Review
Quercetin: A flavonol with multifaceted therapeutic applications?
Graphical abstract
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.
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