Chemistry:Quercetin

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Quercetin
Skeletal formula of quercetin
Ball-and-stick model of the quercetin molecule
Names
Pronunciation /ˈkwɜːrsɪtɪn/
IUPAC name
3,3′,4′,5,7-Pentahydroxyflavone
Systematic IUPAC name
2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one
Other names
5,7,3′,4′-flavon-3-ol, Sophoretin, Meletin, Quercetine, Xanthaurine, Quercetol, Quercitin, Quertine, Flavin meletin
Identifiers
3D model (JSmol)
317313
ChEBI
ChEMBL
ChemSpider
DrugBank
EC Number
  • 204-187-1
579210
KEGG
UNII
UN number 2811
Properties
C15H10O7
Molar mass 302.236 g/mol
Appearance yellow crystalline powder[1]
Density 1.799 g/cm3
Melting point 316 °C (601 °F; 589 K)
Practically insoluble in water; soluble in aqueous alkaline solutions[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
Tracking categories (test):
UV visible spectrum of quercetin, with lambda max at 369 nm

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.[2][3] 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.[2] The name has been used since 1857, and is derived from quercetum (oak forest), after the oak genus Quercus.[4][5] It is a naturally occurring polar auxin transport inhibitor.[6]

Quercetin is one of the most abundant dietary flavonoids,[2][3] with an average daily consumption of 25–50 mg.[7]

Foods Quercetin,
mg / 100 g
capers, raw 234[3]
capers, canned 173[3]
lovage leaves, raw 170[3]
dock like sorrel 86[3]
radish leaves 70[3]
carob fiber 58[3]
dill weed, fresh 55[3]
coriander 53[3]
yellow wax pepper, raw 51[3]
fennel leaves 49[3]
onion, red 32[3]
radicchio 32[3]
watercress 30[3]
kale 23[3]
chokeberry 19[3]
bog blueberry 18[3]
buckwheat seeds 15[3]
cranberry 15[3]
lingonberry 13[3]
plums, black 12[3]

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.[8] One study found that organically grown tomatoes had 79% more quercetin than non-organically grown fruit.[9] Quercetin is present in various kinds of honey from different plant sources.[10]

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.[11] 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.[11]

Glycosides

3-O-Glycosides of quercetin

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.[2] 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.[12]

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.[13] This enzyme hydrolyzes the glycoside quercitrin to release quercetin and L-rhamnose. It is an enzyme in the rutin catabolic pathway.[14]

Pharmacology

Pharmacokinetics

The bioavailability of quercetin in humans after oral intake is very low, with one study concluding it must be less than 1%.[15] 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).[15] Because it undergoes rapid and extensive metabolism, the biological effects presumed from in vitro studies are unlikely to apply in vivo.[2][16][17][18] Quercetin supplements in the aglycone form are less bioavailable than the quercetin glycoside often found in foods, especially red onions.[2][19] Ingestion with high-fat foods may increase bioavailability compared to ingestion with low-fat foods,[19] and carbohydrate-rich foods may increase absorption of quercetin by stimulating gastrointestinal motility and colonic fermentation.[2] 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.[20] 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.[21]

Metabolism

Quercetin is rapidly metabolized (via glucuronidation) after the ingestion of quercetin foods or supplements.[22] Five metabolites (quercetin glucuronides) have been found in human plasma after quercetin ingestion.[23][22] Taken together, the quercetin glucuronides have a half-life around 11–12 hours.[22]

In rats, quercetin did not undergo any significant phase I metabolism.[24] 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.[24] A methyl metabolite of quercetin has been shown in vitro to be more effective than quercetin at inhibiting lipopolysaccharide-activated macrophages.[18]

Compared to other flavonoids, quercetin is one of the most effective inducers of the phase II detoxification enzymes.[25]

In vitro studies show that quercetin is a strong inhibitor of the cytochrome P450 enzymes CYP3A4 and CYP2C19 and a moderate inhibitor of CYP2D6.[26][27] 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.[28]

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.[29]

Health claims

Quercetin has been studied in basic research and small clinical trials.[2][30][31][32] While supplements have been promoted for the treatment of cancer and various other diseases,[2][33] there is no high-quality evidence that quercetin (via supplements or in food) is useful to treat cancer[34] or any other disease.[2][35]

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.[36][37] 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",[36][37] 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.[38]

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.[38]

See also


References

  1. ↑ 1.0 1.1 1.2 "Quercetin dihydrate safety sheet". http://www.pvp.com.br/EN_quercetin_dihydrate_safety_data.htm. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 "Flavonoids". Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, OR. November 2015. http://lpi.oregonstate.edu/mic/dietary-factors/phytochemicals/flavonoids. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 3.19 3.20 3.21 "USDA Database for the Flavonoid Content of Selected Foods, Release 3". U.S. Department of Agriculture. 2011. http://www.ars.usda.gov/SP2UserFiles/Place/12354500/Data/Flav/Flav_R03.pdf. 
  4. ↑ "Quercetin". Merriam-Webster. 29 November 2023. http://www.merriam-webster.com/dictionary/quercetin. 
  5. ↑ "Quercetin (biochemistry)". Encyclopædia Britannica. http://www.britannica.com/EBchecked/topic/487030/quercitin. 
  6. ↑ "Induction of Zygotic Polyembryos in Wheat: Influence of Auxin Polar Transport". The Plant Cell 9 (10): 1767–1780. Oct 1997. doi:10.1105/tpc.9.10.1767. PMID 12237347. 
  7. ↑ "Review of the biology of quercetin and related bioflavonoids". Food and Chemical Toxicology 33 (12): 1061–80. 1995. doi:10.1016/0278-6915(95)00077-1. PMID 8847003. 
  8. ↑ "Onions: a source of unique dietary flavonoids". Journal of Agricultural and Food Chemistry 55 (25): 10067–80. December 2007. doi:10.1021/jf0712503. PMID 17997520. 
  9. ↑ "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. doi:10.1021/jf070344+. PMID 17590007. 
  10. ↑ "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. doi:10.1007/s00216-010-4614-7. PMID 21229237. 
  11. ↑ 11.0 11.1 "Flavonoid biosynthesis. A colorful model for genetics, biochemistry, cell biology, and biotechnology". Plant Physiology 126 (2): 485–93. Jun 2001. doi:10.1104/pp.126.2.485. PMID 11402179. 
  12. ↑ "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. doi:10.1055/s-2003-45148. PMID 14735439. 
  13. ↑ "Information on EC 3.2.1.66 - quercitrinase". BRENDA (BRaunschweig ENzyme DAtabase). Helmholtz Centre for Infection Research. http://www.brenda-enzymes.org/php/result_flat.php4?ecno=3.2.1.66. 
  14. ↑ "The rutin catabolic pathway with special emphasis on quercetinase". Biodegradation 21 (6): 833–59. Nov 2010. doi:10.1007/s10532-010-9359-7. PMID 20419500. 
  15. ↑ 15.0 15.1 Gugler, R.; Leschik, M.; Dengler, H. J. (1 March 1975). "Disposition of quercetin in man after single oral and intravenous doses". European Journal of Clinical Pharmacology 9 (2): 229–234. doi:10.1007/BF00614022. PMID 1233267. 
  16. ↑ "Flavonoids: antioxidants or signalling molecules?". Free Radical Biology & Medicine 36 (7): 838–49. Apr 2004. doi:10.1016/j.freeradbiomed.2004.01.001. PMID 15019969. 
  17. ↑ "The metabolism and analysis of isoflavones and other dietary polyphenols in foods and biological systems". Food & Function 2 (5): 235–44. May 2011. doi:10.1039/c1fo10025d. PMID 21779561. 
  18. ↑ 18.0 18.1 "Bioactivity of dietary polyphenols: The role of metabolites". Critical Reviews in Food Science and Nutrition 60 (4): 626–659. 2020. doi:10.1080/10408398.2018.1546669. PMID 30614249. 
  19. ↑ 19.0 19.1 "Dietary Quercetin and Kaempferol: Bioavailability and Potential Cardiovascular-Related Bioactivity in Humans". Nutrients 11 (10): 2288. 2019. doi:10.3390/nu11102288. PMID 31557798. 
  20. ↑ "Potential Implications of Quercetin in Autoimmune Diseases". Front Immunol 12: 689044. 2021. doi:10.3389/fimmu.2021.689044. PMID 34248976. 
  21. ↑ "Quercetin derivatives: Drug design, development, and biological activities, a review". Eur J Med Chem 229: 114068. February 2022. doi:10.1016/j.ejmech.2021.114068. PMID 34971873. 
  22. ↑ 22.0 22.1 22.2 "Pharmacokinetics and bioavailability of the flavonol quercetin in humans". International Journal of Clinical Pharmacology and Therapeutics 37 (5): 219–33. 1999. PMID 10363620. http://ucce.ucdavis.edu/files/datastore/608-67.pdf. Retrieved 2016-01-01. 
  23. ↑ Wittig, Jörg; Herderich, Markus; Graefe, Eva Ulrike; Veit, Markus (April 2001). "Identification of quercetin glucuronides in human plasma by high-performance liquid chromatography–tandem mass spectrometry". Journal of Chromatography B: Biomedical Sciences and Applications 753 (2): 237–243. doi:10.1016/s0378-4347(00)00549-1. PMID 11334336. 
  24. ↑ 24.0 24.1 "Characterization of polyphenol metabolites". Phytochemicals in health and disease. New York, NY: Dekker. 2004. pp. 50–67. ISBN 0-8247-4023-8. https://books.google.com/books?id=ruD5AWlELmgC&q=Quercetin%20%E2%80%8E%20estrogen%20receptor&pg=PA58. 
  25. ↑ "Antioxidant and prooxidant properties of flavonoids". Fitoterapia 82 (4): 513–523. 2011. doi:10.1016/j.fitote.2011.01.018. PMID 21277359. 
  26. ↑ "Studying the Inhibitory Effect of Quercetin and Thymoquinone on Human Cytochrome P450 Enzyme Activities". Pharmacognosy Magazine 13 (Suppl 4): S895–S899. January 2018. doi:10.4103/0973-1296.224342. PMID 29491651. 
  27. ↑ Rastogi, Himanshu; Jana, Snehasis (December 2014). "Evaluation of Inhibitory Effects of Caffeic acid and Quercetin on Human Liver Cytochrome P450 Activities". Phytotherapy Research 28 (12): 1873–1878. doi:10.1002/ptr.5220. PMID 25196644. 
  28. ↑ Xiao, Jian; Huang, Wei-Hua; Peng, Jing-Bo; Tan, Zhi-Rong; Ou-Yang, Dong-Sheng; Hu, Dong-Li; Zhang, Wei; Chen, Yao (2014). "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: 1–6. doi:10.1155/2014/405071. PMID 25025048. 
  29. ↑ "GRN No. 341 (Quercetin)". US Food and Drug Administration. 22 November 2010. https://www.accessdata.fda.gov/scripts/fdcc/index.cfm?set=GRASNotices&id=341. 
  30. ↑ "Quercetin in prostate cancer: Chemotherapeutic and chemopreventive effects, mechanisms and clinical application potential (Review)". Oncol. Rep. 33 (6): 2659–68. June 2015. doi:10.3892/or.2015.3886. PMID 25845380. 
  31. ↑ New Roles for Polyphenols. A 3-Part Report on Current Regulations & the State of Science, Nutraceuticals World, March 1, 2009, http://www.nutraceuticalsworld.com/issues/2009-03/view_features/new-roles-for-polyphenols/ 
  32. ↑ "Molecular and physiological actions of quercetin: need for clinical trials to assess its benefits in human disease". Nutrition Reviews 72 (11): 720–34. 2014. doi:10.1111/nure.12152. PMID 25323953. 
  33. ↑ "Quercetin: A flavonol with multifaceted therapeutic applications?". Fitoterapia 106: 256–71. 2015. doi:10.1016/j.fitote.2015.09.018. PMID 26393898. 
  34. ↑ "Quercetin". American Cancer Society Complete Guide to Complementary and Alternative Cancer Therapies (2nd ed.). American Cancer Society. 2009. ISBN 9780944235713. https://archive.org/details/americancancerso0000unse. 
  35. ↑ European Food Safety Agency (EFSA) NDA Panel (Dietetic Products, Nutrition and Allergies) (8 April 2011). "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 9 (4): 2067–82. doi:10.2903/j.efsa.2011.2067. http://www.efsa.europa.eu/en/efsajournal/pub/2067. Retrieved 24 September 2014. 
  36. ↑ 36.0 36.1 "Warning Letter to Cape Fear Naturals". Inspections, Compliance, Enforcement, and Criminal Investigations, US Food and Drug Administration. 2 March 2017. https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm545773.htm. 
  37. ↑ 37.0 37.1 "Warning Letter to DoctorVicks.com". Inspections, Compliance, Enforcement, and Criminal Investigations, US Food and Drug Administration. 17 April 2017. https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm554022.htm. 
  38. ↑ 38.0 38.1 "Safety Aspects of the Use of Quercetin as a Dietary Supplement". Mol Nutr Food Res 62 (1). January 2018. doi:10.1002/mnfr.201700447. PMID 29127724. 

External links



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