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Bioavailability of Quercetin

October 2016
Current Research in Nutrition and Food Science Journal 4(Special-Issue-October):146-151

DOI:10.12944/CRNFSJ.4.Special-Issue-October.20

Authors:

Müzeyyen Berkel Kaşıkçı

Manisa Celal Bayar University

Neriman Bağdatlıoğlu

Manisa Celal Bayar University

Quercetin is generally present as quercetin glycoside in nature and involves quercetin aglycone conjugated to sugar moieties such as glucose or rutinose. Quercetin has been reported to exhibit antioxidative, anti-carcinogenic, anti-inflammatory, anti-aggregatory and vasodilating effects. Unfortunately, quercetin bioavailability is generally poor and several factors affect its bioavailability. Quercetin bioavailability varies widely between individuals. Gender may affect quercetin bioavailability, but there is no clear evidence. There has been little research looking for the effects of age and vitamin C status on bioavailability of quercetin supplements, but there is no research seeking out the effects of age and vitamin C status on bioavailability of food-derived quercetin. Presence of sugar moieties increases bioavailability and differences in quercetin-conjugated glycosides affect bioavailability. For instance, onion-derived quercetin, which is mainly quercetin glucoside, is more bioavailable than apple-derived quercetin, which contains quercetin rhamnoside and quercetin galactoside. Quercetin is lipophilic compound, thus dietary fat enhances its bioavailability. Nondigestible fiber may also improve quercetin bioavailability. Quercetin bioavailability is greater when it is consumed as an integral food component. This study reviews and discusses factors affecting quercetin bioavailability. Keywords: quercetin, bioavailability, sugar moiety, solubility, flavonoid, flavonol.

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1st International Multidisciplinary Conference on Nutraceuticals and Functional Foods

Current Research in Nutrition and Food Science Vol. 4(SI. 2), 146-151 (2016)

Bioavailability of Quercetin

MUZEYYEN BERKEL KASIKCI* and NERIMAN BAGDATLIOGLU

Department of Food Engineering, Faculty of Engineering,

Manisa Celal Bayar University, Manisa, Turkey.

*Corresponding author Email: muzeyyen.berkel@cbu.edu.tr

http://dx.doi.org/10.12944/CRNFSJ.4.Special-Issue-October.20

(Received: August, 2016; Accepted: September, 2016)

ABSTRACT

Quercetin is generally present as quercetin glycoside in nature and involves quercetin

aglycone conjugated to sugar moieties such as glucose or rutinose. Quercetin has been reported to

exhibit antioxidative, anti-carcinogenic, anti-inﬂammatory, anti-aggregatory and vasodilating effects.

Unfortunately, quercetin bioavailability is generally poor and several factors affect its bioavailability.

Quercetin bioavailability varies widely between individuals. Gender may affect quercetin bioavailability,

but there is no clear evidence. There has been little research looking for the effects of age and vitamin

C status on bioavailability of quercetin supplements, but there is no research seeking out the effects

of age and vitamin C status on bioavailability of food-derived quercetin. Presence of sugar moieties

increases bioavailability and differences in quercetin-conjugated glycosides affect bioavailability. For

instance, onion-derived quercetin, which is mainly quercetin glucoside, is more bioavailable than

apple-derived quercetin, which contains quercetin rhamnoside and quercetin galactoside. Quercetin is

lipophilic compound, thus dietary fat enhances its bioavailability. Nondigestible ﬁber may also improve

quercetin bioavailability. Quercetin bioavailability is greater when it is consumed as an integral food

component. This study reviews and discusses factors affecting quercetin bioavailability.

Keywords: quercetin, bioavailability, sugar moiety, solubility, ﬂavonoid, ﬂavonol.

INTRODUCTION

Quercetin is a dietary ﬂavonol found widely

in fruits, vegetables and nuts in many different

glycosidic forms. Major dietary sources are lettuce,

chili pepper, cranberry, onion, black chokeberry,

black elderberry, caper, tomato, broccoli and apple

(Rothwell et al., 2013). In onions, quercetin is bound

to 1 or 2 glucose molecules (quercetin-4´-glucoside

and quercetin-3,4´-glucoside). Examples of dietary

quercetin are quercetin galactosides, which are

found in apples, quercetin arabinosides, which are

present in berries, quercetin-3-rutinoside (rutin),

which are found in capers (Erlund, 2004).

Quercetin has been reported to exhibit

antioxidative, anti-carcinogenic, anti-inﬂammatory,

anti-microbial, anti-viral, antiaging,anti-thrombotic,

anti-aggregatory and vasodilating effects (Hayek et

al., 1997; Chopra et al., 2000; Verma et al., 1988;

Deschner et al., 1991; Pereira et al., 1996, Ferry et

al., 1996; Erlund et al., 2004). Although quercetin has

lots of health beneﬁts, its bioavailability is relatively

poor and highly variable. This study compiles and

discusses bioavailability studies of food-derived

quercetin and quercetin in supplements.

Bioavailability of quercetin

Bioavailability is the fraction of an orally

administered substance that is absorbed and

available for physiologic activity or storage (Jackson

et al., 1997). Bioavailability is classiﬁed as absolute or

relative based on its pharmacokinetics assessment

(Toutain et al., 2004). Absolute bioavailability is

more accurate, and is calculated as the area under

the plasma concentration-time curve of an ingested

substance (AUCoral) relative to its intravenous

administration (AUCi.v) (Levine et al., 1996).

147 KASIKCI & BAGDATLIOGLU et al., Curr. Res. Nutr Food Sci Jour., Vol. 4(SI. 2), 146-151 (2016)

Alternatively, relative bioavailability is simpler, but

less accurate, and is calculated as AUCoral. However,

studies examining relative bioavailability of quercetin

are more common (Guo et al., 2015).

In contrast to the form in most supplements,

most of the quercetin in foods is attached to a

sugar molecule and this conjugate is known as a

glycoside. The onion plant tends to attach glucose

to form quercetin-3-glucoside (isoquercetin) while

apple trees and tea plants tend to attach rutinose,

yielding rutin (Heim et al.,2002; Yoo et al., 2010).

Differences in quercetin-conjugated glycosides

affect its bioavailability (Lee et al., 2012; Hollman

et al., 1997a; Hollmann et al., 1997b). The size and

polarities of these compounds can cause difﬁculty

crossing membranes in the gut. Oppositely, this is

not the case for isoquercetin. A clinical research

compared quercetin bioavailability from different

foods and supplements (Hollman et al., 1997a;

Hollman et al., 1997b). Absorption from isoquercetin-

rich onions was 52%, compared to 24% from a

standard quercetin supplement (Hollman et al.,

1997b). Likewise, animal studies showed superior

bioavailability of isoquercetin relative to quercetin

and rutin (Manach et al., 1997). Likewise, in another

study, bioavailability of onion-derived quercetin,

which is mainly quercetin glucoside, compared to

apple-derived quercetin, which contains quercetin

rhamnoside and quercetin galactoside (Yoo et al.,

2010; Lee et al., 2012). In this study, AUC0-24h and

Cmax of quercetin following the consumption of onions

were 2 and 3 times greater, respectively, than those

following the consumption of apples (Lee et al.,

2012). Quercetin Tmax did not differ between dietary

sources, but t1/2 of apple-derived quercetin was more

than 4 times shorter after consuming onions (15 h).

These ﬁndings support that onion-derived quercetin

is more bioavailable due to its greater absorption

(Lee et al., 2012).

Studies in pigs showed that quercetin

glucoside, compared to quercetin aglycone, had

greater bioavailability. Some hypothesis may clarify

this phenomenon. First of all, quercetin glucoside

(0.76±0.01) is more water soluble than quercetin

aglycone (1.82±0.32) on the basis of its lower

octanol-water partition coefﬁcient (Rothwell et al.,

2005). Another hypothesis is quercetin glucoside

is absorbed through sodium-dependent glucose

transporter 1 (SLGT1), but it is not in use for

quercetin aglycone (Wolffram et al., 2002). SGLT1-

mediated absorption provides greater intestinal

uptake of quercetin glucoside (Guo et al., 2015).

The site and manner in which quercetin absorbed

depends upon its chemical structure (Guo et

al., 2015). In vitro studies put a hypothesis that

the glucose moiety was using a transporter that

normally pumps glucose across membranes of the

intestinal wall (Gee et al., 2000). The rapid absorption

observed with isoquercetin is consistent with this

active transport. For quercetin and rutin, which

cannot use the transporter, peak levels are riched

within 2-4 and 6-8 hours respectively (Olthof et al.,

2000; Erlund et al., 2000). Inversely, isoquercetin

can reach peak concentrations in less than 40

minutes (Olthof et al., 2000). Mechanisms explaining

gastric absorption of quercetin aglycone is unclear,

but studies in Caco-2 cell monolayers support that

intestinal absorption of quercetin aglycone occurs

primarily by passive diffusion and secondarily by

organic anion transporting polypeptide (OATP)

(Nait et al., 2009). Contrasting quercetin aglycone,

glycosylated forms of quercetin (quercetin glucoside,

quercetin rutinoside) are not absorbed in the

stomach (Crespy et al., 2002). Quercetin glycosides

such as quercetin glucoside, quercetin galactoside,

quercetin arabinoside, are deglycosylated to

quercetin aglycone prior to absorption by lactase

phlorizin hydrolase (LPH), a â-glucosidase residing

at the brush border (Arts et al., 2004; Nemath

et al., 2003). Afterwards, quercetin aglycone is

passively absorbed (Day, A. J., 2003). Different

from those, quercetin rutinoside is absorbed in the

colon following deglycosylation, which appears to be

mediated by gut microbiota-derived â-glucosidase

that generates quercetin aglycone and facilitates its

colonic absorption (Day, A.J., 2003; Jaganath, I. B.,

2006, Kim, D.H., 2008).

The extent to which quercetin is absorbed

in clinical studies can be estimated by multiplying the

plasma maximum concentration (Cmax) of quercetin

by plasma volume (estimated at 3 L for adults) and

dividing by the administered dose (Davy et al.,

1994; Retzlaff, J. A., 1969; Guo et al.,2015). Healthy

participants ingesting grape juice containing 10

mg quercetin aglycone had a quercetin Cmax of 16

µM, which represents approximately 1.4% of the

ingested dose (Golderg et al., 2003). Quercetin

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glucoside is also poorly absorbed as evidenced by

an estimated absorption of 6.9 in healthy participants

who ingested onion-derived quercetin glucoside at a

dose corresponding to 100 mg quercetin aglycone

(Graefe et al., 2001).

Bioavailability of quercetin is related to its

bioaccessibility and thereby solubility in the vehicle

used for its administration. Quercetin is relatively

lipophilic with low water solubility. The poor solubility

of quercetin and crstalline form at body temperatures

limitnits bioaccessibility and its bioavailability.

Absolute bioavailability of quercetin was 16% in rats

and its Cmax was 2.01 µM following administration

of quercetin suspended in aqueous solution.

Administration of quercetin aglycone dissolved in

an ethanol and PEG 200 solution increased its

absolute bioavailability to 27.5% and Cmax to 3.44

µM(Khaled et al., 2003; Pool et al., 2013). Octanol-

water partition coefﬁcient of quercetin (1.82±0.32)

is nearly double that of quercetin-3-glucoside

(0.76±0.01), but it is lower than that of kaempferol

(3.11±0.54). Water solubility of quercetin is 1.53-12.5

mg/L at gastrointestinal pH levels (pH 2-7) (Pool et

al., 2013).

Poor bioavailability of quercetin aglycone

and glycosides is also related to their propensity,

and that of their metabolites, to be efﬂuxed back

into the intestinal lumen following enterocyte uptake

(Crespy et al., 1999; Crespy et al., 2001). Quercetin

aglycone or glycosides are efﬂuxed across the apical

membrane of enterocytes, as indicated in Caco-2 cell

monolayer studies showing that their permeability

from the basolateral to apical side was more than

2 times greater than their apical to basolateral

permeability (Nait et al., 2009; Walgren et al., 1998).

Most of the absorbed quercetin aglycone is rapidly

metabolized and secreted back into the intestinal

lumen (Crespy et al., 2001).

Quercetin bioavailability is better when

quercetin is consumed as a cereal bar ingredient

instead of capsule (Egert et al., 2012). Its greater

absorption may be related with manufacturing

process that yields a homogenous solid dispersion

of quercetin with other cereal ingredients. Solid

dispersions have greater surface area that promotes

dissolution in the intestinal lumen, thereby promoting

bioavailability (Guo et al., 2015). Dietary fat improved

quercetin bioavailability in a study with pigs (Lesser

et al., 2004). Quercetin ingestion with short chain

fructooligosaccharide (FOS) improves quercetin

bioavailability (Matsukawa et al., 2009). Quercetin

bioavailability of vacuum impregnated apple chips

(AUC0-1440 min = 104±24 µmol.min.L-1) as functional

food was similar to the supplementation with apple

peel extract capsules (AUC0-1440 min = 87±24 µmol.

min.L-1) in humans (Petersen et al., 2016). More

research are needed to prove that quercetin in food

matrix provides greater bioavailability than capsule

forms.

Quercetin bioavailability is characterized

by high intersubject variability (Kaushik et al.,

2012). For instance, quercetin AUC0-24 h was 8.9-

89.1 µM.h following ingestion of onion-derived

quercetin glucosides at a dose equivalent to 100 mg

quercetin aglycone (Graefe et al., 2001). Quercetin

Cmax was 0.29-2.26 µM in adults who ingested a

beverage containing 500 mg quercetin aglycone

(Kaushik et al., 2002). Intersubject variations

for time to Cmax (Tmax) and elimination half-life

(t1/2) of quercetin in adults were 69% and 122%

respectively, following ingestion of 100 mg apple-

derived quercetin glycosides (Lee et al., 2012).

Likewise, 50 mg quercetin supplementation in adults

results in highly variable plasma concentrations

(38-194 nM) (Egert et al., 2008). Differences in

â-glucosidase activity, a determinant of intestinal

uptake of quercetin glucosides, promote intersubject

variation in quercetin glycoside absorption (Nemeth

et al., 2003; Day et al., 2003; Guo et al., 2015).

Additionally, intersubject variations in intestinal and

hepatic phase II quercetin –metabolizing enzymes

(UGT, speciﬁcally UGT1A family; SULT, speciﬁally

SULT1A family; COMT) are speculated to contribute

to interindividual differences in quercetin metabolism

(Egert et al., 2008).

There is no clear evidence demonstrating

that gender and age affect quercetin bioavailability

(Guo et al., 2015). Exceptional ﬁnding was that

quercetin from quercetin-3-rutinoside was more

bioavailable in women compared with men (Erlund

et al., 2000). A quercetin study in humans suggest

that individual differences in plasma vitamin C

status may contribute to intersubject variability in

quercetin bioavailability (Guo et al., 2014). Some

in vitro studies also showed that vitamin C protects

149 KASIKCI & BAGDATLIOGLU et al., Curr. Res. Nutr Food Sci Jour., Vol. 4(SI. 2), 146-151 (2016)

quercetin against oxidative degredation (Skaper

et al., 1997; Takahama et al., 2003). More clinical

studies are necessary to deﬁne if vitamin C status

regulates quercetin bioavailability.

In conclusion, quercetin has several

health effects and thereby, its bioavailability is

really signiﬁcant and unfortunately, is poor. Many

factors such as glucose moieties, solubility, human

factor, vitamin C status and food matrix can affect

bioavailability. More research is warranted to

evaluate and improve bioavailability of quercetin.

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Challenging directions in pediatric diabetes - the place of oxidative stress and antioxidants in systemic decline

Article

Full-text available

Dec 2024

Diabetes is a complex condition with a rising global incidence, and its impact is equally evident in pediatric practice. Regardless of whether we are dealing with type 1 or type 2 diabetes, the development of complications following the onset of the disease is inevitable. Consequently, contemporary medicine must concentrate on understanding the pathophysiological mechanisms driving systemic decline and on finding ways to address them. We are particularly interested in the effects of oxidative stress on target cells and organs, such as pancreatic islets, the retina, kidneys, and the neurological or cardiovascular systems. Our goal is to explore, using the latest data from international scientific databases, the relationship between oxidative stress and the development or persistence of systemic damage associated with diabetes in children. Additionally, we highlight the beneficial roles of antioxidants such as vitamins, minerals, polyphenols, and other bioactive molecules; in mitigating the pathogenic cascade, detailing how they intervene and their bioactive properties. As a result, our study provides a comprehensive exploration of the key aspects of the oxidative stress-antioxidants-pediatric diabetes triad, expanding understanding of their significance in various systemic diseases.

Antioxidant and Antiaging Activity of Houttuynia cordata Thunb. Ethyl Acetate Fraction in Caenorhabditis elegans

Article

Full-text available

Nov 2024

Background/Objectives: In aerobic organisms, such as humans, oxygen radicals are inevitably produced. To counteract oxidation, the body generates antioxidant substances that suppress free radicals. However, levels of reactive oxygen species (ROS) increase due to aging and lifestyle factors, leading to exposure to various diseases. While synthetic antioxidants offer advantages like high stability, low cost, and availability, their safety remains controversial. This study aimed to investigate the antioxidant and antiaging activities of Houttuynia cordata (HC), which is rich in flavonoids and has excellent antioxidant properties, using Caenorhabditis elegans as a model. Methods: Extraction and fractionation of HC were performed to evaluate antioxidant activities (DPPH, ABTS, superoxide radical scavenging activity) and antiaging effects (lifespan). The ethyl acetate fraction (EAF) with the highest activity was selected for further investigation. Results: The EAF of HC exhibited high levels of polyphenols and flavonoids, presenting the highest DPPH, ABTS, and superoxide radical scavenging activities. This fraction increased the activity of antioxidant enzymes in nematodes in a concentration-dependent manner and provided resistance to oxidative stress, reducing ROS accumulation. Additionally, the fraction enhanced the lifespan of nematodes, improved resistance to heat stress, increased survival rates, and decreased the accumulation of aging pigments (lipofuscin). The expression of daf-2, daf-16, and sir-2.1, proteins directly involved in nematode aging, was confirmed. Liquid chromatography/tandem mass spectrometry identified quercitrin in the HC extract, which may contribute to its antioxidant and antiaging effects. Conclusions: The EAF of HC demonstrates significant potential for influencing antioxidant and antiaging, as evidenced by functional investigations using C. elegans.

Exploring the mechanistic pathways of promising bioflavonoid Quercetin in diabetes management

Article

Full-text available

Aug 2024

Quercetin, a secondary metabolite and bioflavonoid, has been explored in recent times for its anti-diabetic potential owing to its wide pharmacological benefits, including antioxidant, anti-inflammatory, anti-allergic, cardiovascular protection, anti-lipidemic, and anti-arthritic properties. The presence of five hydroxyl groups contribute to its therapeutic properties by lowering blood glucose levels, increasing insulin production, improving pancreatic beta cells, and increasing glucose tolerance. Due to its antidiabetic efficacy in clinical studies, similar to other marketed drugs, studies have been conducted on the co-administration of quercetin with metformin, liraglutide, and resveratrol producing marked changes in serum glucose levels synergistically. Furthermore, they have the potential to combat adverse effects such as hypoglycaemia and hypolipidemia caused by other antidiabetic drugs. The mechanistic pathway by which quercetin causes reduced glucose levels is not clearly understood and, in this review, we discuss in detail the predictive pathways by which quercetin executes its anti-oxidant and anti-diabetic efficacy.

New Insights into the Development of Donepezil-Based Hybrid and Natural Molecules as Multi-Target Drug Agents for Alzheimer’s Disease Treatment

Article

Full-text available

Nov 2024
MOLECULES

Alzheimer’s disease (AD) involves a complex pathophysiology with multiple interconnected subpathologies, including protein aggregation, impaired neurotransmission, oxidative stress, and microglia-mediated neuroinflammation. Current treatments, which generally target a single subpathology, have failed to modify the disease’s progression, providing only temporary symptom relief. Multi-target drugs (MTDs) address several subpathologies, including impaired aggregation of pathological proteins. In this review, we cover hybrid molecules published between 2014 and 2024. We offer an overview of the strategies employed in drug design and approaches that have led to notable improvements and reduced hepatotoxicity. Our aim is to offer insights into the potential development of new Alzheimer’s disease drugs. This overview highlights the potential of multi-target drugs featuring heterocycles with N-benzylpiperidine fragments and natural compounds in improving Alzheimer’s disease treatment.

The Effect of Quercetin on the Prevention and Treatment of Gynecologic Cancer

Article

Full-text available

Sep 2024
CLIN EXP OBSTET GYN

Objective This review summarizes the molecular properties, anticancer effects, and bioavailability of quercetin (Que). We discussed its role in preventing and treating gynecologic cancers, assisting in the treatment of drug-resistant cases, and synergizing with other treatments. This review includes an analysis of Que’s impact on breast, ovarian, and cervical cancer. Mechanism Gynecologic cancers are a significant cause of cancer-related deaths, leading to low survival rates and a high burden on patients and healthcare systems. They are regarded as a major health problem in women. The use of complementary therapies, such as Que, can contribute to improving patient outcomes and the quality of life. The utilization of medicinal plants as complementary and alternative medicine (CAM) is on the rise worldwide, offering new approaches to cancer treatment. This approach may provide potential treatments for various cancers, including female cancers such as breast, ovarian, and cervical cancer, either alone or in combination with other medications. Findings in Brief Among various natural compounds, Que is commonly used as an anti-cancer supplement due to its antioxidant and anti-inflammatory properties. Que is effective in preventing and treating female cancers in a dose- and time-dependent manner, as demonstrated by numerous in vitro and in vivo studies and experiments. However, more clinical studies are required to establish this flavonoid as a therapeutic agent or as part of a drug combination in humans. Conclusions Que helps prevent and treat gynecological cancers, reduce drug resistance, and increase the effectiveness of chemical drugs and radiotherapy. It achieves this through its anti-inflammatory, pro-oxidative, anti-proliferative, induction of apoptosis, and cell cycle arrest mechanisms. However, more human studies are needed to accurately determine of the mechanisms of action and the extent of its effectiveness.

Potential Application of Plant-Derived Compounds in Multiple Sclerosis Management

Article

Full-text available

Sep 2024

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by inflammation, demyelination, and neurodegeneration, resulting in significant disability and reduced quality of life. Current therapeutic strategies primarily target immune dysregulation, but limitations in efficacy and tolerability highlight the need for alternative treatments. Plant-derived compounds, including alkaloids, phenylpropanoids, and terpenoids, have demonstrated anti-inflammatory effects in both preclinical and clinical studies. By modulating immune responses and promoting neuroregeneration, these compounds offer potential as novel adjunctive therapies for MS. This review provides insights into the molecular and cellular basis of MS pathogenesis, emphasizing the role of inflammation in disease progression. It critically evaluates emerging evidence supporting the use of plant-derived compounds to attenuate inflammation and MS symptomology. In addition, we provide a comprehensive source of information detailing the known mechanisms of action and assessing the clinical potential of plant-derived compounds in the context of MS pathogenesis, with a focus on their anti-inflammatory and neuroprotective properties.

Biological Evaluation of 2-(3,4-dihydroxyphenyl)-4-((4-methoxyphenyl)imino)-4H-chromene-3,5,7-triol: Design, Synthesis, and Molecular Docking Studies

Article

Dec 2024

Quercetin-based biomaterials for enhanced bone regeneration and tissue engineering

Article

Nov 2024

Sensory Property and Phenolic Profile of Aronia Juice

Chapter

Nov 2024

Formulation development of thermoresponsive quercetin nanoemulgels and in vitro investigation of their inhibitory activity on vascular endothelial growth factor-A inducing neovascularization from the retinal pigment epithelial cells

Article

Full-text available

Jul 2024
J DRUG DELIV SCI TEC

Quercetin is one of natural flavonoids. It has ability to hinder neovascularization in cancers by reducing activities of the vascular endothelial growth factor-A (VEGF-A). Regarding this particular activity, quercetin thus has a potential for managing the vasoproliferative retinopathies. Unfortunately, its hydrophobicity resulted in poor ocular bioavailability. A suitable intravitreal formulation should be developed to overcome this problem. This study was conducted to optimize formulations of thermoresponsive quercetin nanoemulgels (T-QNE-Gs) for intravitreal injection and to examine their in vitro for their inhibitory activity on VEGF-A inducing neovascularization from the retinal pigment endothelial cells. T-QNE-Gs were prepared by incorporation of gels consisting of various ratios of Pluronic F127 (F127) to Pluronic F68 (F68), with a fixed concentration of hydroxypropyl methylcellulose, into a quercetin nanoemulsion concentrate. The optimum formulation of T-QNE-Gs was 2F127–1F68 containing F127 and F68 at a 2:1 ratio. After sterilization, S–2F127–1F68 was obtained. The S–2F127–1F68 could flow properly at a room temperature (27 ± 1 °C) and became gel at a temperature of the posterior eye segment (35 ± 1 °C). It effectively inhibited migration and tube formation of the human umbilical vein endothelial cells and suppressed the VEGF-A gene expression and VEGF-A protein levels in the arising retinal pigment epithelial cells under a hypoxic condition. Therefore, S–2F127–1F68 had a potential for treatment of the vassoproliferative retinopathies and can be used for further investigation in animal models.

Phenol-Explorer 3.0: A major update of the Phenol-Explorer database to incorporate data on the effects of food processing on polyphenol content

Article

Full-text available

Jan 2013

Polyphenols are a major class of bioactive phytochemicals whose consumption may play a role in the prevention of a number of chronic diseases such as cardiovascular diseases, type II diabetes and cancers. Phenol-Explorer, launched in 2009, is the only freely available web-based database on the content of polyphenols in food and their in vivo metabolism and pharmacokinetics. Here we report the third release of the database (Phenol-Explorer 3.0), which adds data on the effects of food processing on polyphenol contents in foods. Data on >100 foods, covering 161 polyphenols or groups of polyphenols before and after processing, were collected from 129 peer-reviewed publications and entered into new tables linked to the existing relational design. The effect of processing on polyphenol content is expressed in the form of retention factor coefficients, or the proportion of a given polyphenol retained after processing, adjusted for change in water content. The result is the first database on the effects of food processing on polyphenol content and, following the model initially defined for Phenol-Explorer, all data may be traced back to original sources. The new update will allow polyphenol scientists to more accurately estimate polyphenol exposure from dietary surveys. Database URL: http://www.phenol-explorer.eu

Enriched cereal bars are moreeffective in increasing plasma quercetin compared withquercetin from powder-filled hard capsules

Article

Jan 2011
BRIT J NUTR

Bioavailability of quercetin in humans and the influence of food matrix comparing quercetin capsules and different apple sources

Article

Feb 2016
FOOD RES INT

The objective of the four-way cross-over pilot study was the investigation of quercetin bioavailability after ingestion of apple quercetin incorporated in different matrices and quercetin dihydrate capsule. Six healthy volunteers were given a standard diet supplemented with 71 μmol quercetin equivalents from vacuum impregnated apple chips, apple peel extract capsules and apple peel. Quercetin dihydrate capsules were used as control. The vacuum impregnated apple chips were enriched with a quercetin rich apple peel extract. The ingestion of vacuum impregnated apple chips, apple peel extract capsules and apple peel resulted in similar plasma quercetin and plasma total flavonol concentrations compared to the quercetin dihydrate capsule. With regard to the bioavailabilities of all quercetin treatments, a reduced release from vacuum impregnated apple chips can be excluded. The apple peel matrix which is rich in indigestible dietary fibers impacted the profile of the plasma flavonol time curve similar to poor soluble quercetin dihydrate. Finally, the quercetin bioavailability of vacuum impregnated apple chips (AUC0-1440 min: 104 ± 24 μmol ∙ min ∙ L-1) as functional food was similar to the supplementation with apple peel extract capsules (AUC0-1440 min: 87 ± 27 μmol ∙ min ∙ L-1).

Endogenous and exogenous mediators of quercetin bioavailability

Article

Nov 2014
J NUTR BIOCHEM

Quercetin is a dietary flavonol that has poor and highly variable bioavailability. Epidemiological studies suggest that higher dietary intakes of quercetin decease cardiovascular disease (CVD) risk. However, experimental findings examining its cardioprotective activities are inconsistent, thereby precluding a full understanding of its health benefits. Bioavailability of dietary constituents is a critical mediator of their health benefits. Thus, a better understanding of the factors regulating quercetin bioavailability is expected to support its potential role in managing CVD risk. This review provides an update on the evidence describing endogenous and exogenous factors responsible for the limited and highly variable bioavailability of quercetin. It focuses on pharmacokinetics studies in clinical and animal models, while also describing strategies aimed at improving quercetin bioavailability to better realize its cardioprotective activities in vivo that are routinely observed in vitro. Although significant advances have been made in understanding determinants of quercetin bioavailability, additional research in controlled trials is needed to more comprehensively examine dose–response effects, whether its cardioprotective activities improve in response to its greater bioavailability, and if the putative health benefits of quercetin are mediated directly or indirectly from one or more of its metabolites generated during xenobiotic metabolism.

Quercetin Bioavailability Is Associated With Inadequate Plasma Vitamin C Status And Greater Plasma Endotoxin In Adults1,2

Article

Nov 2014
NUTRITION

Objective Quercetin bioavailability exhibits high inter-individual variations for reasons that remain unclear. We conducted a 24 h pharmacokinetic study to investigate whether individual differences in circulating antioxidants, oxidative stress and inflammation, and intestinal permeability affect quercetin bioavailability. Methods Healthy adults (n = 9M/7F; 34.3 ± 4.5 y; 27.0 ± 1.7 kg/m2) ingested 1095 mg quercetin aglycone with a standardized meal. Plasma antioxidants, biomarkers of oxidative stress and inflammation, and endotoxin were measured at baseline (0 h), and quercetin and its methylated metabolites isorhamnetin and tamarixetin were measured at timed intervals for 24 h. Results Plasma pharmacokinetics of quercetin, isorhamnetin and tamarixetin were highly variable between participants (CVinter = 37-96%). Plasma vitamin C concentrations (34.6 ± 2.5 μmol/L), but no other antioxidants, were inversely correlated to the Cmax and AUC0-24 h of total quercetin (Qtotal; sum of quercetin, isorhamnetin and tamarixetin; r = -0.52 to -0.53; P<0.05). Plasma endotoxin (0.13 ± 0.01 EU/mL), a surrogate marker of intestinal permeability, was correlated to Qtotal Cmax (r = 0.45; P<0.05) and tended to be correlated to Qtotal AUC0-24 h (r = 0.38; P = 0.07). Additionally, vitamin C was inversely related to C-reactive protein, myeloperoxidase, and endotoxin (r = -0.46 to -0.55; P<0.05), whereas endotoxin was positively correlated to C-reactive protein (r = 0.73; P<0.05). Conclusion These findings suggest that vitamin C status and plasma endotoxin may be associated with inter-individual variations in quercetin bioavailability. Greater quercetin absorption and bioavailability may be associated with poor vitamin C status and increased intestinal permeability in healthy adults.

Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivties, bioavailability, and epidemiology

Article

Oct 2004
NUTR RES

Iris Erlund

The bioactivities, dietary sources, bioavailability, metabolism, and epidemiology of 3 flavonoids, quercetin, hesperetin, and naringenin, are reviewed. The use of their plasma concentrations as biomarkers of dietary intake is also discussed. The compounds were chosen because of their significant dietary intakes and promising bioactivities, and in the case of quercetin, because epidemiological studies suggest protection against cardiovascular disease.

Encapsulation and release of hydrophobic bioactive components in nanoemulsion-based delivery systems: Impact of physical form on quercetin bioaccessibility

Article

Nov 2012

Many bioactive compounds are hydrophobic materials that are crystalline at ambient and body temperatures, which reduces their bioavailability and poses challenges to their successful incorporation into pharmaceuticals and functional foods. The aim of this study was to determine whether a hydrophobic crystalline bioactive component (quercetin) could be successfully incorporated into nanoemulsion-based delivery systems, and to evaluate the extent to which these delivery systems altered its bioaccessibility. The maximum amount of soluble quercetin that could be loaded into a carrier oil phase (medium chain triglycerides, MCT) at ambient temperature was C(Sat) ≈ 0.15 mg mL(-1). At quercetin concentrations <C(Sat), nanoemulsions remained stable throughout 30 days storage at 5, 20 and 37 °C, i.e., no droplet growth, droplet creaming, or crystal formation were observed. At quercetin concentrations >C(Sat), nanoemulsions remained physically stable (no droplet growth or creaming), but quercetin crystals formed in the samples during storage. The bioaccessibility of quercetin was determined using an in vitro digestion model simulating the mouth, stomach, and small intestine. A higher percentage of quercetin was solubilized in the micelle phase after small intestine digestion when it was incorporated in nanoemulsions than when it was dispersed in either bulk oil or pure water. The bioaccessibility of crystalline quercetin was less than that of dissolved quercetin. The knowledge gained from this study is valuable for the rational design of delivery systems to incorporate crystalline hydrophobic bioactive compounds into pharmaceuticals and functional foods, and to increase their bioaccessibility.

Comparison of Quercetin Pharmacokinetics Following Oral Supplementation in Humans

Article

Oct 2012
J FOOD SCI

Unlabelled: The objective of the study was to investigate the absorption of quercetin aglycone in 18 healthy human subjects administered via the following oral carrier systems: suspension of quercetin (quercetin QU995 powder in Tang(®) and spring water), nutritional bars (First Strike™), and chews (RealFX™ Q-Plus™). Subjects were divided into 3 groups of 6 individuals each receiving 500 mg quercetin in one of the aforementioned formulations. Blood levels were monitored immediately pre- and for 32 h postadministration. The concentration of total quercetin in blood samples was determined by solid phase extraction followed by high-performance liquid chromatography analysis. Pharmacokinetic parameters were determined by noncompartmental modeling using Kinetica software. The C(max) of quercetin was highest with RealFX™ Q-Plus™ Chews (1051.9 ± 393.1 μg/L) achieved within 3.3 h as compared to that for First Strike™ Bars (698.1 ± 189.5 μg/L in 2.3 h) and Tang(®) suspension (354.4 ± 87.6 μg/L in 4.7 h). The results showed no statistically significant difference in quercetin absorption among groups due to high variability within groups receiving quercetin from same dosage form. This study represents the first comprehensive evaluation of quercetin absorption from quercetin fortified oral food products at doses commonly used for quercetin supplementation. Practical application: The current study describes for the first time, comprehensive evaluation of quercetin PK in humans from quercetin fortified oral food products at doses commonly used for quercetin supplementation. Owing to quercetin's potent antioxidant and anti-inflammatory actions, quercetin is widely being used as a nutritional supplement. In order to maximize the bioavailability of quercetin for its use in efficacy studies, it is important to determine its ideal oral carrier system and route for its delivery. The current research unveils vital information about quercetin supplementation to the international community, especially to soldiers, athletes, and the dietary supplement industry.

Quercetin Protects Cutaneous Tissue-Associated Cell Types Including Sensory Neurons From Oxidative Stress Induced By Glutathione Depletion: Cooperative Effects of Ascorbic Acid

Article

Feb 1997
FREE RADICAL BIO MED

Oxidation reactions are essential biological reactions necessary for the formation of high-energy compounds used to fuel metabolic processes, but can be injurious to cells when produced in excess. Cutaneous tissue is especially susceptible to damage mediated by reactive oxygen species and low-density lipoprotein oxidation, triggered by dysmetabolic diseases, inflammation, environmental factors, or aging. Here we have examined the ability of the flavonoid quercetin to protect cutaneous tissue-associated cell types from injury induced by oxidative stress, and possible cooperative effects of ascorbic acid. Human skin fibroblasts, keratinocytes, and endothelial cells were cultured in the presence of buthionine sulfoximine (BSO), an irreversible inhibitor of glutathione (GSH) synthesis. Depletion of intracellular levels of GSH leads to an accumulation of cellular peroxides and eventual cell death. Quercetin concentration-dependently (EC50: 30–40 μM) reduced oxidative injury of BSO to all cell types, and was also effective when first added after BSO washout. BSO caused marked decreases in the intracellular level of GSH, which remained depressed in quercetin-protected cells. Ascorbic acid, while by itself not cytoprotective synergized with quercetin, lowered the quercetin EC50 and prolonged the window for cytoprotection. The related flavonoids rutin and dihydroquercetin also decreased BSO-induced injury to dermal fibroblasts, albeit less efficaciously so than quercetin. The cytoprotective effect of rutin, but not that of dihydroquercetin, was enhanced in the presence of ascorbic acid. Further, quercetin rescued sensory ganglion neurons from death provoked by GSH depletion. Direct oxidative injury to this last cell type has not been previously demonstrated. The results show that flavonoids are broadly protective for cutaneous tissue-type cell populations subjected to a chronic intracellular form of oxidative stress. Quercetin in particular, paired with ascorbic acid, may be of therapeutic benefit in protecting neurovasculature structures in skin from oxidative damage. Copyright © 1997 Elsevier Science Inc.

Pharmacokinetics of Quercetin Absorption from Apples and Onions in Healthy Humans

Article

Mar 2012
J AGR FOOD CHEM

A high-throughput method for the extraction and analysis of quercetin in human plasma using 96-well SPE and LC-(ESI)MS/MS (7 min/run) is described. Quercetin exists as a range of glycosides in foods. The dominant types of quercetin glycosides vary depending on genetics (i.e., species and cultivar). Dietary sources include onions and apples (i.e., the peel). Herein the quercetin glycoside composition was determined in a composite standard of dried apple peel and in onion powder. The predominant forms of quercetin in apple peel include quercetin O-arabinoside, 3-O-galactoside, 3-O-glucoside, and 3-O-rhamnoside. In the onion powder, quercetin occurred as the quercetin 3,4'-O-glucoside and 4'-O-glucoside. Pharmacokinetics relating to absorption (C(max), t(max), and AUC(0-24 h)) and elimination (k(el) and t(1/2)) were compared after the consumption of apple peel powder (AP), onion powder (OP), or a mixture of the apple peel and onion powder enriched applesauce (MP) by healthy volunteers (eight females and eight males). The enriched applesauce delivered ∼100 mg of quercetin aglycone equivalents. Consumption of the OP resulted in C(max) = 273.2 ± 93.7 ng/mL, t(max) = 2.0 ± 1.7 h, and t(1/2) = 14.8 ± 4.8 h, whereas the AP resulted in C(max) = 63.8 ± 22.4 ng/mL, t(max) = 2.9 ± 2.0 h, and t(1/2) = 65.4 ± 80.0 h. The MP resulted in an intermediate response with C(max) = 136.5 ± 45.8 ng/mL, t(max) = 2.4 ± 1.5 h, and t(1/2) = 18.7 ± 6.8 h. Consumption of the OP led to faster absorption, higher concentration, and greater bioavailability as compared to the AP. No significant gender-related differences were observed in the absorption of quercetin, whereas significant gender-related differences in the elimination half-time (t(1/2)) were observed.