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Quercetin Inhibits Advanced Glycation End Product Formation by Trapping

Methylglyoxal and Glyoxal

Article  in  Journal of Agricultural and Food Chemistry · November 2014

DOI: 10.1021/jf504132x · Source: PubMed

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Quercetin Inhibits Advanced Glycation End Product Formation by

Trapping Methylglyoxal and Glyoxal
Xiaoming Li,‡ Tiesong Zheng,‡ Shengmin Sang,§ and Lishuang Lv*,‡
‡
Department of Food Science and Technology, Ginling College, Nanjing Normal University, 122 Ninghai Road, Nanjing 210097,
People’s Republic of China
§
Center for Excellence in Post-harvest Technologies, North Carolina Agricultural and Technical State University, North Carolina
Research Campus, 500 Laureate Way, Suite 4222, Kannapolis, North Carolina 28081, United States
*
S Supporting Information

ABSTRACT: Methylglyoxal (MGO) and glyoxal (GO) not only are endogenous metabolites but also exist in exogenous
resources, such as foods, beverages, urban atmosphere, and cigarette smoke. They have been identified as reactive dicarbonyl
precursors of advanced glycation end products (AGEs), which have been associated with diabetes-related long-term
complications. In this study, quercetin, a natural flavonol found in fruits, vegetables, leaves, and grains, could effectively inhibit the
formation of AGEs in a dose-dependent manner via trapping reactive dicarbonyl compounds. More than 50.5% of GO and 80.1%
of MGO were trapped at the same time by quercetin within 1 h under physiological conditions. Quercetin and MGO (or GO)
were combined at different ratios, and the products generated from this reaction were analyzed with LC-MS. Both mono-MGO
and di-MGO adducts of quercetin were detected in this assay using LC-MS, but only tiny amounts of mono-GO adducts of
quercetin were found. Additionally, di-MGO adducts were observed as the dominant product with prolonged incubation time. In
the bovine serum albumin (BSA)−MGO/GO system, quercetin traps MGO and GO directly and then significantly inhibits the
formation of AGEs.
KEYWORDS: quercetin, methylglyoxal, glyoxal, advanced glycation end products (AGEs), diabetic complications

■ INTRODUCTION
Hyperglycemia is considered to be a critical factor in diabetic
complications in epidemiological studies, especially in type 2
diabetes mellitus.1 Accumulating studies have shown that the
formation of advanced glycation end products (AGEs) induced
by hyperglycemia can cause or promote many diseases, such as
cataract generation, retinopathy, atherosclerosis, and nephrop-
athy.2 This is mainly due to the accumulation of AGEs in the
tissues, which can modify protein half-life, alter enzyme activity,
and change protein immunogenicity.3
AGEs are generated from the reaction of the carbonyl groups
of the reducing sugars and the free amino groups of the
proteins,4 followed by an Amadori rearrangement to form the
stable Amadori product. Then the product can generate various
reactive dicarbonyl species, such as deoxyglucosones, glyoxal
(GO), and methylglyoxal (MGO).5,6 In addition, lipid
peroxidation and autoxidation of glucose can also produce
reactive dicarbonyl species.7,8 Both MGO and GO are crucial
intermediates to form AGEs in vivo.9
Due to the reactive carbonyl group, MGO and GO can
effectively modify proteins through reacting with their arginine,
lysine, and cysteine residues9−13 and can also exhibit a potential
cellular toxicity to DNA.14 Any reaction that increases MGO or
GO levels in tissues or plasma can ultimately lead to the
pathology of diabetic complications.15 Previous studies have
focused mainly on scavenging these reactive intermediates with
some pharmaceutical agents, such as aminoguanidine,16,17
tenilsetam,18,19 metformin,20,21 and pyridoxamine.22 However,
the side effects of these AGE inhibitors prompt serious health
concerns. For example, aminoguanidine, an effective AGE
inhibitor in both in vitro and in vivo studies, has a high toxicity
for diabetic patients.5
Flavonoids are dietary constituents contained in vegetables,
fruits, soybeans, grains, and other plant-derived food. Recent
studies show that flavonoids could inhibit oxidative stress and
facilitate the detoxification of dicarbonyl species.23,24 Our
previous studies have found that genistein exhibits a significant
trapping effect on MGO to form mono- and di-MGO
adducts.25 Several studies have also demonstrated the trapping
capacity of reactive dicarbonyl compounds by other food-
derived flavonoids, such as phloretin from apples, (−)-epi-
gallocatechin 3-gallate (EGCG) from tea, and proanthocyani-
dins and anthocyanin from berries.26−28
Quercetin is a flavonol that exists in many plants, flowers,
leaves, and fruits, mostly in the form of glycosides, having an A
ring the same as EGCG, phloretion, and genistein. It has been
reported that quercetin can efficiently inhibit the glycation of
DNA29 as well as suppress α-dicarbonyl compound-induced
protein glycation.30,31 However, the underlying mechanism of
the antiglycation effect of quercetin is still largely unknown. In
this study, we investigated the efficacy of trapping MGO (and
GO) and inhibition of the formation of AGEs with quercetin.
Received: August 30, 2014
Revised: November 16, 2014
Accepted: November 20, 2014
Published: November 20, 2014

© 2014 American Chemical Society 12152 dx.doi.org/10.1021/jf504132x | J. Agric. Food Chem. 2014, 62, 12152−12158
Journal of Agricultural and Food Chemistry Article

Figure 1. Trapping of (A) MGO and (B) GO simultaneously by quercetin under physiological conditions (pH 7.4, 37 °C). MGO (0.5 mM) and
GO (0.5 mM) were incubated with quercetin (0.25, 0.5, 1.5, and 2.5 mM) in pH 7.4 phosphate buffer solutions at 37 °C for 10, 30, 60, 120, and 240
min. Data are presented as the means ± SD of three replications.

Figure 2. LC chromatograms of quercetin after incubation with different ratios of MGO (3:1, 1:1, 1:3, and 1:10) for 4 h (A) and 24 h (B),
respectively.

■ MATERIALS AND METHODS

Materials. Quercetin was obtained from Nanjing Guangrun
Biological Products Co., Ltd. (Nanjing, Jiangsu, China). MGO (40%
in water), GO (40% in water), 1,2-diaminobenzene (DB), and 2,3-
butanedione were purchased from Sigma-Aldrich (St. Louis, MO,
USA). Bovine serum albumin (BSA), DMSO, and streptomycin and
penicillin mixed solution were purchased from Shanghai Sangon
Biological Engineering Technology Co., Ltd. (Shanghai, China).
HPLC grade solvents and other reagents were obtained from Shanghai
Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). HPLC
grade water was prepared using a Millipore Milli-Q purification system
(Bedford, MA, USA).
Determination of the MGO and GO Trapping Capacity of
Quercetin by GC. MGO (0.5 mM) and GO (0.5 mM) were
incubated with quercetin (0.25, 0.5, 1.5, and 2.5 mM) in PBS buffer
(pH 7.4, 100 mM) at 37 °C for 0, 10, 30, 60, 120, or 240 min. At each
time point, the reaction was stopped by adding 10 μL of acetic acid.
The samples were then stored at −80 °C for further use.
Preparation of Samples. One milliliter of 100 mM DB was added
to 1 mL of sample and then mixed with 0.5 mL of 2,3-butanedione
(internal standard) at 1 mM. The reaction mixture was kept at 60 °C
for 10 min. Then, 1 mL of 1 M acetaldehyde was added and incubated
at 60 °C for 15 min to remove the unreacted DB. The mixture was
extracted twice with 2 mL of methylene chloride. The organic phase
was combined and concentrated to 0.5 mL. One microliter of this
sample was injected directly into the GC. The remaining percentage of
MGO and GO was calculated using the equation
remaining (%) = amount of MGO (GO) in test compound (as
quinoxalines)/amount of MGO (GO) in control (as
quinoxalines) × 100

12153 dx.doi.org/10.1021/jf504132x | J. Agric. Food Chem. 2014, 62, 12152−12158

Journal of Agricultural and Food Chemistry
Figure 3. Tandem MS/MS spectra of mono-MGO adducts (A) and di-MGO adducts (B−D) of quercetin.
GC Analysis. The levels of methylquinoxaline and quinoxaline
were analyzed with an Agilent gas chromatograph (7820 series, Agilent
Technologies, Palo Alto, CA, USA) equipped with a flame ionization
detector (FID). The column was an HP-5 MS (5%-phenyl)-
methylpolysiloxane silica capillary (30 m × 0.32 mm i.d., film
thickness = 0.25 μm, Agilent, Wilmington, DE, USA). The injector
temperature was 250 °C, and the detector temperature was 280 °C
with hydrogen, air, and nitrogen flow rates at 30.0, 300, and 5.0 mL/
min, respectively. The injector was in 1:1 split mode. The flow rate of
constant carrier gas (nitrogen) was set to be 2.0 mL/min. The GC
oven temperature was programmed as follows: the initial oven
temperature of 40 °C was held for 1 min, increased to 140 °C at a rate
of 5 °C/min, held for 1 min, then increased to 250 °C at a rate of 50
°C/min, and held for 1 min. The total run time was 25.2 min. All of
the solvents were filtered with a 0.2 μm Nylaflo membrane filter. The
injection volume was 1 μL for each sample solution.
Inhibitory Effects of Quercetin on the Formation of AGEs.
BSA (1.5 mg/mL) was incubated with MGO (500 μM) or GO (500
μM) in PBS buffer, pH 7.4, in the presence or absence of quercetin
(1.5 mM) at 37 °C. Streptomycin and penicillin (0.3 mL) was added
to the solution to prevent bacterial growth. The reaction mixture (500
μL) was collected and frozen at designated time points (0, 4, 8, 12, 72,
144, 288, 432, and 720 h). The amount of AGEs was determined using
fluorescence at an excitation/emission wavelength of 370/440 nm.
LC-MS Analysis. LC-MS analysis was performed using an Agilent
Masshunter System consisting of a 1290 G4220A BinPump, a 1290
G4226A Wellplate sampler, a G4212A fiode array detector, and a 6460
QQQ mass detector (Agilent, Santa Clara, CA, USA) incorporated
with electrospray ionization (ESI) interfaces. A 250 × 4.6 mm i.d., 5
μm, ZORBAX Eclipse XDB-C18 column (Agilent) was used for
separation at a flow rate of 0.5 mL/min. The column was eluted with
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90% solvent B (water with 0.1% formic acid) for 5 min, followed by
linear increases in A (acetonitrile with 0.1% formic acid) to 60% from
5 to 40 min, to 10% from 40 to 41 min, and then with 90% B from 41
to 46 min. The column was then re-equilibrated with 90% B for 5 min.
The LC eluent was introduced into the ESI interface. The negative ion
polarity mode was set for ESI ion source. The typical operating
parameters were as follows: spray needle voltage, 5 kV; nitrogen
sheath gas, 45 (arbitrary units); auxiliary gas, 5 (arbitrary units). The
structural information on quercetin and the major MGO and GO
adducts was obtained by tandem mass spectrometry (MS/MS)
through collision-induced dissociation (CID) with a relative collision
energy setting of 35%. Data acquisition was performed with
Qualitative Analysis of Masshunter (Agilent).
LC-MS Analysis of MGO or GO Adducts of Quercetin in the
BSA−MGO (or GO) System. The procedure of BSA incubation with
MGO/GO and quercetin is the same as the inhibition effect method
described above. Samples were collected at designated time points (0,
1, 2, 4, and 8 h) from the quercetin-treated BSA−MGO (or GO)
system, and mono- and di-MGO conjugated quercetin was detected
using the LC-MS method described above.
■
RESULTS
Trapping of MGO and GO Simultaneously by
Quercetin under Physiological Conditions. The results
shown in Figure 1 suggest that quercetin can trap both MGO
and GO simultaneously and efficiently under physiological
conditions. More than 26.0% of GO and 69.0% of MGO were
trapped within 60 min by 0.5 mM quercetin, and the trapping
efficiency could be up to 50.5 and 80.1%, respectively, when
dx.doi.org/10.1021/jf504132x | J. Agric. Food Chem. 2014, 62, 12152−12158
Journal of Agricultural and Food Chemistry Article

Table 1. Percentagea of Quercetin−MGO Products for 4 and 24 h at Different Ratios

DM-1 DM-2 + DM-3 MM quercetin
quercetin/MGO 4h 24 h 4h 24 h 4h 24 h 4h 24 h
3:1 − b
− − − 4.59 10.91 95.41 89.09
1:1 12.28 7.87 − − 11.43 30.38 76.29 61.75
1:3 16.89 45.33 − 10.07 33.87 38.68 49.24 5.92
1:10 54.05 56.17 3.85 12.90 29.82 30.93 12.28 −
a
Percent (%) = peak area of each product at 4 or 24 h at each ratio/total sum of peak areas of products at 4 or 24 h at each ratio. b−, not detected.

Figure 4. Inhibitory effect of the formation of AGEs by quercetin in the BSA−MGO (or GO) assay: (A) MGO; (B) GO. Data are presented as the
means ± SD of three replications.

using 2.5 mM quercetin. Quercetin appeared to trap MGO
much more efficiently than GO when both GO and MGO
occurred in the same system.
Analyzing the Formation of MGO or GO Adducts of
Quercetin Using LC-MS. We further identified the
quercetin−MGO and quercetin−GO adducts using LC-MS
after incubation of quercetin with MGO or GO at four different
ratios (3:1, 1:1, 1:3, and 1:10) (Figure 2; Supplemental Figure
1 in the Supporting Information). Under selective ion
monitoring (SIM) mode, the structural information on these
products was achieved using tandem mass analysis (Figure 3
and Supplemental Figure 2). After 4 h of incubation of
quercetin with MGO (ratio = 1:1), one product peak (tR 23.91
min) appeared in the LC chromatogram as shown in Figure 2A.
This peak had the molecular ion m/z 373 [M − H] − and
fragment ion m/z 301 [M − 72 − H] −, indicating the loss of
one MGO (m/z 72) molecule, suggesting this product was a
mono-MGO conjugated quercetin (MM) (Figure 3A). When
quercetin and MGO at a 1:3 ratio were incubated for 4 h,
another peak appeared at 21.32 min. This peak had the
molecular ion m/z 445 [M − H]−, which was 142 mass units
heavier than that of the quercetin, indicating that this peak was
a di-MGO adduct of quercetin (DM-1) (Figure 3B). The third
new peak appeared at 22.68 min (Figure 2A), with the addition
of MGO at the ratio of 1:10 for 4 h, which had the same
molecular ion as DM-1, indicating that this peak was also a di-
MGO adduct of quercetin (DM-2) (Figure 3C). Under the
ratio of 1:3, both mono- and di-MGO adducts were the major
products, and the amount of unreacted quercetin dramatically
reduced to 12.28% (Table 1), whereas when quercetin and
MGO at a 1:10 ratio were incubated for 24 h, di-MGO adducts
became the dominant products (Table 1), and one additional
peak corresponding to di-MGO adduct (DM-3) was observed
(Figure 2B). This peak could not be separated fully from the
peak of DM-2 (Figure 2B). When quercetin and GO were
incubated at a 1:10 ratio for 24 h, two new peaks were observed
at 22.02 and 23.98 min (Supplemental Figure 1). They had the
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same molecular ion m/z 359 [M − H]−, which was 58 mass
units heavier than that of quercetin, indicating both of them are
mono-GO adducts of quercetin (Supplemental Figure 2A,B).
However, only tiny amounts of mono-GO adducts were
detected even when quercetin and GO were incubated at a 1:10
ratio for 24 h, and di-GO adducts were not detectable
(Supplemental Figure 1A,B).
Inhibitory Effects of Quercetin on the Formation of
AGEs. We found that quercetin significantly inhibited the
formation of AGEs in the BSA−MGO/GO system (Figure 4).
This result is consistent with our observation on the trapping
efficacy of MGO/GO by quercetin. When quercetin (0.25
mM) was present in the incubation mixture, the inhibition
efficiency could be up to 91.0% at 24 h in the BSA−MGO
system (Figure 4A), whereas in the quercetin−BSA−GO
system, the inhibitory effect of quercetin on the formation of
AGEs seems less than that of the BSA−MGO system, only
76.8% within 30 days (Figure 4B). This may be related to the
fact that the formation of AGEs by GO was slow.
Determining the Adduct Formation of Quercetin in
the BSA−MGO or BSA−GO System by LC-MS. To clarify
whether trapping of MGO (or GO) by quercetin is the major
mechanism to prevent the formation of AGEs, LC-MS was used
to determine the existence of the mono- and di-MGO/GO
conjugated quercetin in the samples, which were collected after
incubation of quercetin with BSA and MGO or of quercetin
with BSA and GO.
As shown in Figure 5, the mono-MGO adduct could be
detected after 1 h of incubation, and the di-MGO adduct could
be detected after 2 h of incubation. They had retention times
and MS/MS spectra identical to those of the mono- and di-
MGO adducts in the reaction mixture between quercetin and
MGO, but in the BSA−GO system, only mono-GO adducts
were detectable at very low levels (Supplemental Figure 3).
dx.doi.org/10.1021/jf504132x | J. Agric. Food Chem. 2014, 62, 12152−12158
Journal of Agricultural and Food Chemistry
Figure 5. LC chromatograms of quercetin and mono- and di-MGO adducts of quercetin after incubation of quercetin in the BSA−MGO assay for 1,
2, 4, and 8 h as well as after the incubation of quercetin with MGO at a 1:3 ratio for 4 h.
■ DISCUSSION
Our results revealed that quercetin can rapidly trap MGO and
then inhibit the formation of AGEs through forming of mono-
and di-MGO adducts under neutral and alkaline conditions in
vitro. In this assay, both mono- and di-MGO adducts of
quercetin were detected, and the di-MGO adducts became the
dominant products during prolonged incubation, whereas only
a tiny amount of mono-GO adducts of quercetin was detectable
in the reaction mixtures of quercetin and GO.
α-Dicarbonyl compounds are known as important precursors
of AGEs, which can be generated endogenously through either
degradation of glucose or early glycation products. Rising levels
of dietary fructose in the Western diet have been associated
with an increase of serum MGO and GO.32 In our study,
quercetin efficiently trapped MGO and GO simultaneously
under physiological conditions, as MGO and GO appear in the
same system. Furthermore, we found that quercetin preferred
trapping of MGO to that of GO. The potential reason may be
that in aqueous solution GO exists mainly as the hydrated
monomer, dimer, or trimer, the conversion of which to free GO
is slowed by the trapping reaction between quercetin and
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GO.33 Similar results have been reported for EGCG26 and
phloretin;27 both of them appeared to trap for GO much more
slowly than for MGO.
To further study whether quercetin can inhibit the formation
of AGEs via trapping MGO/GO, we analyzed the inhibitory
effect of quercetin on the formation of AGEs in the BSA−
MGO/GO system and then determined the formation of MGO
(GO) adducts of quercetin by LC-MS. We demonstrated that
quercetin can inhibit the formation of AGEs via trapping MGO
and GO. The amount of AGEs rose dramatically with time
during incubation with MGO until reaching a plateau. Although
no plateau appeared during incubation with GO, the parameter
increased progressively with time. Results of this study are
consistent with previous reports that MGO rather than GO is
the main dicarbonyl compound responsible for albumin
glycation.34 Moreover, the inhibitory activity on the formation
of AGEs by quercetin was much higher in the BSA−MGO
system than in the BSA−GO system; one of the major causes
was that the glycation was dragged down by the conversion
among hydrated monomer, dimer, and trimer to free GO.
dx.doi.org/10.1021/jf504132x | J. Agric. Food Chem. 2014, 62, 12152−12158
Journal of Agricultural and Food Chemistry
Flavonoids, consisting of two hydroxy-substituted aromatic
rings joined by a three-carbon link (a C6−C3−C6 config-
uration), can be categorized into flavones, flavanones,
isoflavones, chalcones, anthocyanidins, and flavonols according
to different C-ring chemical structures. It has been reported
that the mechanism of inhibition of AGEs is done via trapping
MGO for EGCG26 (flavanols), genistein25 (isoflavones),
phloretin27 (chalcones), and proanthocyanidins35 (oligomers
of flavanols). In view of this fact, we investigated quercetin
(flavonols) inhibition of the formation of AGEs via trapping
MGO and GO. With respect to the structure of these
flavonoids, EGCG, genistein, phloretin, and quercetin have
the same A ring. The same mechanism for trapping reactive
dicarbonyl species and forming mono- and di-MGO adducts at
the A ring may be predicted. After quercetin and MGO (1:3)
were incubated for 24 h, the MS/MS spectrum of the most
abundant daughter ion m/z 373 of the mono-MGO (tR 27.34
min) adduct had the typical breakdown of the C ring (m/z
150) and a loss of one H2O to generate the fragment ion 205
[M − H2O − 150] − (Figures 3A and 6), which indicates that
Figure 6. Formation pathway of the major fragments of mono- and di-
MGO adducts of quercetin.
the MGO conjugates at the A ring of quercetin. Similarly, the
MS/MS spectrum of the three di-MGO adducts had the same
fragment patent to generate the daughter ion 277 [M − H2O −
150] − (Figures 3B−D and 6). Therefore, we could determine
that positions 6 and 8 on the A ring of quercetin were the major
active sites for trapping MGO (Figure 6), which comprise the
essential structural requirement for flavonoids to scavenge
methylglyoxal.36 Quercetin is the major representative of the
flavonoid subclass flavonols.37 It is widely distributed in nature,
existing in foods such as apples, onions, tea, berries, red wine,
and some herbs. Quercetin is a strong antioxidant,38 and also
possesses antihistamine and anti-inflammatory properties.39,40
It has been reported that dietary flavonoids including luteolin,
rutin, EGCG, and quercetin show effective inhibition on MGO-
mediated AGE formation by 82.2, 77.7, 69.1, and 65.3%,
respectively.41 Our results demonstrate the reaction kinetics for
quercetin trapping MGO and GO simultaneously, as well as the
mechanism of quercetin inhibiting the formation of AGEs in
the BSA−MGO/GO system.
In conclusion, using the food-borne flavonoid quercetin
intervention to scavenge these dicarbonyl compounds is likely
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to be an effective strategy to inhibit the formation of AGEs and
prevent AGE-mediated processes linked to disease.
■
*
ASSOCIATED CONTENT
S Supporting Information
Supplemental Figures 1−3. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
AUTHOR INFORMATION
Corresponding Author
*(L.L.) Phone: +86 25 83598286. Fax: +86 25 83707623. E-
mail: lishuanglv@126.com or lulishuang@njnu.edu.cn.
Funding
This work was supported by NSF of Jiangsu province of China
(Project BK2012850), Program of Natural Science Research of
Jiangsu Higher Education Institution of China (Project
12KJB5500005), and Natural Science Foundation of Zhejiang
province of China (Project LY12C15001).
Notes
This article does not contain any studies with human or animal
subjects.
The authors declare no competing financial interest.
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