Food Chemistry 239 (2018) 377–384

Contents lists available at ScienceDirect

Food Chemistry
journal homepage: www.elsevier.com/locate/foodchem

A study of the tyramine/glucose Maillard reaction: Variables,

characterization, cytotoxicity and preliminary application
Wei Jiang a, Yaxin Chen b, Xiaoxia He c, Shiwei Hu a, Shijie Li a, Yu Liu a,⇑
a
Laboratory of Seafood Processing, Innovative and Application Institute, Zhejiang Ocean University, Zhoushan, Zhejiang 316022, China
b
College of Food Science and Pharmacy, Zhejiang Ocean University, Zhoushan, Zhejiang 316022, China
c
Qingdao Entry-Exit Inspection and Quarantine Bureau, Qingdao, Shandong 266002, China

a r t i c l e i n f o a b s t r a c t

Article history:
Received 8 March 2017
Received in revised form 14 May 2017
Accepted 14 June 2017
Available online 20 June 2017
Chemical compounds studied in this article:
Tyramine (PubChem CID: 5610)
Glucose (PubChem CID: 5793)
Dansyl chloride (PubChem CID: 11801)
Dimethyl sulfoxide (PubChem CID: 679)
Sodium chloride (PubChem CID: 5234)
Methanol (PubChem CID: 887)
Streptomycin (PubChem CID: 19649)
Ampicillin (PubChem CID: 6249)
The tyramine/glucose Maillard reaction was proposed as an emerging tool for tyramine reduction in a
model system and two commercial soy sauce samples. The model system was composed of tyramine
and glucose in buffer solutions with or without NaCl. The results showed that tyramine was reduced
in the model system, and the reduction rate was affected by temperature, heating time, initial pH value,
NaCl concentration, initial glucose concentration and initial tyramine concentration. Changes in fluores-
cence intensity and ultraviolet–visible (UV–vis) absorption spectra showed three stages of the Maillard
reaction between tyramine and glucose. Cytotoxicity assay demonstrated that tyramine/glucose
Maillard reaction products (MRPs) were significantly less toxic than that of tyramine (p < 0.05).
Moreover, tyramine concentration in soy sauce samples was significantly reduced when heated with
the addition of glucose (p < 0.05). Experimental results showed that the tyramine/glucose Maillard reac-
tion is a promising method for tyramine reduction in foods.
Ó 2017 Elsevier Ltd. All rights reserved.

Keywords:
Tyramine
Biogenic amine
Glucose
Maillard reaction
Reduction
Cytotoxicity
Soy sauce

1. Introduction
Tyramine, (4-(2-aminoethyl) phenol), is a biogenic amine
derived from the decarboxylation of amino acid tyrosine by bacte-
ria. As shown in Fig. 1, tyramine is an aromatic monoamine com-
pound. Tyramine can accumulate in a wide range of foods,
especially fermented foods, such as cheese, fish sauce and soy
sauce (Guidi & Gloria, 2012; Jiang, Xu, Li, Dong, & Wang, 2014;
Linares, Martín, Ladero, Alvarez, & Fernández, 2011). A low level
of tyramine does not cause harmful effects in normal individuals
Abbreviations: UV–vis, ultraviolet–visible; MRPs, Maillard reaction products;
RPMI, Roswell Park Memorial Institute; FBS, fetal bovine serum; DMSO, dimethyl
sulfoxide; 5-HMF, 5-hydroxymethlofurfural; AGEs, advanced glycation end prod-
ucts; Has, heterocyclic amines; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylte
trazolium bromide.
⇑ Corresponding author.
E-mail address: liuyu1987@zjou.edu.cn (Y. Liu).
due to the presence of amine oxidases in the human intestine. Nev-
ertheless, consumption of foods containing high level of tyramine
causes migraine, neurological disorders, headaches, respiratory
disorders and hypertension, which are together known as the
‘‘cheese effect” (Finberg & Gillman, 2011). These symptoms can
be much more severe in people taking antidepressant monoamine
oxidase inhibitor medication (Ladero, Calles-Enriquez, Fernandez,
& Alvarez, 2010). Besides, tyramine can react with nitrite to form
C-nitroso compounds, which are known carcinogenic agents (Gon
zález-Jiménez, Arenas-Valgañón, García-Santos, Calle, & Casado,
2017). Recent studies suggest that tyramine exhibits a stronger
and more rapid cytotoxic effect than histamine (Linares et al.,
2016). Therefore, the prevention of tyramine formation in foods
or reduction of its level once it has formed should be studied.
In the past few decades, high hydrostatic pressure (Matějková,
Křížek, Vácha, & Dadáková, 2013), irradiation (Zhang, Wang,

http://dx.doi.org/10.1016/j.foodchem.2017.06.085
0308-8146/Ó 2017 Elsevier Ltd. All rights reserved.
378 W. Jiang et al. / Food Chemistry 239 (2018) 377–384

HO Park Memorial Institute (RPMI) 1640 medium, fetal bovine serum

(FBS), streptomycin sulphate, ampicillin, trypsin and 3-(4,5-dime
thylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were
obtained from Gibco Invitrogen Co., (Burlington, ON, Canada). Glu-
cose was obtained from Solarbio Inc. (Beijing, China). Methanol
NH2 (HPLC grade) was supplied by Merck (Darmstadt, Germany). Ultra-
pure water was prepared by Milli-Q (Millipore, Billerica, MA, USA).
Fig. 1. Structure of tyramine. The other chemicals used were of analytical grade and obtained
from Sinopharm Chemical Regent Co. Ltd (Shanghai, China).
Zhang, Wang, & Ye, 2016), modified atmosphere packing
(Yassoralipour, Bakar, Rahman, & Abu Bakar, 2012) and low storage
2.2. Tyramine/glucose Maillard reaction model system
temperature (Fan et al., 2016) have been employed to prevent the
formation of tyramine by inhibiting the growth of microorganisms.
Tyramine was incubated with glucose in 16 mm  155 mm
Nevertheless, microbial inhibition by these methods is random, not
glass screw tubes capped with a tight screw-cap. Unless otherwise
only aiming at tyramine producing bacteria. Thus, they are not
stated, the incubations contained 50 mM potassium phosphate, pH
suitable for fermented foods where the growth of microorganisms
8.0, 2.5 mM tyramine and 40 mM glucose in a total volume of
is very important. Moreover, the above techniques cannot decrease
5.0 ml. The tubes were incubated at designed temperature in a Dig-
the level of tyramine that already exists. Tyramine degrading bac-
ital Dry Bath (Jinxin, JX100-4, Shanghai, China). To ensure the reac-
teria can be used as functional starter cultures to reduce already
tion was stopped at appropriate time points, the tubes were cooled
existing tyramine (Xu, Liu, Xu, Wang, & Jiang, 2016), but more
in a mixture of ice and water for 30 min.
effective tyramine degrading strains and professional equipment/
staff are required. Therefore, high efficiency, lower cost and more
2.3. Variables of the tyramine/glucose Maillard reaction model system
convenient methods are desired for tyramine reduction.
The Maillard reaction occurs between the amino group of amino
2.3.1. Temperature
acids, peptides, proteins or other nitrogen containing compounds
To evaluate the effect of temperature on the tyramine reduction
and carbonyl groups of reducing sugars, during the processing
rate, 2.5 mM tyramine and 40 mM glucose were incubated at pH
and storing of foods. This reaction is a series of successive and par-
8.0 and 60, 70, 80, 90, 100 or 110 °C for 12 h without the addition
allel reactions, which can be influenced by many factors such as
of NaCl. Samples were taken at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10 and
temperature, heating time, pH, substrate type, substrate concen-
12 h.
tration and water activity (Caballero, Finglas, & Toldrá, 2016). To
reduce the complexity of the Maillard reaction, the reaction pro-
2.3.2. Initial pH
cess is divided into three stages (namely initial stage, intermediate
To evaluate the effect of initial pH value on the tyramine reduc-
stage and final stage) according to the generation of different com-
tion rate, 2.5 mM tyramine and 40 mM glucose were incubated at
pounds, which can be characterized by fluorescence intensity and
100 °C and pH 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0 or 12.0 for 5 h with-
ultraviolet–visible (UV–vis) absorption (Nursten, 2005). Although
out the addition of NaCl. Samples were taken at 0.5, 1, 3 and 5 h.
the Maillard reaction can result in the loss of essential amino acids,
production of undesired pigment and generation of toxicants
2.3.3. NaCl concentration
(Zhang, Tao, Wang, Chen, & Wang, 2015), it can also enhance the
To evaluate the effect of NaCl concentration on the tyramine
emulsifying property, solubility, antioxidant activity and metal
reduction rate, 2.5 mM tyramine and 40 mM glucose were incu-
chelating activity of food ingredients (Dong et al., 2012; Oliveira,
bated at 100 °C and pH 8.0 with 0, 1, 3, 5, 8, 11, 14, 19, 24 or
Coimbra, Oliveira, Zuñiga, & Rojas, 2016). The Maillard reaction
29% (w/v) of NaCl for 5 h. Samples were taken at 0.5, 1, 3 and 5 h.
has also been used to reduce fumonisin B1 in corn grits
(Bullerman et al., 2008), which expands the application area of
2.3.4. Initial glucose concentration
Maillard reaction to the reduction of toxic substances. As shown
To evaluate the effect of initial glucose concentration on the
in Fig. 1, tyramine has a free amino group, suggesting that it may
tyramine reduction rate, different initial glucose concentrations
be reduced by Maillard reaction. However, the Maillard reaction
of 5, 10, 20, 40, 60, 80, 160 or 320 mM glucose and 2.5 mM tyra-
between tyramine and sugars has not been studied previously.
mine were incubated at 100 °C and pH 8.0 for 5 h without the addi-
In this study, effects of temperature, heating time, initial pH
tion of NaCl. Samples were taken at 0.5, 1, 3 and 5 h.
value, NaCl concentration, initial glucose concentration and initial
tyramine concentration on tyramine reduction in the tyramine/
2.3.5. Initial tyramine concentration
glucose Maillard reaction model system were investigated. Three
To evaluate the effect of initial tyramine concentration on the
stages of the tyramine/glucose Maillard reaction were character-
tyramine reduction rate, different initial tyramine concentrations
ized by fluorescence intensity and UV–vis spectroscopy. Cytotoxi-
of 0.5, 1.0, 2.5, 5.0, 10.0 or 20.0 mM tyramine and 40 mM glucose
city of tyramine, glucose, tyramine-glucose mixture, and
were incubated at 100 °C and pH 8.0 for 5 h without the addition
tyramine/glucose Maillard reaction products (MRPs) was assayed.
of NaCl. Samples were taken at 0.5, 1, 3 and 5 h.
Furthermore, the reduction of tyramine by Maillard reaction in
commercial soy sauce samples was preliminarily evaluated. The
2.4. Tyramine concentration determination
aim was to reveal the possibility of using tyramine/glucose Mail-
lard reaction for tyramine reduction in foods.
Tyramine concentration was determined by HPLC using pre-
column derivatization with dansyl chloride (Jiang et al., 2014).
2. Materials and methods The HPLC system consisted of a Waters 2695 series (Milford,
USA) equipped with a degasser, quaternary pump, column oven,
2.1. Chemicals fluorescence detector and automatic sampler. A reversed-phase
chromatographic column (Capcell PAK 5 lm C18 MG,
Tyramine, dansyl chloride and dimethyl sulfoxide (DMSO) were 150  4.6 mm) was used. The derivatised tyramine was detected
obtained from Sigma-Aldrich, Inc. (St. Louis, MO, USA). Roswell at 350 nm (excitation) and 520 nm (emission). Calibration curves
 W. Jiang et al. / Food Chemistry 239 (2018) 377–384
were constructed of peak area vs standard tyramine concentration
(0.01–2.5 mM).
2.5. Fluorescence intensity
Fluorescence intensities were determined using a fluorescence
spectrophotometer (Hitachi, F-4500, Kyoto, Japan) using the
method described previously (Morales & Jiménez-Pérez, 2001).
Samples were diluted 10-fold with ultrapure water. The fluores-
cence intensities were measured at an excitation wavelength of
350 nm and an emission wavelength of 420 nm.
2.6. UV–vis spectroscopy
UV–vis spectra were determined using an UV–vis spectropho-
tometer (Shimadzu, UV-2600, Kyoto, Japan). Samples were diluted
to 50-fold with ultrapure water. UV–vis spectra were recorded
from 220 to 800 nm with an interval of 0.5 nm. Meanwhile, the
absorbance at 294 and 420 nm was measured.
2.7. Cell culture
The normal human liver HL-7702 cell line (BNCC 100966) was
obtained from BeNa Culture Collection Co. Ltd. (Beijing, China).
Cells were maintained in RPMI 1640 medium containing 10%
(v/v) FBS, 0.01% (w/v) ampicillin and 0.05% (w/v) streptomycin at
37 °C under a humidified atmosphere containing 5% CO2.
2.8. Cytotoxicity assay
Cytotoxicity of tyramine, glucose, tyramine-glucose mixture
and tyramine/glucose Maillard reaction products (MRPs) was eval-
uated by the MTT assay using HL-7702 cells. Briefly, cells were
seeded into a 96-well plate at density of 5  103 cells per well with
100 ll of RPMI 1640 medium containing 10% (v/v) FBS, 0.01% (w/v)
ampicillin and 0.05% (w/v) streptomycin. After incubation for 24 h
at 37 °C under a humidified atmosphere containing 5% CO2, 100 ll
of culture medium containing different test substances as shown in
Table 1 were added to the wells of experiment groups, and 100 ll
of culture medium were added to the wells of the negative control
group. The cells were subsequently cultured for 24 h at 37 °C under
a humidified atmosphere containing 5% CO2. After that, 10 ll of
MTT solution (5 mg/ml) was added to each well and the plate
was incubated for another 4 h. After careful removal of the super-
natant, 100 ll of DMSO was added to each well and the plate was
shaken at room temperature for 20 min. The absorbance at 490 nm
was measured in a microplate reader (PULANG, DNM-9606, Bei-
jing, China). The cell growth inhibition rate was calculated using
the following formula: Cell growth inhibition rate (%) = (Absor-
bance value of control Absorbance value of sample)/Absorbance
value of control  100.
Table 1
Experimental design for cytotoxicity assay.
Levels Concentration (mM)
Tyramine Glucose
1 2 32
2 4 64
3 6 96
4 8 128
5 10 160
A
The mixture was prepared by freeze-drying the mixture of 2.5 mM tyramine and 40 mM glucose in 50 mM PBS (pH 8.0).
B
The MRPs were prepared by freeze-drying the reaction products of 2.5 mM tyramine and 40 mM glucose after heating at 100 °C for 1 h (MRPs-1) or 5 h (MRPs-5) in
50 mM PBS (pH 8.0).
379
2.9. Incubation of soy sauce with glucose
To evaluate the tyramine reduction ability of Maillard reaction
in foods, two commercial soy sauce samples obtained from a mar-
ket in Zhoushan, Zhejiang, China, and were incubated with glucose
under designed conditions. The salt concentrations of sample A and
sample B were measured as 11.28 ± 0.79% (w/v) and 16.12 ± 1.04%
(w/v), respectively. The pH values of sample A and sample B were
measured as 6.21 ± 0.14 and 5.98 ± 0.09, respectively. Sample A
was manufactured using water, white sugar, salt, soybean, wheat
flour, yeast extract, lactic acid, caramel and potassium sorbate,
while sample B was produced using water, white sugar, salt, soy-
bean, wheat, yeast extract, sodium glutamate, sucralose and
sodium benzoate. The obtained soy sauce samples were opened
and their net volumes were measured. Then 2% (w/v) glucose (equal
to 125 mM glucose) was added and mixed gently. The mixture was
transferred to a sealable glass container. After that, the container
was incubated in a water bath at 95 °C. Samples were taken at
the heating time of 0, 1, 2 and 3 h. The same samples without the
addition of glucose were incubated under the same conditions.
2.10. Tyramine extraction
Tyramine was extracted from soy sauce by a reported method
(Yongmei et al., 2009) with some modifications. Two milliliters of
soy sauce were placed into a centrifuge tube containing 3 ml of
400 mM perchloric acid. The tubes were mixed for 70 s by a vortex
mixer (IKA, MS3, Staufen, German) and centrifuged at 1  104 g at
0 °C for 3 min using a refrigerated centrifuge (Zhongke, HC-
3018R, Anhui, China). The supernatant was filtered through qualita-
tive paper. The acid extraction steps were repeated twice again. The
filtrates were all transferred into a calibrated volumetric flask and
diluted with 0.4 M perchloric to 10 ml. The diluted solution was
used for the determination of tyramine concentration in soy sauce.
2.11. Statistical analyses
Statistical analyses were performed using the software IBM
SPSS Statistics 22.0 (IBM, USA). Data were analyzed by one-way
analysis of variance (ANOVA) with the Tukey test. The experiments
were performed in triplicate and the data were expressed as aver-
age ± standard deviation.
3. Results and discussion
3.1. Variables influencing tyramine reduction rates in the tyramine/
glucose Maillard reaction model system
3.1.1. Effect of temperature and heating time on tyramine reduction
rates
Fig. 2A shows the changes of tyramine reduction rates in the
tyramine/glucose Maillard reaction model system during heating
MixtureA MRPs-1B MRPs-5B
34 34 34
68 68 68
102 102 102
136 136 136
170 170 170
380 W. Jiang et al. / Food Chemistry 239 (2018) 377–384

160
A
Equation y = a + b*x (from 0 to 1.5 h)

C
b Equation
Temperature
Value Standard Error Residual Sum of Squares Pearson's r Adj. R-Square
140 60°C 5.33755 0.65174 2.79575 0.97836 0.94292
70°C 8.56659 0.37513 0.76365 0.99714 0.99237

Tyramine reduction rate (%)

80°C 11.24973 0.81391 28.99032 0.96314 0.90353
90°C 24.24657 4.0698 49.74058 0.96024 0.89609
120 100°C 34.00309 4.39051 52.26173 0.97589 0.93649
110°C 52.10133 4.80891 50.55998 0.98746 0.96677

100

80

60

40

20

0 1 2 3 4 5 6 7 8 9 10 11 12
Heating time (h)

100 B ef f C
Tyramine reduction rate (%)

f 100
e
Tyramine reduction rate (%)

ef
e
d de d
80 g 80
de g e ded cd
d f
c f de
60 e 60 c
c
e
c c c
de c bc
d
40 d 40 d c bc b ab
b bc b ab
b c cd b b
c b b a
c bc
a bc ab ab
20 b 20 b ab a a
a b a a a
ab a a
aa
0 0
5 6 7 8 9 10 11 12 0 1 3 5 8 11 14 19 24 29
Initial pH NaCl concentration (%)

100 D g
g
100 E f
f
e
Tyramine reduction rate (%)

Tyramine reduction rate (%)

f f
ef
f d
80 80 f
h c
e e d
d d e
60 d g 60
c e b
c
ef f e d d a
e b
b c de
40 40 c
b d c a
c cd
a c b
a b b a
20 b 20 ab
a ab
a a

0 0
5 10 20 40 60 80 160 320 0.5 1 2.5 5 10 20
Glucose concentration (mM) Tyramine concentration (mM)

Fig. 2. (A) Effect of temperature on tyramine reduction rate in the tyramine/glucose Maillard reaction model for up to 12 h. Temperature: 60 °C ( ), 70 °C ( ), 80 °C ( ),
90 °C ( ), 100 °C ( ), 110 °C ( ). Tyramine heated alone at pH 8.0 and 110 °C was also studied ( ). The inserted table showed the parameters of the liner fitting equation
(y = a + b * x) from 0 to 1.5 h at different temperatures. The slope value represented the mean tyramine reduction rate per hour (%/h, mean ± SD) from 0 to 1.5 h. Effect of (B)
initial pH value, (C) NaCl concentration, (D) initial glucose concentration and (E) initial tyramine concentration on tyramine reduction rates in the tyramine/glucose Maillard
reaction model system after heating for 0.5 h ( ), 1 h ( ), 3 h ( ) and 5 h ( ). Bars of the same color (the same reaction time) with different letters are significantly
different (p < 0.05). Reaction conditions: (A) 2.5 mM tyramine and 40 mM glucose at pH 8.0 and different temperatures; (B) 2.5 mM tyramine and 40 mM glucose at 100 °C
and different initial pH values; (C) 2.5 mM tyramine and 40 mM glucose at 100 °C and pH 8.0 with the addition of different concentration of NaCl; (D) 2.5 mM tyramine and
different initial concentration of glucose at 100 °C and pH 8.0; (E) 40 mM glucose and different initial concentration of tyramine at 100 °C and pH 8.0.
 W. Jiang et al. / Food Chemistry 239 (2018) 377–384
at different temperature (from 60 to 110 °C) and in tyramine solu-
tion during heating at 110 °C for 12 h. It was observed that the
tyramine concentration did not change significantly when heated
alone without glucose at 110 °C for 12 h, exhibiting its thermosta-
bility. However, the tyramine reduction rate was strongly affected
by temperature (from 60 to 110 °C) and heating time (from 0 to
12 h) when 2.5 mM tyramine and 40 mM glucose reacted at pH 8.0.
As shown in Fig. 2A, on the one hand, the tyramine reduction
rate increased in the tyramine/glucose Maillard reaction model
system as the reaction time was prolonged. It also can be seen that
the tyramine reaction rate increased sharply during the first few
hours and rose slowly afterward. For example, when reacted at
80 °C, the tyramine reduction rate increased from 0 to
29.33 ± 2.22% in the first four hours but further increased to only
46.88 ± 1.79% in the next eight hours. On the other hand, the tyra-
mine reduction rate increased in the tyramine/glucose Maillard
reaction model system as temperature increased from 60 to
110 °C. The tyramine reduction rates were 20.55 ± 4.69,
32.50 ± 1.11, 46.88 ± 1.79, 76.50 ± 2.03, 93.00 ± 1.89 and
97.93 ± 1.89% when 2.5 mM tyramine and 40 mM glucose reacted
for 12 h at 60, 70, 80, 90, 100 and 110 °C, respectively. The table
inserted in Fig. 2A shows the parameters of the liner fitting equa-
tion between tyramine reduction rate and time (0–1.5 h). The slope
value represented the initial tyramine reduction rate per hour,
which increased as temperature increased from 60 to 110 °C. The
initial tyramine reduction rate per hour was only 5.34 ± 0.654%/h
at 60 °C, but which increased by nearly 10 times (52.10 ± 4.81%/
h) if the temperature was 110 °C. These results indicated that tyra-
mine was thermostable, but could be reduced with the addition of
glucose during heating in model system.
As the Maillard reaction is endothermic, the extent of reaction
in a certain reaction system always increases as temperature goes
up. In a fumonisin/glucose Maillard action model system, it was
reported that the apparent reaction rate constants of fumonisin
B1 loss increased as temperature increased (Lu et al., 2002). Tem-
perature is an important variable in the Maillard reaction. The
Maillard reaction occurs at both low temperature (storage of food
products) and high temperature (processing and sterilization pro-
cesses) (Caballero et al., 2016). Sheng et al. (2016) investigated
the Maillard reaction in intermediate moisture protein-sugar foods
with or without the addition of resveratrol during storage at 45 °C.
El Hassan Ajandouz, Desseaux, Tazi, and Puigserver (2008) studied
the Maillard reaction between bovine casein peptides and galac-
tose during heating at 70–120 °C. Heating time is another impor-
tant parameter which contributes to the extent of reaction in
Maillard reaction. An equivalent degree of Maillard reaction is
obtained during a high-intensity short time heating and during a
weak treatment for a long time (Caballero et al., 2016).
3.1.2. Effect of initial pH value on tyramine reduction rates
Effect of initial pH value on tyramine reduction rates in the
tyramine/glucose Maillard reaction model system is shown in
Fig. 2B, during heating at 100 °C for 5 h. Firstly, the tyramine reduc-
tion rate significantly increased from 12.17 ± 3.22% after 0.5 h to
58.37 ± 2.36% after 5 h during heating at 100 °C and pH 7.0
(p < 0.05). The similar trends were also seen at initial pH values
of 5.0, 6.0, 8.0, 9.0, 10.0, 11.0 and 12.0, suggesting that the tyra-
mine reduction rate increased as heating time prolongs at different
initial pH values. Secondly, the tyramine reduction rate signifi-
cantly increased from 18.06 ± 3.02% at pH 5.0 to 95.61 ± 2.40% at
pH 12.0 after heat treatment at 100 °C for 5 h (p < 0.05). The similar
trends were also observed at 0.5, 1, and 3 h, indicating that the
tyramine reduction rate increased as initial pH value increased.
Previous studies have demonstrated that the losses of reactants
were promoted at higher initial pH value in casein/glucose
(El Hassan Ajandouz et al., 2008), proline/glucose (Blank, Devaud,
381
Matthey-Doret, & Robert, 2003) and lysine/fructose (Ajandouz &
Tchiakpe, 2001) Maillard reaction systems. The inhibition of tyra-
mine reduction in acidic solution might be explained by the proto-
nation of tyramine, which resulted in hindering the condensation
of amino with carbonyl group and thus reducing the consumption
of tyramine (Liu, Yang, Chen, Chen, & Chen, 2011). Besides, reaction
rate could be slowed down by the fact that the pH value always
decreased in the process of Maillard reaction (Cai et al., 2016;
Liu, Yang, Jin, Hsu, & Chen, 2008), which was attributed to the con-
sumption of the basic amino group and the formation of acidic
MRPs. Furthermore, it was reported that the activation energy
decreased as the system pH increased in glucose/bovine serum
albumin and glucose/casein Maillard reaction systems (El Hassan
Ajandouz et al., 2008), indicating that the Maillard action occurred
more easily at a higher pH value.
3.1.3. Effect of NaCl concentration on tyramine reduction rates
As tyramine has always existed in fermented foods with high
salt content (Yongmei et al., 2009), effect of NaCl concentrations
on tyramine reduction rates in the tyramine/glucose Maillard reac-
tion model system during heating at 100 °C and pH 8.0 for 5 h was
investigated. As shown in Fig. 2C, the tyramine/glucose Maillard
reaction was inhibited by the addition of NaCl. After heating at
100 °C and pH 8.0 for 5 h, the tyramine reduction rate was
significantly decreased from 77.41 ± 3.22% without NaCl to
22.54 ± 4.12% with 29.0% of NaCl (p < 0.05). Similar trends were
also observed at 0.5, 1, and 3 h, indicating that the tyramine reduc-
tion rate was inhibited in foods with high content of salt.
Effect of NaCl addition on the Maillard reaction was also studied
previously. Thongraung and Kangsanan (2010) found that the addi-
tion of 0.5–2.5% NaCl inhibited the Maillard reaction between fruc-
tose and surimi wash water at 95 °C and pH 9.0 for up to 12 h. In
contrast, Rizzi (2008) reported that the addition of 0.040 M NaCl
enhanced the Maillard reaction between ribose and glycine at
100 °C and pH 7.2 for up to 80 min. In another study, Kwak and
Lim (2004) studied the effect of NaCl addition on the Maillard reac-
tion between glucose and each of nine amino acids at 100 °C and
pH 6.5 for up to 6 h. The results showed that the addition of 1%
NaCl enhanced the glucose/alanine and glucose/phenylalanine
Maillard reactions but inhibited the reactions between glucose
and other amino acids, while the addition of 10% NaCl inhibited
the reactions between glucose and each of the nine amino acids.
3.1.4. Effects of initial glucose concentration and initial tyramine
concentration on tyramine reduction rates
Effect of initial glucose concentrations on tyramine reduction
rates in the tyramine/glucose Maillard reaction model system is
shown in Fig. 2D, during heating at 100 °C and pH 8.0 for 5 h. It
was observed that the tyramine reduction rates significantly rose
from 6.89 ± 0.41% with 5 mM glucose to 43.16 ± 3.10% with
320 mM glucose after heating for 0.5 h (p < 0.05). Similar trends
were also observed at 1, 3, and 5 h, indicating that the tyramine
reduction rate increased as glucose concentration increased. Effect
of initial tyramine concentrations on tyramine reduction rates in
the tyramine/glucose Maillard reaction model system is shown in
Fig. 2E, during heating at 100 °C and pH 8.0 for 5 h. After heating
for 5 h, the tyramine reduction rates were 100.00 ± 0.00,
92.07 ± 2.54, 78.25 ± 5.02, 65.54 ± 7.41, 52.03 ± 0.39 and
39.80 ± 4.48% when 40 mM glucose reacted with 0.5, 1, 2.5, 5, 10
and 20 mM tyramine, respectively. The decreased trends were also
observed at 0.5, 1 and 3 h, suggesting that tyramine reduction rate
decreased as tyramine concentration increased.
The results indicate that tyramine loss is enhanced by the
decreasing tyramine concentration or the increasing glucose con-
centration, exhibiting a positive correlation between tyramine
reduction rate and the concentration ratio of glucose to tyramine.
382 W. Jiang et al. / Food Chemistry 239 (2018) 377–384

Effect of the ratio of reactants on Maillard reactions has been 450

reported previously. For example, Li, Luo, and Feng (2011) investi-
400 A

Fluorescence intensity (A.U.)

gated the effect of the weight ratio of whey protein isolate to mal-
tose on the antigenicity of a-lactalbumin and b-lactoglobulin in 350
conjugates of whey protein isolate in whey protein isolate/maltose 300
Maillard reaction. Yang et al. (2015) studied the effect of the
250
weight ratio of soy protein isolate to soy soluble polysaccharide
on the emulsification capacity of the MRPs from soy protein isolate 200
and soy soluble polysaccharide. 150
100
3.2. Characterization of the tyramine/glucose Maillard reaction model
system 50
0
The Maillard reaction is a complex reaction between carbonyl
0 1 2 3 4 5 6 7 8 9 10 11 12
group of reducing sugars and free amino groups from amino acids,
peptides, proteins or other amino containing compounds. Gener- Time (h)
ally, the reaction process of Maillard reaction is divided into three 0.800
B
Time (h) 294 nm 420 nm
stages, namely initial stage, intermediate stage and final stage 0 0.003 0.000
(Nursten, 2005). 0.700 0.5 0.013 0.000
1 0.031 0.000
0.600 1.5 0.078 0.007
2 0.089 0.009
3.2.1. Changes in fluorescence intensity 2.5 0.122 0.015
Fluorescent compounds appeared prior to the formation of the 0.500 3 0.148 0.019

Absorbance
4 0.161 0.022
visible brown pigments. This is always used as the indicator of 0.400
12 h
6 0.204 0.033
10 h
the initial stage of the Maillard reaction (Baisier & Labuza, 1992). 8h
8
10
0.247
0.274
0.044
0.053
Fig. 3A shows the changes of fluorescence intensity of 2.5 mM tyra- 0.300 6h 12 0.298 0.057
heating time
mine, 40 mM glucose, the MRPs of 2.5 mM tyramine and 40 mM 4h
3h
0.200
glucose during heating at 100 °C and pH 8.0 for 12 h. It was
2.5 h
2h

observed that fluorescence intensity of tyramine or glucose was 0.100 1.5 h

1h

weak and did not change significantly during heating alone for
12 h. However, fluorescence intensity of the MRPs of 2.5 mM tyra-
mine and 40 mM glucose during heating at 100 °C and pH 8.0
increased significantly to the maximum value of 402.5 ± 12.7 at
3 h, and decreased dramatically with prolonged heating time to
12 h. The development of fluorescence intensity in various Maillard
reaction systems has been widely investigated. Jiang, Wang, Wu,
and Wang (2013) studied fluorescence intensity changes of Mail-
lard reactions between different sugars and bovine casein peptides.
The results showed that the fluorescence intensity of bovine casein
peptides/lactose MRPs rose steadily during heating at 95 °C for up
to 5 h, but bovine casein peptides/ribose MRPs decreased dramati-
cally after a maximum was reached at 1 h. Jiang and Brodkorb
(2012) found that fluorescence intensity of b-lactoglobulin/ribose
MRPs during heating at 95 °C reached the maximum at 2 h, fol-
lowed by a quick decline. Jing and Kitts (2002) revealed that fluo-
rescence intensity of ribose/casein MRPs during heating at 55 °C
reached the maximum within 5 days and decreased to a plateau
phase with prolonged heating time. These findings suggest that
the fluorescence intensity of MRPs of different Maillard reaction
systems change in various patterns. The reasons may be due to
the formation of different fluorescent substances, which is dictated
by the types of reactants and the reaction conditions.
3.2.2. UV–vis absorption spectra
Fig. 3B shows the UV–vis absorption spectra of tyramine/glu-
cose MRPs during heating at 100 °C and pH 8.0 for up to 12 h.
Without heat treatment, no detectable absorbance was observed
from 220 to 800 nm in the mixture of 2.5 mM tyramine and
40 mM glucose. As the heating time increased, the absorbance of
tyramine/glucose MRPs increased significantly, indicating that
new compounds were formed in this process. The development
of UV–vis spectra has been studied in different Maillard reaction
systems, which is reported affected by temperature (Li et al.,
2014), pH (Kim & Lee, 2008) and so on.
The UV absorbance at 294 nm is often used as the representa-
tive of the MRPs in the intermediate stage, whereas the absorbance
at 420 nm is related to the browning development in the final stage
0.5 h
0h
0.000
220 250 300 350 400 450 500 550 600 650 700 750 800
nm
Fig. 3. (A) Change in fluorescence intensity of 2.5 mM tyramine ( ), 40 mM glucose
( ) and the mixture of 2.5 mM tyramine and 40 mM glucose ( ), during heating at
100 °C and pH 8.0 for up to 12 h. Samples were diluted 10-fold with ultrapure water
prior to analysis. (B) UV–vis absorbance spectra of the mixture of 2.5 mM tyramine
and 40 mM glucose during heating at 100 °C and pH 8.0 for up to 12 h. Samples
were diluted 50-fold with ultrapure water prior to analysis. The inserted table
shows the absorbance change at 294 and 420 nm during heating.
of the Maillard reaction (Morales & Jiménez-Pérez, 2001). As
shown in the inserted table in Fig. 3B, absorbance at 294 nm
increased with the prolonging of heating time, implying that the
intermediate MRPs formed within 0.5 h. Nevertheless, absorbance
at 420 nm did not rise in the first 1 h, but increased dramatically
after that. This result indicates that browning pigments formed
after the tyramine/glucose Maillard reaction had progressed for
1 h. Besides, a characteristic absorbance peak was observed at
265 nm, which might suggest the generation of new products. This
phenomenon was also reported in the Maillard reaction between
e-polylysine and dextran, where a characteristic absorbance peak
at 325 nm was observed (Li et al., 2014).
3.3. Cytotoxicity assay
Although tyramine concentration was reduced during heating
with glucose under the proper conditions, the toxicity of the MRPs
was still unknown. Some categories of toxic MRPs such as
5-hydroxymethlofurfural (5-HMF), dicarbonyls, advanced glyca-
tion end products (AGEs) and heterocyclic amines (HAs), have
attracted considerable attention (Zhang et al., 2015). Therefore,
cytotoxicity of tyramine, glucose, tyramine-glucose mixture and
tyramine/glucose MRPs was evaluated by the MTT method using
normal human liver HL-7702 cells. As shown in Table 2, tyramine
exhibited obvious cytotoxicity to HL-7702 cells, and cell growth
 W. Jiang et al. / Food Chemistry 239 (2018) 377–384 383

inhibition rates increased from 16.99 ± 2.47% at the concentration 3.0

of 2 mM to 57.44 ± 2.40% at 10 mM (p < 0.05), indicating dose- A a
a

Tyramine concentration (mM)

dependent cytotoxicity to HL-7702 cells, whereas glucose did not a
2.5 a a
show observable toxicity. The results also showed that tyramine-
glucose mixture without heat treatment showed similar cytotoxi-
city to tyramine alone (p > 0.05). However, after heating at 100 °C ab
2.0
and pH 8.0 for 1 h, the cytotoxicity of MRPs-1 was significantly
lower than that of tyramine (p < 0.01). Furthermore, after at the b
c
same conditions for 5 h, the cytotoxicity of MRPs-5 was even lower 1.5
than that of MRPs-1. The results show that not only the tyramine
concentration was reduced in the tyramine/glucose Maillard reac-
tion, but also its cytotoxicity was lowered. The results were consis- 1.0
tent with a previous study which showed that the cytotoxicity of
fumonisin B1 could be reduced by Maillard reaction with glucose
(Meca et al., 2010). 0.5
0 1 2 3
Heating time (h)
3.4. Preliminary study on tyramine reduction in soy sauce
2.0

As food matrix is much more complex than the model system, B a

a a
a a

Tyramine concentration (mM)

the tyramine reduction ability of the tyramine/glucose Maillard
reaction was further assayed in soy sauce which has been reported
to contain high content of tyramine (Guidi & Gloria, 2012; Yongmei ab b
1.5
et al., 2009). Soy sauce is a traditional seasoning commonly used in
b
Asian countries. It is manufactured by fermentation of a mixture of
defatted soybean, roasted wheat flour, water and salt in the pres-
ence of koji mould for months. Soy sauce was mainly produced
by two types of manufacturing techniques, namely low-salt 1.0
solid-state fermentation and high-salt dilute-state fermentation
(Zhang, Zhou, Cui, Huang, & Wu, 2016). The low-salt soy sauce
sample is produced by low-salt solid-state fermentation and con-
tains 11.28 ± 0.79% (w/v) of salt with a pH of 6.21 ± 0.14, while
0.5
the high-salt soy sauce sample is produced by high-salt dilute- 0 1 2 3
state fermentation and contains 16.12 ± 1.04% (w/v) of salt with a Heating time (h)
pH of 5.98 ± 0.09. Tyramine concentrations of the low-salt soy
sauce and the high-salt soy sauce were measured as 2.54 ± 0.11 Fig. 4. Changes in tyramine concentrations in (A) low-salt and (B) high-salt soy
and 1.75 ± 0.09 mM, respectively. sauce samples with ( ) or without ( ) the addition of 2% (125 mM)
glucose during heating at 95 °C at different incubation times (0, 1, 2 and 3 h). Data
As the results in Fig. 2B and C show, soy sauce samples with
of the same group with different letters are significantly different (p < 0.05).
high salt content and low pH value are not ideal matrixes for the
tyramine/glucose Maillard reaction to proceed. Fig. 4 shows the
changes of tyramine concentrations in two soy sauce samples dur- other substances (such as amino acids, peptides, proteins and so
ing heating at 95 °C with or without the addition of 2% glucose on), or the presence of metal ions (Rizzi, 2017). These results
(125 mM). Tyramine concentrations in both samples without the indicate that tyramine reduction in the glucose-treated soy sauce
addition of glucose did not changed significantly during heating samples is mainly attributed to the tyramine/glucose Maillard
(p > 0.05). Nevertheless, after 3 h of glucose treatment, tyramine reaction. The influence on physiochemical properties of soy sauce
concentrations of low-salt soy sauce and high-salt soy sauce by Maillard reaction should be investigated in further experiments.
decreased significantly by 41.98 and 27.75%, respectively
(p < 0.05). The higher tyramine reduction rate in low-salt soy sauce 4. Conclusion
than in high-salt soy sauce might be explained by their differences
in salt content and pH value. Moreover, the tyramine reduction in In the tyramine/glucose Maillard reaction, effects of tempera-
soy sauce might be inhibited by the reactions between glucose and ture, heating time, initial pH value, NaCl concentration, initial

Table 2
Cytotoxicity assay of tyramine, glucose, tyramine-glucose mixture and tyramine/glucose Maillard reaction products (MRPs).

LevelsA Cell growth inhibition rate (%)

Tyramine Glucose MixtureB MRPs-1B MRPs-5C
1 16.99 ± 2.47a 1.87 ± 0.56**a 20.37 ± 5.59a 10.05 ± 1.53**a 5.22 ± 1.06**a
2 25.96 ± 2.93b 1.34 ± 0.76**b 25.28 ± 1.68ab 13.68 ± 1.84**a 8.51 ± 2.54**ab
3 30.05 ± 1.87bc 1.35 ± 0.12**b 31.01 ± 1.70b 22.50 ± 2.54*b 13.63 ± 4.93**bc
4 35.93 ± 3.18c 1.14 ± 0.94**b 33.21 ± 1.00b 25.04 ± 1.89**b 15.69 ± 1.44**bc
5 57.44 ± 2.40d 1.29 ± 0.81**b 53.49 ± 4.86c 32.85 ± 2.42**c 19.70 ± 2.57**c

Data in the same row with ** are significantly different vs Tyramine group (p < 0.01), * are significantly different vs Tyramine group (p < 0.05).
Data in the same column with different letters are significantly different (p < 0.05).
A
The details of levels were shown in Table 1.
B
The mixture was prepared by freeze-drying the mixture of 2.5 mM tyramine and 40 mM glucose in 50 mM PBS (pH 8.0).
C
The MRPs were prepared by freeze-drying the reaction products of 2.5 mM tyramine and 40 mM glucose after heating at 100 °C for 1 h (MRPs-1) or 5 h (MRPs-5) in
50 mM PBS (pH 8.0).
384 W. Jiang et al. / Food Chemistry 239 (2018) 377–384
glucose concentration and initial tyramine concentration on tyra-
mine reduction rate were investigated. The increase of tempera-
ture, heating time, initial pH value or initial glucose concentration
enhanced tyramine reduction, whereas the increase of NaCl con-
centration or tyramine concentration inhibited tyramine reduction.
Fluorescence intensity and UV–vis spectroscopy were used to
characterize three stages (initial, intermediate and final stages) of
the tyramine/glucose Maillard reaction. Cytotoxicity of tyramine,
glucose, tyramine-glucose mixture and tyramine/glucose MRPs to
HL-7702 cells was assayed, revealing that tyramine/glucose MRPs
were less toxic than tyramine. Furthermore, tyramine concentra-
tions in two commercial soy sauce samples were significantly
reduced by heating with the addition of glucose. From a practical
standpoint, this study provides a scientific basis for the application
of the Maillard reaction in foods for tyramine reduction.
Conflict of interest
The authors declare that they have no conflicts of interest.
Acknowledgements
This work was supported by the Zhejiang Provincial Natural
Science Foundation of China [grant number LQ15C200008], the
Natural Science Foundation of China [grant number 31501573],
and the Research Start-up Funding of Zhejiang Ocean University
[grant numbers Q1442 and Q1443].
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