201 (g)(1)(C) of the Act [21 U.S.C. § 321(g)(1)(B) and/or 21 U.S.C. § 321(g)(1)(C)] because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease",[34] [35] conditions not met by the manufacturers.

Safety

Little research has been conducted into the safety of quercetin supplementation in humans, and the results are insufficient to give confidence that the practice is safe. In particular, a lack of safety information exists on the effect of quercetin supplementation for pregnant women, breastfeeding women, children, and adolescents. The hormonal effects of quercetin found in animal studies raise the suspicion of a parallel effect in humans, particularly in respect of estrogen-dependent tumors.

Quercetin supplementation can interfere with the effects of medications. The precise nature of this interaction is known for some common medicines, but for many, it is not.[36]

See also

Notes and References

  1. Web site: Flavonoids . Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, OR. November 2015. 1 April 2018.
  2. Web site: Quercetin. 29 November 2023 . Merriam-Webster.
  3. Web site: Quercetin (biochemistry). Encyclopædia Britannica.
  4. Fischer C, Speth V, Fleig-Eberenz S, Neuhaus G . Induction of Zygotic Polyembryos in Wheat: Influence of Auxin Polar Transport . The Plant Cell . 9 . 10 . 1767–1780 . Oct 1997 . 12237347 . 157020 . 10.1105/tpc.9.10.1767 .
  5. Web site: USDA Database for the Flavonoid Content of Selected Foods, Release 3 . 2011 . U.S. Department of Agriculture.
  6. Formica JV, Regelson W . Review of the biology of quercetin and related bioflavonoids . Food and Chemical Toxicology . 33 . 12 . 1061–80 . 1995 . 8847003 . 10.1016/0278-6915(95)00077-1 .
  7. Slimestad R, Fossen T, Vågen IM . Onions: a source of unique dietary flavonoids . Journal of Agricultural and Food Chemistry . 55 . 25 . 10067–80 . December 2007 . 17997520 . 10.1021/jf0712503 .
  8. Mitchell AE, Hong YJ, Koh E, Barrett DM, Bryant DE, Denison RF, Kaffka S . Ten-year comparison of the influence of organic and conventional crop management practices on the content of flavonoids in tomatoes . Journal of Agricultural and Food Chemistry . 55 . 15 . 6154–9 . Jul 2007 . 17590007 . 10.1021/jf070344+ .
  9. Petrus K, Schwartz H, Sontag G . Analysis of flavonoids in honey by HPLC coupled with coulometric electrode array detection and electrospray ionization mass spectrometry . Analytical and Bioanalytical Chemistry . 400 . 8 . 2555–63 . Jun 2011 . 21229237 . 10.1007/s00216-010-4614-7 . 24796542 .
  10. Winkel-Shirley B . Flavonoid biosynthesis. A colorful model for genetics, biochemistry, cell biology, and biotechnology . Plant Physiology . 126 . 2 . 485–93 . Jun 2001 . 11402179 . 1540115 . 10.1104/pp.126.2.485 .
  11. Juergenliemk G, Boje K, Huewel S, Lohmann C, Galla HJ, Nahrstedt A . In vitro studies indicate that miquelianin (quercetin 3-O-beta-D-glucuronopyranoside) is able to reach the CNS from the small intestine . Planta Medica . 69 . 11 . 1013–7 . Nov 2003 . 14735439 . 10.1055/s-2003-45148 . 260253046 .
  12. Web site: Information on EC 3.2.1.66 - quercitrinase . Helmholtz Centre for Infection Research . BRENDA (BRaunschweig ENzyme DAtabase) .
  13. Tranchimand S, Brouant P, Iacazio G . The rutin catabolic pathway with special emphasis on quercetinase . Biodegradation . 21 . 6 . 833–59 . Nov 2010 . 20419500 . 10.1007/s10532-010-9359-7 . 30101803 .
  14. Gugler . R. . Leschik . M. . Dengler . H. J. . Disposition of quercetin in man after single oral and intravenous doses . European Journal of Clinical Pharmacology . 1 March 1975 . 9 . 2 . 229–234 . 10.1007/BF00614022. 1233267 . 23812714 .
  15. Williams RJ, Spencer JP, Rice-Evans C . Flavonoids: antioxidants or signalling molecules? . Free Radical Biology & Medicine . 36 . 7 . 838–49 . Apr 2004 . 15019969 . 10.1016/j.freeradbiomed.2004.01.001 . (review) .
  16. Barnes S, Prasain J, D'Alessandro T, Arabshahi A, Botting N, Lila MA, Jackson G, Janle EM, Weaver CM . The metabolism and analysis of isoflavones and other dietary polyphenols in foods and biological systems . Food & Function . 2 . 5 . 235–44 . May 2011 . 21779561 . 10.1039/c1fo10025d . (review) . 4122511.
  17. Luca SV, Macovei I, Bujor A, Trifan A . Bioactivity of dietary polyphenols: The role of metabolites . . 60 . 4 . 626–659 . 2020 . 10.1080/10408398.2018.1546669 . 30614249. 58651581 .
  18. Dabeek WM, Marra MV . Dietary Quercetin and Kaempferol: Bioavailability and Potential Cardiovascular-Related Bioactivity in Humans . Nutrients . 11 . 10 . 2288 . 2019 . 10.3390/nu11102288 . 6835347 . 31557798. free .
  19. Shen P, Lin W, Deng X, Ba X, Han L, Chen Z, Qin K, Huang Y, Tu S . Potential Implications of Quercetin in Autoimmune Diseases . Front Immunol . 12 . 689044 . 2021 . 34248976 . 8260830 . 10.3389/fimmu.2021.689044 . free .
  20. Alizadeh SR, Ebrahimzadeh MA . Quercetin derivatives: Drug design, development, and biological activities, a review . Eur J Med Chem . 229 . 114068 . February 2022 . 34971873 . 10.1016/j.ejmech.2021.114068 . 245485982 .
  21. Graefe EU, Derendorf H, Veit M . Pharmacokinetics and bioavailability of the flavonol quercetin in humans . International Journal of Clinical Pharmacology and Therapeutics . 37 . 5 . 219–33 . 1999 . 10363620 . (review) . 2016-01-01 . 2017-05-17 . https://web.archive.org/web/20170517030352/http://ucce.ucdavis.edu/files/datastore/608-67.pdf . dead .
  22. Wittig . Jörg . Herderich . Markus . Graefe . Eva Ulrike . Veit . Markus . Identification of quercetin glucuronides in human plasma by high-performance liquid chromatography–tandem mass spectrometry . Journal of Chromatography B: Biomedical Sciences and Applications . April 2001 . 753 . 2 . 237–243 . 10.1016/s0378-4347(00)00549-1. 11334336 .
  23. Book: Bao Y, Fenwick R . Phytochemicals in health and disease . Characterization of polyphenol metabolites . Day AJ, Rothwell JA, Morgan RA . 2004 . Dekker . New York, NY . 0-8247-4023-8 . 50–67 . https://books.google.com/books?id=ruD5AWlELmgC&q=Quercetin%20%E2%80%8E%20estrogen%20receptor&pg=PA58.
  24. Procházková D, Boušová I, Wilhelmová N . Antioxidant and prooxidant properties of flavonoids . . 82 . 4 . 513–523 . 2011 . 10.1016/j.fitote.2011.01.018 . 21277359. free .
  25. Elbarbry F, Ung A, Abdelkawy K . Studying the Inhibitory Effect of Quercetin and Thymoquinone on Human Cytochrome P450 Enzyme Activities . Pharmacognosy Magazine . 13 . Suppl 4 . S895–S899 . January 2018 . 29491651 . 5822518 . 10.4103/0973-1296.224342 . 31 January 2024 . free.
  26. Rastogi . Himanshu . Jana . Snehasis . Evaluation of Inhibitory Effects of Caffeic acid and Quercetin on Human Liver Cytochrome P450 Activities. Phytotherapy Research . December 2014 . 28 . 12 . 1873–1878 . 10.1002/ptr.5220. 25196644 . 41563915 . free .
  27. Quercetin Significantly Inhibits the Metabolism of Caffeine, a Substrate of Cytochrome P450 1A2 Unrelated to CYP1A2*1C (−2964G>A) and 1F* (734C>A) Gene Polymorphisms. BioMed Research International. 2014. 10.1155/2014/405071. free. Xiao. Jian. Huang. Wei-Hua. Peng. Jing-Bo. Tan. Zhi-Rong. Ou-Yang. Dong-Sheng. Hu. Dong-Li. Zhang. Wei. Chen. Yao. 2014. 1–6. 25025048. 4082882.
  28. Web site: GRN No. 341 (Quercetin). US Food and Drug Administration. 22 November 2010. 27 October 2021.
  29. Yang F, Song L, Wang H, Wang J, Xu Z, Xing N . Quercetin in prostate cancer: Chemotherapeutic and chemopreventive effects, mechanisms and clinical application potential (Review) . Oncol. Rep. . 33 . 6 . 2659–68 . June 2015 . 25845380 . 10.3892/or.2015.3886 . free .
  30. Miles SL, McFarland M, Niles RM . Molecular and physiological actions of quercetin: need for clinical trials to assess its benefits in human disease . Nutrition Reviews . 72 . 11 . 720–34 . 2014 . 25323953 . 10.1111/nure.12152 . free .
  31. D'Andrea G . Quercetin: A flavonol with multifaceted therapeutic applications? . Fitoterapia . 106 . 256–71 . 2015 . 26393898 . 10.1016/j.fitote.2015.09.018 .
  32. Book: . American Cancer Society Complete Guide to Complementary and Alternative Cancer Therapies . 2nd . 2009 . 9780944235713 . Ades TB . Quercetin . registration .
  33. European Food Safety Agency (EFSA) NDA Panel (Dietetic Products, Nutrition and Allergies) . Scientific Opinion on the substantiation of health claims related to quercetin and protection of DNA, proteins and lipids from oxidative damage (ID 1647), "cardiovascular system" (ID 1844), "mental state and performance" (ID 1845), and "liver, kidneys" (ID 1846) pursuant to Article 13(1) of Regulation (EC) No 1924/2006 . EFSA Journal . 8 April 2011 . 9 . 4 . 2067–82 . 10.2903/j.efsa.2011.2067 . 24 September 2014 . free .
  34. Web site: Warning Letter to Cape Fear Naturals . 2 March 2017 . King JL . Inspections, Compliance, Enforcement, and Criminal Investigations, US Food and Drug Administration . 29 November 2018 .
  35. Web site: Warning Letter to DoctorVicks.com. Inspections, Compliance, Enforcement, and Criminal Investigations, US Food and Drug Administration. 17 April 2017. Pace R . 29 November 2018.
  36. Andres S, Pevny S, Ziegenhagen R, Bakhiya N, Schäfer B, Hirsch-Ernst KI, Lampen A . Safety Aspects of the Use of Quercetin as a Dietary Supplement . Mol Nutr Food Res . 62 . 1 . January 2018 . 29127724 . 10.1002/mnfr.201700447 . 24772872 . Review. free .

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