Quercetin

Quercetin
Skeletal formula of quercetin
Ball-and-stick model of the quercetin molecule
Names
IUPAC name
2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one
Other names
Sophoretin
Meletin
Quercetine
Xanthaurine
Quercetol
Quercitin
Quertine
Flavin meletin
Identifiers
117-39-5 YesY
6151-25-3 (Quercetin dihydrate)[1] N
ChEBI CHEBI:16243 N
ChEMBL ChEMBL50 YesY
ChemSpider 4444051 YesY
DrugBank DB04216 N
5346
Jmol 3D model Interactive image
KEGG C00389 YesY
PubChem 5280343
UNII 9IKM0I5T1E YesY
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).
N verify (what is YesYN ?)
Infobox references
UV visible spectrum of quercetin, with lambda max at 369 nm.

Quercetin /ˈkwɜːrsᵻtᵻn/ is a flavonol found in many fruits, vegetables, leaves and grains. It can be used as an ingredient in supplements, beverages, or foods.

Health effects

While quercetin supplements have been promoted for prevention and treatment of cancer, "there is no reliable clinical evidence that quercetin can prevent or treat cancer in humans".[2] Also, there is no evidence that consuming foods rich in quercetin reduces the risk of cancer or any other disease.[3]

Quercetin supplements have also been promoted for the treatment of a wide spectrum of other diseases.[4] However, the European Food Safety Authority evaluated possible health claims associated with consumption of quercetin, and found that no cause-and-effect relationship has been established for any physiological effect in human health or diseases.[5]

Drug interactions

Quercetin is contraindicated with some antibiotics; it may interact with fluoroquinolones (an antibiotic), as quercetin competitively binds to bacterial DNA gyrase. Whether this inhibits or enhances the effect of fluoroquinolones is not certain.[6]

AHFS Drug Information (2010) identifies quercetin as an inhibitor of CYP2C8, and specifically names it as a drug with potential to have harmful interactions with taxol/paclitaxel. As paclitaxel is metabolized primarily by CYP2C8, its bioavailability may be increased unpredictably, potentially leading to harmful side-effects.[7][8]

Occurrence

Quercetin is a flavonoid widely distributed in nature. The name has been used since 1857, and is derived from quercetum (oak forest), after Quercus.[9][10] It is a naturally occurring polar auxin transport inhibitor.[11]

Quercetin is one of the most abundant dietary flavonoids with an average daily consumption of 25–50 mgs.[12]

Foods containing quercetin Quercetin (mg/100g of edible portion)
capers, raw 234[13]
capers, canned 173[13]
lovage 170[13]
dock like sorrel 86[13]
radish leaves 70[13]
carob fiber 58[13]
dill 55[14] (48-110)[15]
cilantro 53[13]
Hungarian wax pepper 51[13]
fennel leaves 48.8[13]
onion, red 32[16]
radicchio 31.5[13]
watercress 30[16]
buckwheat 23[17]
kale 23[16]
chokeberry 19[16]
cranberry 15[16]
lingonberry 13[16]
plums, black 12[16]
cow peas 11[16]
sweet potato 10[16]
blueberry, cultivated 8[16]
sea buckthorn berry 8[16]
rowanberry 7[16]
crowberry 5[16]
prickly pear cactus fruits 5[16]
apples, Red Delicious 4[16]
broccoli 3[16]
bilberry 3[16]
tea, black or green Camellia sinensis 2[16]

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.[18] One study found that organically grown tomatoes had 79% more quercetin than chemically grown fruit.[19] Quercetin is present in various kinds of honey from different plant sources.[20]

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.[21] 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.[21]

Glycosides

Quercetin is the aglycone form of a number of other flavonoid glycosides, such as rutin and quercitrin, found in citrus fruit, buckwheat and onions. 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.[22]

Rutin degradation pathway

The enzyme quercitrinase can be found in Aspergillus flavus.[23] This enzyme hydrolyzes the glycoside quercitrin to release quercetin and L-rhamnose. It is an enzyme in the rutin catabolic pathway[24]

Pharmacology

Pharmacokinetics

The oral bioavailability of quercetin in humans is low and highly variable (0-50%) and is rapidly cleared (elimination half-life of 1-2 hours after IV injection).[25] Following dietary ingestion, quercetin undergoes rapid and extensive metabolism that makes the biological effects presumed from in vitro studies unlikely to apply in vivo.[26][27]

Metabolism

In rats, quercetin did not undergo any significant phase I metabolism.[28] In contrast, quercetin did undergo extensive phase II (conjugation) to produce metabolites that are more polar than the parent substance and hence are more rapidly excreted from the body. 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.[28][29]

In vitro pharmacology

Quercetin has been reported to inhibit the oxidation of other molecules and hence is classified as an antioxidant.[26][29] Quercetin contains a polyphenolic chemical substructure that stops oxidation by acting as a scavenger of free radicals that are responsible for oxidative chain reactions.[30]

Quercetin also activates or inhibits the activities of a number of proteins.[31] For example, quercetin is a non-specific protein kinase enzyme inhibitor.[26][29] Quercetin has also been reported to have estrogenic (female sex hormone like) activities by activating estrogen receptors. Quercetin activates both estrogen receptor alpha (ERα) and beta (ERβ)[32] with binding IC50s of 1015 nM and 113 nM respectively. Hence quercetin is somewhat ERβ selective (9 fold) and is roughly two to three orders of magnitude less potent than the endogenous estrogenic hormone 17β-estradiol.[33][34] In human breast cancer cell lines, quercetin has also been found to act as an agonist of the G protein-coupled estrogen receptor (GPER).[35][36]

Clinical research

Although quercetin is under basic and early-stage clinical research for a variety of disease conditions,[37][38] there exists no evidence that it has any beneficial effect on DNA repair, liver and kidney systems, mental performance or cardiovascular health in the human body.[5] The US FDA has issued warning letters,[39] e.g., to emphasize that quercetin is not a defined nutrient nor an antioxidant, cannot be assigned a dietary content level and is not regulated as a drug to treat any human disease.

See also

References

  1. 1 2 3 Quercetin dihydrate safety sheet on http://www.pvp.com.br (English)
  2. ↑ Ades TB, ed. (2009). Quercetin. American Cancer Society Complete Guide to Complementary and Alternative Cancer Therapies (2nd ed.) (American Cancer Society). ISBN 9780944235713.
  3. ↑ "Flavonoids". Linus Pauling Institute, Micronutrient Information Center, Oregon State University, Corvallis. 2015. Retrieved 19 October 2015.
  4. ↑ D'Andrea G (2015). "Quercetin: A flavonol with multifaceted therapeutic applications?". Fitoterapia 106: 256–71. doi:10.1016/j.fitote.2015.09.018. PMID 26393898.
  5. 1 2 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. Retrieved 24 September 2014.
  6. ↑ Hilliard JJ, Krause HM, Bernstein JI, Fernandez JA, Nguyen V, Ohemeng KA, Barrett JF (1995). "A comparison of active site binding of 4-quinolones and novel flavone gyrase inhibitors to DNA gyrase". Advances in Experimental Medicine and Biology 390: 59–69. doi:10.1007/978-1-4757-9203-4_5. PMID 8718602.
  7. ↑ Bun SS, Ciccolini J, Bun H, Aubert C, Catalin J (Jun 2003). "Drug interactions of paclitaxel metabolism in human liver microsomes". Journal of Chemotherapy 15 (3): 266–74. doi:10.1179/joc.2003.15.3.266. PMID 12868554.
  8. ↑ Bun SS, Giacometti S, Fanciullino R, Ciccolini J, Bun H, Aubert C (Jul 2005). "Effect of several compounds on biliary excretion of paclitaxel and its metabolites in guinea-pigs". Anti-Cancer Drugs 16 (6): 675–82. doi:10.1097/00001813-200507000-00013. PMID 15930897.
  9. ↑ "Quercetin". Merriam-Webster.
  10. ↑ "Quercitin (biochemistry)". Encyclopædia Britannica.
  11. ↑ Fischer C, Speth V, Fleig-Eberenz S, Neuhaus G (Oct 1997). "Induction of Zygotic Polyembryos in Wheat: Influence of Auxin Polar Transport". The Plant Cell 9 (10): 1767–1780. doi:10.1105/tpc.9.10.1767. PMC 157020. PMID 12237347.
  12. ↑ Formica JV, Regelson W (1995). "Review of the biology of Quercetin and related bioflavonoids". Food and Chemical Toxicology 33 (12): 1061–80. doi:10.1016/0278-6915(95)00077-1. PMID 8847003.
  13. 1 2 3 4 5 6 7 8 9 10 "USDA Database for the Flavonoid Content of Selected Foods, Release 3.1" (PDF). U.S. Department of Agriculture. 2013.
  14. ↑ "Dill weed, fresh". Merschat family website.
  15. ↑ Justesen U, Knuthsen P (May 2001). "Composition of flavonoids in fresh herbs and calculation of flavonoid intake by use of herbs in traditional Danish dishes". Food Chemistry 73 (2): 245–50. doi:10.1016/S0308-8146(01)00114-5.
  16. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 "USDA Database for the Flavonoid Content of Selected Foods, Release 3" (PDF). U.S. Department of Agriculture. 2011.
  17. ↑ "Food Nutrition Facts: Buckwheat". Merschat family website.
  18. ↑ Smith C, Lombard KA, Peffley EB, Liu W (2003). "Genetic Analysis of Quercetin in Onion (Allium cepa L.) Lady Raider" (PDF). The Texas Journal of Agriculture and Natural Resource (Agriculture Consortium of Texas) 16: 24–8. Archived from the original (PDF) on February 25, 2007.
  19. ↑ Mitchell AE, Hong YJ, Koh E, Barrett DM, Bryant DE, Denison RF, Kaffka S (Jul 2007). "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. doi:10.1021/jf070344. PMID 17590007.
  20. ↑ Petrus K, Schwartz H, Sontag G (Jun 2011). "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. doi:10.1007/s00216-010-4614-7. PMID 21229237.
  21. 1 2 Winkel-Shirley B (Jun 2001). "Flavonoid biosynthesis. A colorful model for genetics, biochemistry, cell biology, and biotechnology". Plant Physiology 126 (2): 485–93. doi:10.1104/pp.126.2.485. PMC 1540115. PMID 11402179.
  22. ↑ Juergenliemk G, Boje K, Huewel S, Lohmann C, Galla HJ, Nahrstedt A (Nov 2003). "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. doi:10.1055/s-2003-45148. PMID 14735439.
  23. ↑ "Information on EC 3.2.1.66 - quercitrinase". BRENDA (BRaunschweig ENzyme DAtabase). Helmholtz Centre for Infection Research.
  24. ↑ Tranchimand S, Brouant P, Iacazio G (Nov 2010). "The rutin catabolic pathway with special emphasis on quercetinase". Biodegradation 21 (6): 833–59. doi:10.1007/s10532-010-9359-7. PMID 20419500.
  25. ↑ Graefe EU, Derendorf H, Veit M (1999). "Pharmacokinetics and bioavailability of the flavonol quercetin in humans" (PDF). (review). International Journal of Clinical Pharmacology and Therapeutics 37 (5): 219–33. PMID 10363620.
  26. 1 2 3 Williams RJ, Spencer JP, Rice-Evans C (Apr 2004). "Flavonoids: antioxidants or signalling molecules?". (review). Free Radical Biology & Medicine 36 (7): 838–49. doi:10.1016/j.freeradbiomed.2004.01.001. PMID 15019969.
  27. ↑ Barnes S, Prasain J, D'Alessandro T, Arabshahi A, Botting N, Lila MA, Jackson G, Janle EM, Weaver CM (May 2011). "The metabolism and analysis of isoflavones and other dietary polyphenols in foods and biological systems". (review). Food & Function 2 (5): 235–44. doi:10.1039/c1fo10025d. PMID 21779561.
  28. 1 2 Day AJ, Rothwell JA, Morgan RA (2004). "Characterization of polyphenol metabolites". In Bao Y, Fenwick R. Phytochemicals in health and disease. New York, NY: Dekker. pp. 50–67. ISBN 0-8247-4023-8.
  29. 1 2 3 Russo GL, Russo M, Spagnuolo C, Tedesco I, Bilotto S, Iannitti R, Palumbo R (2014). "Quercetin: a pleiotropic kinase inhibitor against cancer" (PDF). (review). Cancer Treatment and Research 159: 185–205. doi:10.1007/978-3-642-38007-5_11. PMID 24114481.
  30. ↑ Murakami A, Ashida H, Terao J (2008). "Multitargeted cancer prevention by quercetin". (review). Cancer Letters 269 (2): 315–25. doi:10.1016/j.canlet.2008.03.046. PMID 18467024.
  31. ↑ Feitelson MA, Arzumanyan A, Kulathinal RJ, Blain SW, Holcombe RF, Mahajna J, Marino M, Martinez-Chantar ML, Nawroth R, Sanchez-Garcia I, Sharma D, Saxena NK, Singh N, Vlachostergios PJ, Guo S, Honoki K, Fujii H, Georgakilas AG, Bilsland A, Amedei A, Niccolai E, Amin A, Ashraf SS, Boosani CS, Guha G, Ciriolo MR, Aquilano K, Chen S, Mohammed SI, Azmi AS, Bhakta D, Halicka D, Keith WN, Nowsheen S (2015). "Sustained proliferation in cancer: Mechanisms and novel therapeutic targets". (review). Seminars in Cancer Biology. 35 Suppl: S25–54. doi:10.1016/j.semcancer.2015.02.006. PMID 25892662.
  32. ↑ Moutsatsou P (2007). "The spectrum of phytoestrogens in nature: our knowledge is expanding". (review). Hormones (Athens, Greece) 6 (3): 173–93. PMID 17724002.
  33. ↑ Maggiolini M, Bonofiglio D, Marsico S, Panno ML, Cenni B, Picard D, Andò S (2001). "Estrogen receptor alpha mediates the proliferative but not the cytotoxic dose-dependent effects of two major phytoestrogens on human breast cancer cells". (primary). Molecular Pharmacology 60 (3): 595–602. PMID 11502892.
  34. ↑ van der Woude H, Ter Veld MG, Jacobs N, van der Saag PT, Murk AJ, Rietjens IM (2005). "The stimulation of cell proliferation by quercetin is mediated by the estrogen receptor". (primary). Molecular Nutrition & Food Research 49 (8): 763–71. doi:10.1002/mnfr.200500036. PMID 15937998.
  35. ↑ Maggiolini M, Vivacqua A, Fasanella G, Recchia AG, Sisci D, Pezzi V, Montanaro D, Musti AM, Picard D, Andò S (2004). "The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17beta-estradiol and phytoestrogens in breast cancer cells". (primary). The Journal of Biological Chemistry 279 (26): 27008–16. doi:10.1074/jbc.M403588200. PMID 15090535.
  36. ↑ Prossnitz ER, Barton M (May 2014). "Estrogen biology: new insights into GPER function and clinical opportunities". (review). Molecular and Cellular Endocrinology 389 (1-2): 71–83. doi:10.1016/j.mce.2014.02.002. PMC 4040308. PMID 24530924.
  37. ↑ Gross P (March 1, 2009), New Roles for Polyphenols. A 3-Part report on Current Regulations & the State of Science, Nutraceuticals World
  38. ↑ Miles SL, McFarland M, Niles RM (2014). "Molecular and physiological actions of quercetin: need for clinical trials to assess its benefits in human disease". Nutrition Reviews 72 (11): 720–34. doi:10.1111/nure.12152. PMID 25323953.
  39. ↑ Adams, AM (22 April 2014). "River Hills Harvest dab Elderberrylife". Inspections, Compliance, Enforcement, and Criminal Investigations, US FDA. Retrieved 5 November 2014.

External links

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