Elsevier

Fitoterapia

Volume 106, October 2015, Pages 256-271
Fitoterapia

Review
Quercetin: A flavonol with multifaceted therapeutic applications?

https://doi.org/10.1016/j.fitote.2015.09.018 Get rights and content

Abstract

Great interest is currently centered on the biologic activities of quercetin a polyphenol belonging to the class of flavonoids, natural products well known for their beneficial effects on health, long before their biochemical characterization. In particular, quercetin is categorized as a flavonol, one of the five subclasses of flavonoid compounds. Although flavonoids occur as either glycosides (with attached glycosyl groups) or as aglycones, most altogether of the dietary intake concerning quercetin is in the glycoside form. Following chewing, digestion, and absorption sugar moieties can be released from quercetin glycosides. Several organs contribute to quercetin metabolism, including the small intestine, the kidneys, the large intestine, and the liver, giving rise to glucuronidated, methylated, and sulfated forms of quercetin; moreover, free quercetin (such as aglycone) is also found in plasma. Quercetin is now largely utilized as a nutritional supplement and as a phytochemical remedy for a variety of diseases like diabetes/obesity and circulatory dysfunction, including inflammation as well as mood disorders. Owing to its basic chemical structure the most obvious feature of quercetin is its strong antioxidant activity which potentially enables it to quench free radicals from forming resonance-stabilized phenoxyl radicals.

In this review the molecular, cellular, and functional bases of therapy will be emphasized taking strictly into account data appearing in the peer-reviewed literature and summarizing the main therapeutic applications of quercetin; furthermore, the drug metabolism and the main drug interaction as well as the potential toxicity will be also spotlighted.

Introduction

Most of the successful medical treatments in ancient times seem to be due to the employment of flavonoids, which use has persevered until now. Consequently, new interest by the scientific community towards flavonoids and their derivatives centers on numerous flavonoid compounds and their diverse biological properties (e.g. antioxidative, antimicrobial, anticarcinogenic, cardioprotective). Certainly, in this context quercetin is one of the most often studied dietary flavonoid ubiquitously present in various vegetables as well as in tea and red wine [1], [2], [3]. In a typical Western diet the daily intake of quercetin is estimated to be in the range of 0 and 30 mg (median of 10 mg). Tea, red wine, fruits, and vegetables are the chief dietary sources of quercetin in Western populations [4], [5]. In some countries quercetin is available as a dietary supplement with daily doses between 200 and 1200 mg. In addition, as a nutraceutical for functional foods, quercetin may be used within 0.008–0.5% or 10–125 mg/serving [6].

Yet, like other similar antioxidant flavonoids quercetin is an exceptional free radical scavenger [7] and from that feature arises the ability of quercetin to scavenge highly reactive species such as peroxynitrite and the hydroxyl radical; for this reason quercetin is suggested to be involved in imaginable beneficial health effects. On the contrary, only few, and mostly in vitro, studies report some damaging effects of quercetin; in particular, its oxidation product such as quercetin-quinone seems to be very reactive towards thiols and can instantaneously form an adduct with glutathione, the most abundant endogenous thiol [8], [9]. Furthermore, among other damaging effects quercetin has also been reported to display genotoxic effects in vitro, but these mutagenic effects of quercetin have been found only in bacteria and are suggested to require the quinone formation as mediators as well [10], [11], [12], [13].

In any case, it is assumed that the bioactivity of quercetin is mainly due to its metabolization in the intestines and/or liver starting from various naturally occurring conjugated isoforms that are absorbed and extensively distributed in animal tissues [14], [15], [16]. In particular, quercetin-3-O-β-d-glucuronide (Q3GA), a major metabolite of quercetin and found as such in many foods (Table 1), seems to exert the foremost beneficial functions in target tissues [17].

Thus, since numerous studies have been performed to gather scientific evidence for these beneficial health claims the principal aim of this review is to evaluate these studies in order to elucidate the possible health-beneficial effects of quercetin. In particular, among the beneficial effects, the antihypertensive effects of quercetin in humans and the improvement of endothelial function seem to be the most relevant. Nevertheless, besides its anti-thrombotic and anti-inflammatory effects, quercetin could be used for preventing obesity related diseases, but also to treat some kinds of cancer. Most exciting are the recent findings that quercetin enhances physical power by yet unclear mechanisms.

Even though quercetin bioavailability is generally poor it is a critical mediator of its bioactivities, in this review besides the molecular, cellular, and functional bases of therapy that will be emphasized and critically evaluated, the quercetin metabolism and its main drug interaction as well as its potential toxicity will be also spotlighted.

Section snippets

Structural features of quercetin

The name quercetin derives from quercetum (oak forest), after Quercus and has been used since 1857. Naturally, quercetin is a polar auxin transport inhibitor [18] whose structure is shown in Fig. 1 whereas its main identifiers and properties are reported in Table 2.

Chemically speaking quercetin belongs to the class of flavonoids (from flavus which means yellow, their common color), natural products derived from 2-phenylchromen-4-one (flavone) (Fig. 2).

However, further derivations encompass the

Dietary sources

The edible portions of many food plants, leafy vegetables, tubers and bulbs, various fruits, herbs and spices, as well as tea and wine contain flavonols mainly in the form of glycosides [50]. Among flavonols molecules quercetin is the most abundant (see Table 3 for selected foods containing quercetin), anyway the majority of the dietary intake of quercetin-type flavonols consists of quercetin glycosides a kind of conjugates in which quercetin is linked either with one or two glucose residues

Quercetin bioavaiability

Bioavailability is defined as a ratio between the amount of an orally administered substance and the amount which is absorbed and then available for physiologic activity or storage [67]. Founded on its pharmacokinetics assessment bioavailability could be sorted out as absolute or relative [68]. Absolute bioavailability is more accurate, whereas relative bioavailability is simpler, but less accurate [53]. As already reported [69] the factors that most influence quercetin absorption are the

Quercetin metabolism in vivo overview

As stated above quercetin as such is usually found linked to a sugar moiety giving rise β-glycosides derivatives which, once ingested, undergo hydrolysis by the glycosidase activity of intestinal bacteria releasing quercetin (the aglycone form) and the sugar moiety [75]. However, it was recently demonstrated that the predominant quercetin conjugates in human plasma, in which the quercetin as such could not be detected, are quercetin 3-O-β-d-glucuronide (Q3GA) and quercetin-3′-sulfate [76], [77]

Clinical trials

Since the first Phase I clinical trial in which, following a tyrosine kinase inhibition, an evidence of antitumor activity was seen [108], several very recent randomized, double-blind, placebo-controlled, crossover trials have been performed with quercetin demonstrating that: a) quercetin supplementation reduced systolic blood pressure significantly but had no effect on other cardiovascular risk factors and inflammatory biomarker [109]; b) quercetin (3-glucoside) supplementation had no effect

Drug interaction

Quercetin exhibits an in vivo inhibitory effect both on CYP3A4 [187], [188] and CYP1A2 whereas it increases CYP2A6, xanthine oxidase, and N-acetyltransferase activity [189]. Quercetin in vivo inhibits also the P-glycoprotein (Pgp), a drug efflux transporter that can play a pivotal role in the intestinal and biliary transport and elimination of many drugs and their metabolites [187], [188], [190], [191]. Due to these interactions, quercetin might alter the serum levels of all drugs metabolized

Toxicity

Most in vivo animal studies certify that quercetin is not carcinogenic; anyway, based on the Ames test quercetin is regarded as mutagenic. Interestingly, in 1999 the International Agency for Research on Cancer (IARC) ascertained that quercetin should not be classified as carcinogenic to humans [42], [43], [197]. Although in vitro studies suggest that quercetin might have mild negative effects on embryo development [198], until nowadays there is no definitive evidence regarding some teratogenic

Conclusions

The bioflavonoid quercetin has an extended spectrum of well characterized biological effects that include the promotion of health, the enhancement of physical and mental activity, and several distinct pharmacological effects. Of course, bioavailability of quercetin is an important mediator of its health benefits and, for that, a better understanding of the factors regulating quercetin metabolism and bioavailability is expected to confirm its potential role in managing different diseases.

Despite

Conflict of interest

The author declares that there are no conflicts of interest.

Acknowledgments

Financial support “Grant Year 2014” from MIUR (Ministero dell'Istruzione, Università e Ricerca), Rome, Italy, is gratefully acknowledged. Susan Edwards deserves sincere thanks for her considerable skill in helping to edit the manuscript.

References (209)

  • G.R.M.M. Haenen et al.

    Peroxynitrite scavenging byflavonoids

    Biochem. Biophys. Res. Commun.

    (1997)
  • C.G. Heijnen et al.

    Flavonoids as peroxynitrite scavengers: the role of the hydroxyl groups

    Toxicol. in Vitro

    (2001)
  • P.C.H. Hollman et al.

    Absorption, metabolism and health effects of dietary flavonoids in man

    Biomed. Pharmacother.

    (1997)
  • Y. Sakanashi et al.

    Possible use of quercetin, an antioxidant, for protection of cells suffering from overload of intracellular Ca2 +: a model experiment

    Life Sci.

    (2008)
  • R. Kahl et al.

    Methodology for studying antioxidant activity and mechanisms of action of antioxidants

    Food Chem. Toxicol.

    (1986)
  • M.A. Ansari et al.

    Protective effect of quercetin in primary neurons against Aβ (1–42): relevance to Alzheimer's disease

    J. Nutr. Biochem.

    (2009)
  • D.A. Shoskes et al.

    Quercetin in men with category III chronic prostatitis: a preliminary prospective, double blinded, placebo controlled trial

    Urology

    (1999)
  • A.N. Begum et al.

    Protective effect of quercetin against cigarette tar extract induced impairment of erythrocyte deformability

    J. Nutr. Biochem.

    (2002)
  • M.J.T.J. Arts et al.

    A new approach to assess the total antioxidant capacity using the TEAC assay

    Food Chem.

    (2004)
  • S.M. Nabavi et al.

    In vivo protective effects of quercetin against sodium fluoride-induced oxidative stress in the hepatic tissue

    Food Chem.

    (2012)
  • A.W. Boots et al.

    The quercetin paradox

    FEBS Lett.

    (2007)
  • D. Utesch et al.

    Evaluation of the potential in vivo genotoxicity of quercetin

    Mutat. Res.

    (2008)
  • A. Bast et al.

    The toxicity of antioxidants and their metabolites

    Environ. Toxicol. Pharmacol.

    (2002)
  • P.C. Hollman et al.

    Dietary flavonoids: intake, health effects and bioavailability

    Food Chem. Toxicol.

    (1999)
  • C.F. Skibola et al.

    Potential health impacts of excessive flavonoid intake

    Free Radic. Biol. Med.

    (2000)
  • A.W. Boots et al.

    Oxidative damage shifts from lipid peroxidation to thiol arylation by catechol-containing antioxidants

    Biochim. Biophys. Acta

    (2002)
  • A.W. Boots et al.

    Oxidized quercetin reacts with thiols rather than with ascorbate: implication for quercetin supplementation

    Biochem. Biophys. Res. Commun.

    (2003)
  • J.T. Brown

    A review of the genetic effects of naturally occurring flavonoids, anthraquinones and related compounds

    Mutat. Res.

    (1980)
  • L. Sampson et al.

    Flavonol and flavone intakes in US health professionals

    J. Am. Diet. Assoc.

    (2002)
  • N. Fang et al.

    Flavonoids from Ageratina calophylla

    Phytochemistry

    (1986)
  • T. Walle et al.

    Carbon dioxide is the major metabolite of quercetin in humans

    J. Nutr.

    (2001)
  • A.W. Boots et al.

    Health effects of quercetin: from antioxidant to nutraceutical

    Eur. J. Pharmacol.

    (2008)
  • C. Manach et al.

    Bioavailability and bioefficacy of polyphenols in humans. Review of 97 bioavailability studies

    Am. J. Clin. Nutr.

    (2005)
  • C. Manach et al.

    Quercetin is recovered in human plasma as conjugated derivatives which retain antioxidant properties

    FEBS Lett.

    (1998)
  • J. Moon et al.

    Identification of quercetin 3-O-β-d-glucuronide an antioxidative metabolite in rat plasma after oral administration of quercetin

    Free Radic. Biol. Med.

    (2001)
  • C. Manach et al.

    Dietary quercetin is recovered in rat plasma as conjugated derivatives of isorhamnetin and quercetin

    Nutr. Biochem.

    (1996)
  • E.L. da Silva et al.

    Quercetin metabolites inhibit copper ion-induced lipid peroxidation in rat plasma

    FEBS Lett.

    (1998)
  • Y. Guo et al.

    Endogenous and exogenous mediators of quercetin bioavailability

    J. Nutr. Biochem.

    (2015)
  • P.C. Hollman et al.

    Absorption and disposition kinetics of the dietary antioxidant quercetin in man

    Free Radic. Biol. Med.

    (1996)
  • J.A. Conquer et al.

    Supplementation with quercetin markedly increases plasma quercetin concentration without effect on selected risk factors for heart disease in healthy subjects

    J. Nutr.

    (1998)
  • A.J. Day et al.

    Absorption of quercetin-3-glucoside and quercetin-4′-glucoside in the rat small intestine: the role of lactase phlorizin hydrolase and the sodium-dependent glucose transporter

    Biochem. Pharmacol.

    (2003)
  • B.A. Graf et al.

    Rat gastrointestinal tissues metabolize quercetin

    J. Nutr.

    (2006)
  • M.G. Hertog et al.

    Intake of potentially anticarcinogenic flavonoids and their determinants in adults in The Netherlands

    Nutr. Cancer

    (1993)
  • G.R. Beecher et al.

    Analysis of tea polyphenols

    Proc. Soc. Exp. Biol. Med.

    (1999)
  • J. Linseisen et al.

    Flavonoidzufuhr erwachsener in einem bayrischen teilkollektiv der nationalen verzehrsstudie

    Z. Ernahrungswiss.

    (1997)
  • H. Böhm et al.

    Flavonols, flavone and anthocyanins as natural antioxidants of food and their possible role in the prevention of chronic diseases

    Z. Ernahrungswiss.

    (1998)
  • H.M. Awad et al.

    The regioselectivity of glutathione adduct formation with flavonoid quinone/quinone methides is pH-dependent

    Chem. Res. Toxicol.

    (2002)
  • J. Jurado et al.

    Study on the mutagenic activity of 13 bioflavonoids with the Salmonella Ara test

    Mutagenesis

    (1991)
  • J. Rueff et al.

    Structural requirements for mutagenicity of flavonoids upon nitrosation. A structure-activity study

    Mutagenesis

    (1995)
  • I.D. Silva et al.

    Chemical features offlavonols affecting their genotoxicity. Potential implications in their use as therapeutical agents

    Chem. Biol. Interact.

    (2000)
  • Cited by (588)

    • The significance of caloric restriction mimetics as anti-aging drugs

      2024, Biochemical and Biophysical Research Communications
    View all citing articles on Scopus
    View full text