Quercetin is a plant
flavonol
Flavonols are a class of flavonoids that have the 3-hydroxyflavone backbone (IUPAC name: 3-hydroxy-2-phenylchromen-4-one). Their diversity stems from the different positions of the phenolic –OH groups. They are distinct from flavanols (with ...
from the
flavonoid
Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans.
Chemically, flavonoids ...
group of
polyphenol
Polyphenols () are a large family of naturally occurring phenols. They are abundant in plants and structurally diverse. Polyphenols include phenolic acids, flavonoids, tannic acid, and ellagitannin, some of which have been used historically as ...
s. It is found in many fruits, vegetables, leaves, seeds, and grains; capers, red onions, and
kale
Kale (), also called leaf cabbage, belongs to a group of cabbage (''Brassica oleracea'') cultivars primarily grown for their Leaf vegetable, edible leaves; it has also been used as an ornamental plant. Its multiple different cultivars vary quite ...
are common foods containing appreciable amounts of it.
[ It has a bitter flavor and is used as an ingredient in ]dietary supplement
A dietary supplement is a manufactured product intended to supplement a person's diet by taking a pill (pharmacy), pill, capsule (pharmacy), capsule, tablet (pharmacy), tablet, powder, or liquid. A supplement can provide nutrients eithe ...
s, beverages, and foods.
Occurrence
Quercetin is a flavonoid
Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans.
Chemically, flavonoids ...
widely distributed in nature.[ The name has been used since 1857, and is derived from ''quercetum'' (oak forest), after the oak genus '']Quercus
An oak is a hardwood tree or shrub in the genus ''Quercus'' of the beech family. They have spirally arranged leaves, often with lobed edges, and a nut called an acorn, borne within a cup. The genus is widely distributed in the Northern Hemisp ...
''. It is a naturally occurring polar auxin transport
Polar auxin transport is the regulated transport of the plant hormone auxin in plants. It is an active process, the hormone is transported in cell-to-cell manner and one of the main features of the transport is its asymmetry and directionality ( p ...
inhibitor.
Quercetin is one of the most abundant dietary flavonoids, with an average daily consumption of 25–50 mg.
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. One study found that organically grown tomato
The tomato (, ), ''Solanum lycopersicum'', is a plant whose fruit is an edible Berry (botany), berry that is eaten as a vegetable. The tomato is a member of the nightshade family that includes tobacco, potato, and chili peppers. It originate ...
es had 79% more quercetin than non-organically grown fruit. Quercetin is present in various kinds of honey
Honey is a sweet and viscous substance made by several species of bees, the best-known of which are honey bees. Honey is made and stored to nourish bee colonies. Bees produce honey by gathering and then refining the sugary secretions of pl ...
from different plant sources.
Biosynthesis
In plants, phenylalanine
Phenylalanine (symbol Phe or F) is an essential α-amino acid with the chemical formula, formula . It can be viewed as a benzyl group substituent, substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of ...
is converted to 4-coumaroyl-CoA in a series of steps known as the general phenylpropanoid
The phenylpropanoids are a diverse family of organic compounds that are biosynthesized by plants from the amino acids phenylalanine and tyrosine in the shikimic acid pathway. Their name is derived from the six-carbon, aromatic phenyl group and ...
pathway using phenylalanine ammonia-lyase
The enzyme phenylalanine ammonia lyase (EC 4.3.1.24) catalysis, catalyzes the conversion of L-phenylalanine to ammonia and cinnamic acid, ''trans''-cinnamic acid.:
:L-phenylalanine = ''trans''-cinnamate + NH3
Phenylalanine ammonia lyase (PAL) i ...
, cinnamate-4-hydroxylase, and 4-coumaroyl-CoA-ligase. One molecule of 4-coumaroyl-CoA is added to three molecules of malonyl-CoA
Malonyl-CoA is a coenzyme A derivative of malonic acid.
Biosynthesis
Malonyl-CoA cannot cross membranes and there is no known malonyl-CoA import mechanism. The biosynthesis therefore takes place locally:
* cytosol: Malonyl-CoA is formed by c ...
to form tetrahydroxychalcone using 7,2′-dihydroxy-4′-methoxyisoflavanol synthase. Tetrahydroxychalcone is then converted into naringenin
Naringenin is a flavanone from the flavonoid group of polyphenols. It is commonly found in citrus fruits, especially as the predominant flavonone in grapefruit.
The fate and biological functions of naringenin in vivo are unknown, remaining und ...
using chalcone isomerase.
Naringenin is converted into eriodictyol
Eriodictyol is a bitter-masking flavanone, a flavonoid extracted from yerba santa ('' Eriodictyon californicum''), a plant native to North America. Eriodictyol is one of the four flavanones identified in this plant as having taste-modifying prop ...
using flavanoid 3′-hydroxylase. Eriodictyol is then converted into dihydroquercetin with flavanone 3-hydroxylase, which is then converted into quercetin using flavonol synthase
In enzymology, a flavonol synthase () is an enzyme that catalyzes the following chemical reaction :
dihydroflavonol + 2-oxoglutarate + \rightleftharpoons a flavonol + succinate + C + H2O
The 3 substrates of this enzyme are dihydroflavonol, 2- ...
.
Glycosides
Quercetin is the aglycone
An aglycone (aglycon or genin) is the chemical compound remaining after the glycosyl group on a glycoside is replaced by a hydrogen atom. For example, the aglycone of a cardiac glycoside would be a steroid
A steroid is an organic compoun ...
form of a number of other flavonoid glycoside
In chemistry, a glycoside is a molecule in which a sugar is bound to another functional group via a glycosidic bond. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. ...
s, such as rutin
Rutin (rutoside, quercetin-3-O-rutinoside or sophorin) is the glycoside combining the flavonol quercetin and the disaccharide rutinose (α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranose). It is a flavonoid glycoside found in a wide variety of pla ...
(also known as quercetin-3-O-rutinoside) and quercitrin, found in citrus
''Citrus'' is a genus of flowering trees and shrubs in the family Rutaceae. Plants in the genus produce citrus fruits, including important crops such as oranges, mandarins, lemons, grapefruits, pomelos, and limes.
''Citrus'' is nativ ...
fruit, buckwheat
Buckwheat (''Fagopyrum esculentum'') or common buckwheat is a flowering plant in the knotweed family Polygonaceae cultivated for its grain-like seeds and as a cover crop. Buckwheat originated around the 6th millennium BCE in the region of what ...
, and onions.[ Quercetin forms the ]glycoside
In chemistry, a glycoside is a molecule in which a sugar is bound to another functional group via a glycosidic bond. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. ...
s quercitrin and rutin
Rutin (rutoside, quercetin-3-O-rutinoside or sophorin) is the glycoside combining the flavonol quercetin and the disaccharide rutinose (α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranose). It is a flavonoid glycoside found in a wide variety of pla ...
together with rhamnose
Rhamnose (Rha, Rham) is a naturally occurring deoxy sugar. It can be classified as either a methyl- pentose or a 6-deoxy- hexose. Rhamnose predominantly occurs in nature in its L-form as L-rhamnose (6-deoxy-L- mannose). This is unusual, since mo ...
and rutinose
Rutinose is the disaccharide also known as 6-''O''-α-L- rhamnosyl-D-glucose (C12H22O10) that is present in some flavonoid glycosides. It is prepared from rutin by hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of wat ...
, respectively. Likewise guaijaverin is the 3-''O''- arabinoside, hyperoside is the 3-''O''-galactoside
A galactoside is a glycoside containing galactose. The H of the OH group on carbon-1 of galactose is replaced by an organic moiety.
Depending on whether the glycosidic bond lies "above" or "below" the plane of the galactose molecule, galactosides ...
, isoquercitin is the 3-''O''-glucoside
A glucoside is a glycoside that is chemically derived from glucose. Glucosides are common in plants, but rare in animals. Glucose is produced when a glucoside is hydrolysed by purely chemical means, or decomposed by fermentation or enzymes.
Th ...
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.
Several taxifolin
Taxifolin (5,7,3',4'-flavan-on-ol), also known as dihydroquercetin, belongs to the subclass flavanonols in the flavonoids, which in turn is a class of polyphenols. It is extracted from plants such as Siberian larch and milk thistle.
Stereocent ...
(also known as dihydroquercetin) glycosides also exist. Isoquercetin
Isoquercetin, isoquercitrin or isotrifoliin is a flavonoid, a type of chemical compound. It is the 3-''O''-glucoside of quercetin. Isoquercitrin can be isolated from various plant species including ''Mangifera indica'' (mango) and '' Rheum nobile'' ...
is the 3-''O''-glucoside of quercetin.
Rutin degradation pathway
The enzyme quercitrinase can be found in ''Aspergillus flavus
''Aspergillus flavus'' is a saprotrophic and pathogenic fungus with a cosmopolitan distribution. It is best known for its colonization of cereal grains, legumes, and tree nuts. Postharvest rot typically develops during harvest, storage, and/or ...
''. This enzyme hydrolyzes
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
the glycoside quercitrin to release quercetin and L-rhamnose
Rhamnose (Rha, Rham) is a naturally occurring deoxy sugar. It can be classified as either a methyl- pentose or a 6-deoxy- hexose. Rhamnose predominantly occurs in nature in its L-form as L-rhamnose (6-deoxy-L- mannose). This is unusual, since mo ...
. It is an enzyme in the rutin
Rutin (rutoside, quercetin-3-O-rutinoside or sophorin) is the glycoside combining the flavonol quercetin and the disaccharide rutinose (α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranose). It is a flavonoid glycoside found in a wide variety of pla ...
catabolic pathway.
Pharmacology
Pharmacokinetics
The bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...
of quercetin in humans after oral intake is very low, with one study concluding it must be less than 1%. Intravenous injection of quercetin shows a rapid decay in concentration described by a two-compartment model (initial half-life Half-life is a mathematical and scientific description of exponential or gradual decay.
Half-life, half life or halflife may also refer to:
Film
* Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang
* ''Half Life: ...
of 8.8 minutes, terminal half-life of 2.4 hours). Because it undergoes rapid and extensive metabolism, the biological effects presumed from ''in vitro'' studies are unlikely to apply ''in vivo''. Quercetin supplements in the aglycone
An aglycone (aglycon or genin) is the chemical compound remaining after the glycosyl group on a glycoside is replaced by a hydrogen atom. For example, the aglycone of a cardiac glycoside would be a steroid
A steroid is an organic compoun ...
form are less bioavailable
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...
than the quercetin glycoside
In chemistry, a glycoside is a molecule in which a sugar is bound to another functional group via a glycosidic bond. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. ...
often found in foods, especially red onions. 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
Gastrointestinal physiology is the branch of Human body, human physiology that addresses the physical function of the Human gastrointestinal tract, gastrointestinal (GI) tract. The function of the GI tract is to process ingested food by mechanical ...
and colonic fermentation
Fermentation is a type of anaerobic metabolism which harnesses the redox potential of the reactants to make adenosine triphosphate (ATP) and organic end products. Organic molecules, such as glucose or other sugars, are catabolized and reduce ...
.[ 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.] 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.
Metabolism
Quercetin is rapidly metabolized (via glucuronidation
Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...
) after the ingestion of quercetin foods or supplements. Five metabolites (quercetin glucuronides) have been found in human plasma after quercetin ingestion. Taken together, the quercetin glucuronides have a half-life around 11–12 hours.
In rats, quercetin did not undergo any significant phase I metabolism. In contrast, quercetin did undergo extensive phase II (conjugation) to produce metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s that are more polar than the parent substance, hence are more rapidly excreted from the body. ''In vitro'', the meta-hydroxyl group
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
of catechol
Catechol ( or ), also known as pyrocatechol or 1,2-dihydroxybenzene, is an organic compound with the molecular formula . It is the ''ortho'' isomer of the three isomeric benzenediols. This colorless compound occurs naturally in trace amounts. It ...
is methylated by catechol-O-methyltransferase. Four of the five hydroxyl groups of quercetin are glucuronidated by UDP-glucuronosyltransferase
Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UDPGT or UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecu ...
. 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. A methyl metabolite of quercetin has been shown ''in vitro ''to be more effective than quercetin at inhibiting lipopolysaccharide
Lipopolysaccharide (LPS), now more commonly known as endotoxin, is a collective term for components of the outermost membrane of the cell envelope of gram-negative bacteria, such as '' E. coli'' and ''Salmonella'' with a common structural archit ...
-activated macrophage
Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s.
Compared to other flavonoid
Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans.
Chemically, flavonoids ...
s, quercetin is one of the most effective inducers of the phase II detoxification enzymes.
''In vitro'' studies show that quercetin is a strong inhibitor of the cytochrome P450
Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
enzymes CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
and CYP2C19
Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some ...
and a moderate inhibitor of CYP2D6
Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.
CYP2 ...
. Drugs that are metabolized by these pathways may have increased effect. An ''in vivo'' study found that quercetin supplementation slows the metabolism of caffeine
Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class and is the most commonly consumed Psychoactive drug, psychoactive substance globally. It is mainly used for its eugeroic (wakefulness pr ...
to a statistically significant extent in a particular genetic subpopulation, but in absolute terms the effect was almost negligible.
Food safety
In 2010, the U. S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
acknowledged high-purity quercetin as generally recognized as safe
Generally recognized as safe (GRAS) is a United States Food and Drug Administration (FDA) designation that a chemical or substance added to food is considered safe by experts under the conditions of its intended use. An ingredient with a GRAS d ...
for use as an ingredient in various specified food categories at levels up to 500 mg per serving.
Health claims
Quercetin has been studied in basic research
Basic research, also called pure research, fundamental research, basic science, or pure science, is a type of scientific research with the aim of improving scientific theories for better understanding and prediction of natural or other phenome ...
and small clinical trials
Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
. While supplements have been promoted for the treatment of cancer and various other diseases,[ there is no high-quality evidence that quercetin (via supplements or in food) is useful to treat cancer] or any other disease.
The US Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
has issued warning letters to several manufacturers advertising on their product labels and websites that quercetin product(s) can be used to treat diseases. The FDA regards such quercetin advertising and products as unapproved – with unauthorized health claim
A health claim on a food label and in food marketing is a claim by a manufacturer of food products that their food will reduce the risk of developing a disease or condition. For example, it is claimed by the manufacturers of oat cereals that oa ...
s concerning the anti-disease products – as defined by "sections 201(g)(1)(B) and/or 201 (g)(1)(C) of the Act 1 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",[ 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
Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
-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.]
See also
* List of ineffective cancer treatments
* Flavonol 3-sulfotransferase
* Phenolic compounds in wine
Phenolic compounds— natural phenol and polyphenols—occur naturally in wine. These include a large group of several hundred chemical compounds that affect the taste, color and mouthfeel of wine. These compounds include phenolic acids, sti ...
* Phytochemical
Phytochemicals are naturally-occurring chemicals present in or extracted from plants. Some phytochemicals are nutrients for the plant, while others are metabolites produced to enhance plant survivability and reproduction.
The fields of ext ...
* Quercetin 2,3-dioxygenase
* Quercetin 3-O-methyltransferase
* Quercetin-3-sulfate 3'-sulfotransferase
* Quercetin-3-sulfate 4'-sulfotransferase
* Quercetin-3,3'-bissulfate 7-sulfotransferase
References
External links
*
{{Authority control
Aromatase inhibitors
CYP2C8 inhibitors
CYP3A4 inhibitors
Flavonoid antioxidants
GPER agonists
Xanthine oxidase inhibitors
Experimental medical treatments
Phytoestrogens
Selective ERβ agonists
Pentols