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The colorants, antioxidants, and toxicants from

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Cite this: Food Funct., 2015, 6, 345

nonenzymatic browning reactions and the impacts
of dietary polyphenols on their thermal formation
Xinchen Zhang,a Ningping Tao,a Xichang Wang,a Feng Chenb and Mingfu Wang*a

Nonenzymatic browning reactions proceed with the starting reactants of sugar and/or protein during
thermal processing and storage of food. In addition to food color formation, the process also contributes
to the loss of essential nutrients, generation of beneficial antioxidants, and production of toxicants,
including 5-hydroxymethylfurfural (5-HMF), reactive carbonyl species, advanced glycation end products
(AGEs), and heterocyclic amines (HAs). Recent research has demonstrated that dietary polyphenols can
actively participate in nonenzymatic browning reactions, contributing to the generation of new colorants
and antioxidants. More importantly, polyphenol addition has been found to be an effective approach to
mitigate heat-induced formation of toxicants, mainly through inhibiting oxidative pathways and trapping
reactive intermediates. In the matrix of polyphenol-fortified foods, a complex array of chemical inter-
actions happen among polyphenols, traditional nutritional components, and neo-formed compounds
Received 4th November 2014, they are thermally converted to. These reactions play a significant role in the colorants, antioxidants as
Accepted 11th November 2014
well as toxicants production. Our findings support the potential of dietary polyphenols for increasing
DOI: 10.1039/c4fo00996g the antioxidant content and for reducing the level of toxicants when they participate in nonenzymatic
www.rsc.org/foodfunction browning reactions in fortified food products.

1. Introduction includes two representative types: caramelization and the Mail-

lard reaction.
Browning is one of the most important chemical processes Caramelization is initiated by thermal treatment of carbo-
occurring in food during processing and storage. It not only hydrates. Monosaccharides (glucose and fructose), disacchar-
represents changes towards a darker color, as seen by the ides (sucrose) or hydrolyzed polysaccharides (dextrose and
naked eye, but indicates possible alterations in the stability, glucose syrup) are usually selected for industrial caramel pro-
nutritional composition as well as health-related effects of duction. The raw carbohydrates undergo a few unselective and
food products.1 Browning reactions can be either desirable, chemoselective reactions, and finally lead to the formation of
such as in the case of generating the golden-brown crust of numerous polymeric and degradation products, including
bakery foods, or undesirable, such as when the browning both volatile and non-volatile products associated with food
deteriorates the appearance and economic value of stored fruit flavor and color. The key aroma compounds produced by sugar
juice. A variety of chemical species present in food may take caramelization have been well characterized as diacetyl, furans
part in browning reactions via multiple chemical pathways. (furfural, hydroxymethylfurfural, acetylfuran, and hydroxy-
Based on whether enzymes are involved in the reaction, brown- acetylfuran), furanones (hydroxydimethylfuranone, dihydro-
ing reactions can be divided into enzymatic and non-enzy- xydimethylfuranone), 4-pyrone derivatives, maltol and
matic browning. The phenomenon of a cut apple slice turning hydroxymaltol.2,3 In comparison, identification of the diverse
brown when exposed to air is a typical example of enzymatic non-volatile caramelization products still remains a challenge
browning facilitated by polyphenol oxidase. In comparison, due to a lack of powerful analytical techniques. One de-
nonenzymatic browning is favored by thermal treatment and hydration product (C12H18O9) and two polymers (C36H50O25 and
C96H102O51) were firstly observed in sucrose caramel.4 Furfur-
als remaining in the non-volatile portion were examined and
a
quantified by chromatographic analysis.5,6 A recent advance
School of Food Science and Technology, Shanghai Ocean University, Shanghai,
P. R. China. E-mail: [email protected]
chemical characterization of the non-volatile caramel com-
b
Institute for Food & Bioresource Engineering, College of Engineering, ponents has been achieved by taking advantage of combined
Peking University, P. R. China mass spectrometric techniques. A few chemical species have

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been reported, such as carbohydrate oligomers (up to six sugar These reactive products in turn decarboxylate and incorporate
units), dehydration products of sugar oligomers (a maximum into nitrogen compounds to form aldehydes via Strecker degra-
of eight water molecules lost, hydroxyfurfural derivatives dation. The sugar degradation products, ARPs, Strecker inter-
included), hydration products of sugar oligomers, redox dis- mediates and the further derived reaction products, such as
proportionation products, and colored aromatic products.2 rearranged sugars, pyrroles, furans, carbonyls, Strecker alde-
The Maillard reaction is another typical nonenzymatic hydes and pyrrazines, are all important Maillard reaction-
browning reaction, which is named after its first describer—a derived flavor compounds.8 Formation of brown nitrogenous
French chemist called Louis Maillard. The Maillard reaction is polymeric melanoidins occurs in the advanced stage of the
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even more important than caramelization due to its contri- Maillard reaction, as a result of reactions such as cyclization,
bution towards food aroma, color and taste. Not only are the dehydration, retroaldolization, rearrangement, isomerization
wide range of Maillard reaction products closely associated and condensation.9
with sensory attributes, they are responsible for alternations in The formation of nonenzymatic browning reaction products
the nutritional values of foods regarding digestibility and the depends on the type and concentration of sugar/amino com-
formation of antioxidants and toxicants. Starting with the con- pounds, pH as well as the thermal preparation variables such
densation of a reducing sugar and a compound possessing a as heating temperature and duration. It has been a major task
free amino group, such as a protein, the reaction proceeds to in the food industry since a long time to understand nonenzy-
encompass an entire network of reactions with great complex- matic browning reaction pathways and the key factors affecting
ity and variety. Hodge7 originally proposed the first compre- product composition. In the recent decades, dietary polyphe-
hensive scheme of the Maillard reaction (Fig. 1), which nols have been popularly proposed as functional food ingredi-
represents a milestone in the understanding of the reaction ents, capable of affecting the formation of nonenzymatic
and provides the basis for later interpretation and elaboration browning reaction products and therefore improving the
by food scientists. According to the reaction scheme, conden- appearance, taste and health effects of food so as to meet cus-
sation of a reducing sugar and a compound with a free amino tomers’ needs. Dietary polyphenols represent a large group of
group gives rise to an N-substituted glycosylamine in the early natural compounds synthesized as secondary metabolites of
stage, which rearranges to become Amadori rearrangement plants for defense against ultraviolet radiation or patho-
products (ARP). The Amadori products undergo further degra- gens.10,11 Over 8000 polyphenol structures have been identi-
dation and dehydration depending on the pH of the reaction fied,12 with the common feature of multiple phenol rings.13
system: at acidic pH, 1,2-enolization dominates and 5-hydroxy- Distinction among the diverse polyphenol structures relies on
methylfurfural (5-HMF) or furfural are formed as intermedi- the number of phenol rings and the structural elements that
ates; at alkaline pH, the ARPs are engaged in 2,3-enolization, connect and bind to the rings.14 In addition, natural polyphe-
giving rise to reductones, dehydroreductones, and a variety of nols may be associated with various carbohydrates and
fission products, including acetol, diacetyl, and pyruvaldehyde. organic acids.11 The structural diversity is important for the

Fig. 1 Maillard reaction scheme.7

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various physicochemical properties of these phytochemicals12 grouped into either low molecular weight pigments (two to
and this review focuses on the potential of dietary polyphenols four linked rings with extended double-bond conjugation) or
to affect the formation of colorants, antioxidants and toxicants high molecular weight melanoidins (molecular weight of
from nonenzymatic browning reactions in chemical and food several thousand daltons, with discrete chromophores).19 Iso-
models under thermal conditions. lation of melanoidins has been attempted by gel/paper/capil-
lary zone electrophoresis and reversed-phase HPLC but the
diverse chemical properties of melanoidins hinder the pro-
2. Impact of dietary polyphenols duction of satisfactory results.18 Analytical techniques that
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have been applied to characterize the structure of melanoidins

on the thermal formation of include infrared (IR) spectroscopy, mass spectrometry (MS)
nonenzymatic browning reaction and advanced multidimensional nuclear magnetic resonance
products (NMR).18,20
Some previous studies have attempted to correlate color
2.1 Colorants development with 5-hydroxymethylfurfural (5-HMF) content,
The “brownness” of food is one of the most evident quality but the results suggested that 5-HMF alone is not sufficient to
attributes that consumers respond to. The brown color can account for color formation.21 The sources of the colorants
either increase the attractiveness or deteriorate the acceptance include Strecker aldehydes, sugar fragments, furfurals and
of a food product. Caramel has been applied as a natural dehydroreductones, which undergo self-condensation or con-
pigment in food additives for over a hundred years.14 The use dense with each other to form the brownness.22,23 Experiments
of caramel colorants accounts for more than 80% by weight of conducted in a sugar-protein system supplemented that
colorants used in the food manufacturing industry.3 Caramel proteins can act as the backbone of melanoidins and protein
has many advantages over synthetic colorants in terms of oligomers are cross-linked by low molecular weight color-
safety, digestibility, and dispersibility in the food system and ants.24,25 Altogether, the formation of high molecular weight
stability against heat and pressure.3 Depending on the type or melanoidins may follow two paths: (1) polymerization of low
amount of reactants and the manufacturing conditions, molecular weight colored/colorless reaction intermediates; (2)
caramel colors vary in composition and provide great variety attachment of chromophoric low molecular weight substruc-
ranging from pale yellow to dark brown.15 The colorants effec- tures ( possibly derived from carbohydrates) to the backbone of
tively make food products more indicative of their taste and colorless oligomers.17
more appealing to consumers. For example, the addition of The possible effect of dietary polyphenols on the formation
powdered or liquid caramel allows manufacturers to standar- of colorants from nonenzymatic browning reactions and there-
dize the color of baking mixes and seasoning blends.3 In fore fortified food color development is an important issue to
addition, caramel colors possess useful functional properties. consider regarding the application of polyphenols as functional
Caramel can be applied to enhance adhesion in rice cakes and food ingredients. The potential alteration in color induced by
energy bars.16 Other functional characteristics include colloid natural dietary polyphenols could be both physical, upon food
stabilization, flavor retention, foaming promotion, dispersion product appearance, and chemical, related to the stability and
facilitation and haze prevention, which are desirable in certain compatibility of the color in a certain food category.14
food products.15 In the fructose caramelization model at 120 °C, the
Either a sensory panel or an analytical instrument can be addition of six selected polyphenols ( phloretin, naringenin,
utilized to evaluate the color. Absorbance at 420 nm is often quercetin, epicatechin, chlorogenic acid and rosmarinic acid)
adopted to indicate the presence of brown pigments. This significantly increased the browning intensity of caramel.26
spectrophotometrically measured browning value can be trans- The effects were particularly great for phloretin and epicate-
lated into the concentration of colorants if the average molar chin. Accordingly, the addition of phloretin and epicatechin
extinction coefficients of the colorants formed in the nonenzy- resulted in a lower L* value, a higher a* value and correspond-
matic browning reaction system are determined.17 Under the ingly a higher Chroma value, and a smaller E index of caramel.
3-dimensional color scale developed according to human per- pH was found to be a relevant factor regarding the impacts of
ception, the chromatic coordinate L* indicates the lightness of polyphenols on the caramel’s yellowness. Moreover, the
color (L* = 0 yields black and L* = 100 means diffuse white); observed difference between the browning intensity of the
a* characterizes the position between red and green (negative polyphenol-treated caramel and the calculated sum of the
values indicate green and positive values indicate red); browning of the control caramel and the heated polyphenol
b* suggests the position between yellow and blue (negative solution suggested that in addition to the oxidative browning
values indicate blue and positive values indicate yellow). of polyphenols themselves, chemical reactions between poly-
Knowledge on the chemical nature and formation mechan- phenols (or their thermal transformation products) and sugar
ism of the colorants is limited;17 however, research interest is caramelization products also contributed to the production of
growing in consideration of the pigments’ physically and bio- new brown pigments in the reaction system.26 The shifts in
chemically valuable functions.18 The colorants are either chromatic coordinates were attributable to the formation of
unsaturated nitrogenous or nitrogen-free polymers and can be thermal oxidative transformation products of polyphenols as

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well as new unknown compounds from the participation of products from heating fructose or glucose solutions. Both
polyphenols in the sugar caramelization.26 There have been sugar solutions potentially produce caramelization products
examples in Maillard reaction models as well. When glucose with pronounced antioxidant activity at an alkaline pH for an
and lysine were mildly heated at 140 °C, the addition of two extended time but fructose was superior to glucose in forming
apple polyphenols, phloretin and phloridzin, was reported to antioxidants. Moreover, the antioxidant activity was concurrent
affect color development, to lower lightness and yellowness with the formation of intermediates and browning.35
but increase redness.27 Ferulic acid significantly inhibited the The electron donating ability and 2,2′-azino-bis(3-ethylben-
formation of brown melanoidins in model glycation mixture zothiazoline-6-sulphonic acid) (ABTS) cation radical scaven-
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systems containing fructose and soy glycinin or BSA heated at ging activity of a heated fructose solution was also reported to
60 °C.28 increase with increasing heating temperature and time.36 Com-
Furthermore, in chemical model systems, attempts to add pared with disaccharides, heating of monosaccharides was
polyphenol into real food have generated evidence of polyphe- found to produce caramel of stronger antioxidant capacity and
nols’ potential to influence food color. Grape seed extract high sugar concentration was suggested to partially overcome
(GSE) addition prior to bread baking induced visual colori- the negative influence of low pH on monosaccharides or high
metric changes by reducing lightness but promoting redness pH on disaccharides.37 This study further pointed out that the
and yellowness, therefore resulting in a lower E index value brown pigments in caramel, instead of the colorless carameli-
inversely correlated to the levels of GSE addition.29 Green tea zation intermediates, likely contributed to the antioxidant
extract (GTE) addition led to a similar decrease in bread activity and the increased rate of antioxidant capacity might be
brightness.30 0.25% (w/w) quercetin, chlorogenic acid or ros- closely reflected by ΔpH.37
marinic acid decreased the redness and increased the yellow- Protein itself is a weak antioxidant but heating protein and
ness of fortified cookies, whereas epicatechin or naringenin sugar together may result in enhanced antioxidant activity, as
elevated the cookie’s redness or yellowness, respectively. reported by an experiment conducted in a model system com-
Comprehensively, the polyphenols increased the chroma value posed of casein and glucose/lactose. The enhancement in anti-
but not the E index.31 On the basis of the analyses conducted in oxidant capacity was indicated to be attributed to Maillard
chemical models, the colorimetric changes induced by poly- reaction products (MRPs) and was a function of the initial
phenol fortification in food products are likely to be accounted sugar and protein concentrations.38 A recent study incorpor-
for by the colorants formed from the thermal transformation ated porcine plasma protein and reducing sugars (glucose,
of polyphenols together with the unknown neo-colorants pro- fructose and galactose) heated at 100 °C without pH control.
duced from the interaction of polyphenols with other nutri- As in the caramelization model, the antioxidant capacity of the
tional components of food.31 MRPs increased with the sugar concentration and was concur-
rent with the development of intermediates and browning.
2.2 Antioxidants Comparison among the different types of sugar revealed that
In addition to aroma and color compounds, nonenzymatic the MRPs derived from galactose had higher DPPH radical scaven-
browning reactions have been shown to produce compounds ging activity and reducing power than those from glucose or
exhibiting antioxidant activity. The exact chemical nature of fructose.39 The amino acid–sugar model was found to more
the antioxidants formed, however, remains unclear. One of the readily generate antioxidants than the protein–sugar model,
early observations indicated that the addition of 5% glucose and the antioxidant activity of MRPs may also be affected by
prevented sugar cookies from oxidative rancidity.32 Heat treat- temperature and pH.39
ment of milk products and cereals led to improved oxidative Ultrafiltration has been applied to separate MRPs into frac-
stability, which was believed to be associated with the for- tions based on molecular weight.40 MRPs of different mole-
mation of antioxidative nonenzymatic browning reaction pro- cular weight were proposed to exhibit different antioxidant
ducts. These novel antioxidants may partially explain the activities,41 and the high molecular weight MRPs, such as mel-
phenomenon of roasted coffee brews having higher antioxida- anoidins, were indicated to be the major antioxidants formed
tive activity than unroasted brews containing higher concen- by the Maillard reaction in this study. Melanoidins extracted
trations of phenolic antioxidants.33 from vinegar exhibited DPPH/hydroxyl radical scavenging
When different sugar (glucose, fructose, ribose and xylose) activity and reducing power.42 Melanoidins prepared from
solutions were heated at 100 °C, the nonvolatile fraction of pre- xylose and glycine showed comparable antioxidant activity to
pared sugar caramel possessed 2,2-diphenyl-1-picrylhydrazyl butylated hydroxyanisole (BHA) and butylated hydroxytoluene
(DPPH) radical scavenging activity, which reduced power and (BHT) and a synergistic effect was observed when melanoidin
ferrous ion chelating activity.34 The production of antioxidants was applied in addition to tocopherol, BHA, or BHT for inhi-
seemed to be tightly associated with the formation of carameli- biting linoleic acid autoxidation.33 It is possible to draw a
zation intermediates and brown compounds, which was simple positive correlation between color and antioxidant pro-
dependent on the type of sugar, heating time and pH. Fructose perties in foods where the formation of antioxidant MRPs is
heated at more alkaline conditions for a sufficiently long time prevalent during processing. In this case, color could be con-
showed the highest antioxidant activity.34 Similar results were sidered as an index of antioxidant properties as the formation
generated in another study trying to prepare caramelization of antioxidants and color follow the same pathway.1

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Traditionally, synthetic antioxidants such as BHA and BHT chemical degradation or oxidation of the original polyphenol
are used to prevent oxidative food deterioration by inhibiting structure or chemical reaction between polyphenols and cara-
free radical facilitated lipid peroxidation. The neo-antioxidants melization intermediates, such as sugar fragments, both poss-
produced during nonenzymatic browning reactions may be ibly leading to the loss of the specific structural motifs
promising safer natural alternatives for improving the oxi- carrying antioxidant activity.26
dative stability of foods.33 However, attention should be paid The addition of polyphenols into food has been reported to
to the stability of these neo-antioxidants. Fructose caramel result in a health-beneficial increase in food’s antioxidant
could retard the formation of thiobarbituric acid reactive sub- potential. Grape seed extract fortification at levels of 0.06%–
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stances (TBARS) in a comminuted saury model system during 0.2% (w/w), for example, evidently elevated the antioxidant
iced storage.34 MRPs prepared by reacting casein peptides with activity of the corresponding bread sample.29 Naringenin,
glucose at 80 °C showed an improvement in the oxidative quercetin, epicatechin, chlorogenic acid and rosmarinic acid
stability of fish oil in water emulsions, as evaluated by the at a fortification level of 0.25% (w/w) led to significantly
length of the lag phase of oxidation.43 increased antioxidant capacity of fortified cookie extracts pre-
One of the most recognizable physicochemical properties of pared by extraction with solvents of different polarity.31 The
dietary polyphenols is their potential for inhibiting oxidative two studies shared a similar observation that the thermal pro-
processes in vitro and free radical scavenging is the most cessing lowered the antioxidant capacity of the originally
widely investigated antioxidant mechanism for polyphenols.44 added polyphenols, particularly in the cases of polyphenols
On the basis of comparison of the rate constants of the reac- with poor thermal stability. The influence of the usual thermal
tions to the hydroxyl radical (•OH), azide radical (N3•), super- food cooking conditions on the overall antioxidant activity of
oxide anion (O2•−), lipid peroxyl radical (LOO•) and t-butyl foods is a result of different events occurring consecutively or
alkoxyl radicals (tBuO•) as well as the stability of the resulting simultaneously.49 It is expected that thermal processing may
antioxidant-derived radical, polyphenols are more effective cause structural degradation of polyphenols. For example,
antioxidants than vitamin C and E in vitro on a molar when boiling and steaming black beans, a significant decrease
basis.13,45 Furthermore, polyphenols have also been reported in phenolic quantity was associated with reduced antioxidant
to have metal-chelating activity, which contributes to the pre- power.50 Under the low-moisture and high-temperature
vention of free radical formation catalyzed by transition metals (200 °C) cookie baking environment, it took as little as 10 min
such as iron and copper.13,44,45 for naringenin to lose over 30% of its primary compound and
The antioxidant activity of polyphenols is derived from around 88% significant loss was recorded for quercetin.31 For
their ubiquitous chemical structure – a highly conjugated quercetin, besides degradation, heat-stimulated oxidation is
system sometimes with specific hydroxylation patterns.12 The an alternative way to deteriorate the polyphenol structure for
structure is ideal for donating electrons or hydrogens to sca- expressing antioxidant activity.31
venge, neutralize and stabilize the free radicals and therefore In some other cases, including the processes of pressure
break the oxidative chain reactions.12 The ortho 3,4-dihydroxy steaming yellow beans, cooking tomatoes, and high pressure
moiety in the B ring and the meta 5,7-dihydroxy moiety in the processing of tomato and carrot purees, thermal processing
A ring of flavonoids appear to be important structural determi- may have positive effects on the phenolic content and antioxi-
nants of their antioxidant capacity, and hydroxylation on the dant activity.50–52 Partially oxidized polyphenols are able to
carbon ortho to the 4-C position may further increase the anti- exhibit similar antioxidant activity as non-oxidized polyphe-
oxidant capacity.45,46 The 2,3-double bond combined with the nols.1 Moreover, the thermal reactions between polyphenols
3-hydroxyl and 4-keto groups in the C ring has been suggested and other food nutritional components may lead to an
to assist antioxidant activity as well.45 Glycosidation, however, improvement in the antioxidant capacity of the originally
probably alters the pattern of hydroxyl groups, or substitutes/ occurring compounds and the formation of neo-antioxi-
blocks the functional groups responsible for radical scaven- dants.29,31,49 Therefore, it seems to be necessary to consider
ging or metal chelating and therefore weakens the antioxidant the thermal stability and reactivity of polyphenols in the food
activity of flavonoids.45,47 The degree of polymerization also matrix when the food product is fortified with polyphenols for
has effects on antioxidant capacity.48 the purpose of increasing the level of health-beneficial
A recent study investigated the effects of polyphenols on antioxidants.
the formation of heat-induced antioxidants during fructose
caramelization at 120 °C and how the thermal conditions of 2.3 Toxicants
caramelization would affect the polyphenols’ antioxidant In the recent decades, the toxicological activities of Maillard
activity. Results showed that the six tested polyphenols ( phlor- reaction products (MRPs) have attracted considerable attention
etin, naringenin, quercetin, epicatechin, chlorogenic acid and as certain types of MRPs have been reported to contribute to
rosmarinic acid) all greatly enhanced the antioxidant activity disease and cancer development. Four major categories of
of caramel but the increase was generally less than that of ther- toxic compounds originating from nonenzymatic browning
mally processed polyphenols. Further instrumental analysis reactions are 5-hydroxymethylfurfural (5-HMF), dicarbonyls,
illustrated that in a thermal caramelization system, reduction advanced glycation end products (AGEs) and heterocyclic
in the polyphenols’ antioxidant capacity could be due to either amines (HAs).

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2.3.1 5-Hydroxymethylfurfural (5-HMF). 5-Hydroxymethyl- It is regarded as a difficult and challenging task to specifi-
furfural (5-HMF) is a common type of furfural intermediate of cally mitigate 5-HMF formation during thermal food proces-
nonenzymatic browning reactions and it is regarded as the sing because its formation pathways tightly correlate with the
most important heat-induced contaminant in bakery pro- production of color and flavor compounds. None of the pre-
ducts.53 Measurement of 5-HMF content in foods was tra- viously proposed strategies, including lowering heating temp-
ditionally performed by colorimetric absorbance reading at erature, shortening heating time or using less reactive
443 nm, which reflects the amount of the complex formed carbohydrates, is capable of lowering 5-HMF formation
from 5-HMF with 2-thiobarbituric acid. The method, however, without negatively affecting browning development. A recent
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suffers from low specificity for 5-HMF because 2-thiobarbituric study found that in the fructose caramelization model at
acid generally reacts with all aldehydes. Therefore, reverse- 120 °C, rosmarinic acid addition showed over 40% inhibition
phase HPLC is currently widely adopted for considerably more of 5-HMF formation at both neutral and alkaline pH, whereas
accurate quantification of 5-HMF.54 Given that sugar is the the inhibitory activity of quercetin and epicatechin was only
source of precursor to 5-HMF formation, foods rich in sugars shown at neutral pH. A concurrent reduction in furfural level
or ingredients such as sugar caramel or honey tend to contain was also observed for rosmarinic acid addition.26 Given that
higher quantities of 5-HMF. Furthermore, the amount of rosmarinic acid addition caused no destruction on the brown-
5-HMF is directly related to the heat load during processing. ing intensity of caramel, rosmarinic acid might be a promising
Dietary intake of 5-HMF is mainly through bread and coffee natural HMF inhibitor with practicality in caramel-type food
and the daily exposure is estimated to be several orders of preparation.
magnitude higher than that of other heat-induced food toxi- 2.3.2 Reactive carbonyl species. The α-dicarbonyl com-
cants such as acrylamide and furan.53 pounds are another group of important nonenzymatic brown-
As shown in Fig. 2, formation of 5-HMF starts from 1,2-eno- ing reaction intermediates, including glyoxal (GO),
lization and dehydration of sugar to produce the key inter- methylglyoxal (MGO) and glucosones. During food processing,
mediate, 3-deoxyosone, which further dehydrates and cyclizes they are either directly derived from sugar fragmentation,
to yield 5-HMF. The rate of formation increases with the thermal transformation of Schiff bases and Amadori
increase in temperature and time and is favored in acidic con- rearrangement products, or lipid degradation.58,59 As shown in
ditions.53,55 The type and concentration of sugar, water Fig. 3, glucosone is produced by sugar autoxidation; GO can be
activity, the concentration of divalent cations, and other nutri- generated from glucose by retro-aldol condensation or through
tional components, such as fat, in the reaction media/food oxidation of early Maillard reaction products; deprotonation
system have also been reported to affect 5-HMF formation.53,56 and dehydration of glucose lead to the formation of 1,2-enol
An alternative mechanism of 5-HMF formation under high- or 2,3-enol and thereby 1-deoxyglucosone (1-DG) or 3-deoxyglu-
temperature dry pyrolytic conditions was proposed, which cosone (3-DG), fragmentation of which forms MGO.59,60 Sugar
emphasized the formation of a very reactive fructofuranosyl fragmentation is favored by alkaline and oxidative con-
cation that could be effectively converted into 5-HMF.57 ditions.60 Monosaccharides are more capable of forming dicar-

Fig. 2 Formation pathway of 5-HMF from D-fructose.53

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Fig. 3 Formation of GO and MGO from glucose and the Maillard reaction.59,60

bonyls and glucose tends to yield more dicarbonyls than fruc- cursors, including Schiff bases and fructosamine.63 The same
tose.59 Moreover, the formation of dicarbonyls is influenced by research group also attempted to investigate the carbonyl
phosphate buffer and trace metal ions, which may catalyze the inhibitory activity of dietary polyphenols in the cookie model
deprotonation and autoxidation of sugar.60 with a baking temperature of 200 °C and it was found that the
Compared to sugar, dicarbonyls possess a considerably five tested polyphenols (naringenin, quercetin, epicatechin,
higher browning activity and their formation during food pro- chlorogenic acid and rosmarinic acid) were all GO inhibitors
cessing is essential to the production of heterocyclic aroma but not MGO inhibitors. On the basis of the correlative analy-
and color compounds.33,58 Dicarbonyls have been detected in sis between inhibition rate and polyphenols’ free radical
a range of food products, including cookies, honey, coffee, and scavenging capability, the GO inhibition mechanism was
other beverages,58 but the data are still limited. The high reac- hypothesized to be through blocking the peroxidation of the
tivity and ease of volatilization and polymerization make it unsaturated lipids contained in the cookie recipe.31 Therefore,
difficult to specifically quantify the amounts of dicarbonyls, it seems that under thermal conditions, multiple mechanisms
such as GO and MGO, in food products and biological may exist for polyphenols’ inhibition against the formation of
samples.61 The quantification is facilitated by a necessary deri- reactive dicarbonyls, depending on the type of chemical com-
vatization process with derivatization agents before HPLC or ponents in the reaction model and condition parameters.
GC analysis and the derivatives can then be detected by UV, 2.3.3 Advanced glycation end products (AGEs). As indi-
MS, ECD (electron-capture detector), NPD (nitrogen phos- cated by the name, advanced glycation end products (AGEs)
phorus detector), or FPD (flame photometric detector).60 are produced in the advanced stage of the Maillard reaction.
In aqueous thermal Maillard reaction model systems at The group of intermediate compounds produced during the
125 °C, epicatechin (EC) was found to directly trap MGO in Amadori rearrangements, including the reactive carbonyl
such a way that the C6 or C8 of EC’s A ring could covalently species (glyoxal, methylglyoxal and 3-deoxyglucosone), have
link to the C1 of MGO, presumably by hydroxyalkylation and been proposed to be the immediate precursors of
aromatic substitution reactions.62 In another thermal glucose- AGEs.28,61,64–67 The reaction between these precursors and the
casein glycation model at 120 °C, chlorogenic acid was eluci- amino groups of proteins could happen either oxidatively
dated to be a GO and MGO inhibitor and the inhibition was or non-oxidatively, giving rise to different types of AGEs.68
likely to be achieved by lowering the amount of dicarbonyl pre- Carboxymethyllysine (CML) and pentosidine are two of the best

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Review Food & Function

characterized AGEs detectable in a wide variety of foodstuffs during lipoxidation.69,73,76 Niquet-Leridon and Tessier77 added
such as meat, milk products and bakery products.69 that the more the protein that is present, the lesser the
CML is a type of nonfluorescent and non-crosslinking AGE. proportion of lysine residues that are converted to CML. Redu-
Several instrumental methods have been utilized to quantify cing sugars were considered to be the primary precursor of
CML in foods, including GC-MS,70 RP-HPLC,71 (UP)LC-MS/ CML in drink mixes and the sugar contained in the sauce
MS72,73 and ELISA (enzyme-linked immunosorbent assay).69,74 exerted synergistic effects with heat during pentosidine for-
In a previous study, CML was relied on as a base marker to mation in sauced meat and fish.73,76,77 It is generally believed
reflect the general AGE level in foods.74 It was found that foods that both the Maillard reaction and lipid peroxidation play
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belonging to the meat and meat substitutes category are richer roles in the formation of dietary AGEs and their relative impor-
in CML than those in the carbohydrates group. Thermal pro- tance varies.78 Typically, the formation of AGEs in food is a
cessing elevated CML from lower than a thousand kilounits in comprehensive result of amino group blockage by the oxidative
raw meat and fish to several thousand kilounits in the pro- degradation products of sugar, lipid or ascorbic acid. Metal
cessed state.74 The extent of new CML formation was ions, such as iron, were noted for catalyzing the formation
suggested to be largely dependent on the cooking styles, which of dietary AGEs by activating sugar and ascorbate
differ in temperature, duration and moisture content. Broiling oxidation.71,72,79
and frying led to more CML formation than roasting and There have been limited investigations of the antiglycation
boiling, whereas microwaving tended to be the practice result- activity of dietary polyphenols under thermal conditions but
ing in the lowest amount of CML.69 the available results suggest the potential effectiveness of poly-
Pentosidine, in contrast, is fluorescent and cross-linked. It phenols. For example, ferulic acid inhibited the formation of
is present at relatively low levels in foods and can be quantified fluorescent AGEs and carboxymethyllysine (CML) by nearly
by ion exchange chromatography with fluorescence detection 90% and 85%, respectively, in a thermal fructose/soy glycinin
and subsequent ninhydrin derivatization.75 Roasted coffee was model heated at 60 °C.28 In a glucose-casein glycation model
found to contain the highest amount of pentosidine up to at 120 °C, five tested polyphenols ( phloretin, naringenin, epi-
40 mg kg−1 protein, followed by bakery goods from non-detect- catechin, chlorogenic acid and rosmarinic acid) inhibited the
able to over 20 mg kg−1 protein.75 148–672 μg of pentosidine formation of total fluorescent AGEs by over 50% at pH = 7; the
was detected per 100 g of sauced meat or fish sample cooked inhibition rates for phloretin and naringenin were as high as
in three different ways (boiling, frying, and baking).76 over 70%. For CML, weaker inhibitory activity ranging from
The formation of both CML and pentosidine in food is an 13% to 45% was recorded at pH = 7. Moreover, the antiglyca-
oxidative process (Fig. 4). In addition to heat and dryness, the tion activity at pH = 10 of polyphenols followed a similar order
glycoxidation process is tightly associated with the nutritional but was generally lower.63 Under baking condition at 190 °C, a
composition of food products. High lipid content, particularly significant reduction in the CML level of sponge cake was
polyunsaturated fatty acids, has been reported to promote the observed as a result of the addition of ferulic acid.80 Dose-
formation of AGEs possibly due to the free radicals released dependent CML inhibition during bread baking was reported

Fig. 4 Formation pathways of CML and pentosidine in food.68

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Food & Function Review

for grape seed extract (GSE) rich in phenolic compounds.29 beef patties (200 °C) revealed the efficacy of apple or grape
When fortified at the same mass proportion into model seed extracts in reducing total and three individual HAs
cookies baked at 200 °C, quercetin was the most potent fluo- (MeIQx, 4,8-DiMeIQx and PhIP), and phloridzin or proantho-
rescent AGEs inhibitor (over 80%), followed by naringenin, cyanidins were pointed out to be the key inhibitors in either
rosmarinic acid and epicatechin.31 apple or grape seed extracts.90 The research group further
Free radical scavenging and reactive carbonyl trapping are explored the HAs inhibitory potential of twelve polyphenols
the two most recognizable antiglycation mechanisms for poly- in both chemical models (composed of glucose, phenyl-
phenols proposed by researchers. These two mechanisms, alanine and creatinine, heated at 125 °C) and fried beef
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however, seem to be insufficient to account for the poly- patties and the results supported the effectiveness of theafla-
phenols’ antiglycation activity under thermal conditions. The vin 3, 3′-digallate, epicatechin gallate, rosmarinic acid, and
thermal treatment, including heating temperature and time, particularly naringenin.91
would influence the polyphenols’ structural integrity and The addition of phenolic antioxidants did not always lead
therefore their reactivity effectiveness in inhibiting the protein to lowered HAs levels.92 In addition, the inhibition rate was
glycation process. Moreover, the food context represents a con- found to show no significant correlation with polyphenols’
siderably more complicated reaction system than the sugar- antioxidant activity.91 These phenomena suggest the occur-
protein chemical model, in which the extra nutritional com- rence of alternative HAs inhibitory mechanisms other than
ponents or chemical additives might influence the process antioxidation. Breakthroughs in mechanistic study elucidated
either positively or negatively. More studies, therefore, need to that in chemical models, naringenin, a weak phenolic antioxi-
be performed in thermal and food models regarding the anti- dant, could scavenge the reactive carbonyl species by forming
glycation activity and mechanisms of dietary polyphenols, in stable adducts, therefore diverting these Maillard reaction
order to shed light on the mitigation strategies of AGEs during intermediates from HAs formation pathways.93 The two
food processing and storage. adducts were identified to be 8-C-(E-phenylethenyl)naringenin
2.3.4 Heterocyclic amines. Heterocyclic amines (HAs) are a and 6-C-(E-phenylethenyl)naringenin, which were electrophilic
class of amino compounds produced in proteinaceous foods substitution products from naringenin and phenylacetalde-
of both animal and plant origin.81 They can be divided into hyde. This phenylacetaldehyde scavenging mechanism was
different groups based on their formation temperature or later proven for EGCG and in real food systems and was
polarity. Amino acids or proteins are the main precursors for suggested to be the dominant mechanism for the inhibition of
HAs formation above 300 °C; HAs formation under mild HAs by weak or non-antioxidants.93,94
thermal conditions lower than 300 °C, however, is a result of
the Maillard reaction and Strecker degradation involving
sugars, amino acids, peptides and creatinine.82 The molecules 3. Summary and concluding remarks
of HAs formed at lower temperature are composed of two
parts, either from creatinine cyclization and dehydration or Nonenzymatic browning reactions are particularly important
aldol condensation of Strecker degradation products.81 Gener- chemical reactions during thermal food processing. The active
ally, the formation pathways have been suggested to be participation of dietary polyphenols during the thermal pro-
mediated by free radicals and reactive fragments.82 Further- ceeding of nonenzymatic browning reactions, with regards to
more, the yield is influenced by a variety of factors such as the the production of color, antioxidative and toxic compounds,
heating parameters (temperature and duration), type and con- has been documented in both chemical and food models. The
centration of principle precursors, as well as the type and thermal stability and transformation of polyphenols affects
content of fats. Therefore, it is expected that the types and their antioxidant activity and inhibitory efficacy of toxicant for-
levels of HAs that predominate in a certain food product are mation. The mechanisms for inhibition of toxicants have not
dependent on the food’s nutritional composition and thermal been completely understood, but polyphenols’ free radical
processing conditions.83 The quantitative analysis of HAs in scavenging and reactive carbonyl trapping activities are
food usually starts from liquid–liquid or solid phase extraction suggested to take important roles. It is a general conclusion
followed by liquid or gas chromatography coupled to mass that dietary polyphenols are promising agents for developing
spectrometry.84 The amounts are higher in cooked pure meat colorful and healthy food products containing more antioxi-
than mixed meat products or fish and the crust contains more dants but less toxicants than traditional foods, but more
HAs than the inner parts. PhIP is the most abundant HA efforts need to be focused on the structural conversions and
detected in cooked food, with the level up to several hundred reaction mechanisms behind the phenomena. It may be useful
ng per g of food.85 to develop cautious strategies to efficiently retain the primary
Polyphenols and plant extracts rich in polyphenols have active structural motifs of polyphenols during thermal treat-
been realized to be promising HAs inhibitors during food ment. In addition, the complex array of chemical transform-
processing. Rosemary, thyme, sage, garlic, pycnogenol, and ations taking place in polyphenol-fortified food matrices still
tea extracts have all been reported to either suppress the awaits clearer understanding and the neo-formed compounds’
thermal formation of HAs or alleviate HAs-induced structure, physicochemical properties and bioactivity need to
toxicity.86–89 Recently, experiments performed using fried be better characterized.

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 Critical Reviews in Food Science and Nutrition

ISSN: 1040-8398 (Print) 1549-7852 (Online) Journal homepage: https://www.tandfonline.com/loi/bfsn20

Impact of Maillard reaction products on nutrition

and health: Current knowledge and need to
understand their fate in the human digestive
system

Nesreen ALjahdali & Franck Carbonero

To cite this article: Nesreen ALjahdali & Franck Carbonero (2019) Impact of Maillard reaction
products on nutrition and health: Current knowledge and need to understand their fate in the
human digestive system, Critical Reviews in Food Science and Nutrition, 59:3, 474-487, DOI:
10.1080/10408398.2017.1378865

To link to this article: https://doi.org/10.1080/10408398.2017.1378865

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Sep 2017.
Published online: 20 Oct 2017.

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CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
2019, VOL. 59, NO. 3, 474–487
https://doi.org/10.1080/10408398.2017.1378865

Impact of Maillard reaction products on nutrition and health: Current knowledge

and need to understand their fate in the human digestive system
Nesreen ALjahdalia and Franck Carboneroa,b
a
Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR, USA; bDepartment of Food Science, University of Arkansas, Fayetteville,
AR, USA

ABSTRACT KEYWORDS
The Maillard Reaction (MR) is a non-enzymatic chemical reaction which results in the linkage between the Advanced glycation end-
amino group of amino acids and the carbonyl group of reduced sugars. MR products (MRPs) are common products; gut microbiota;
components of processed foods, mainly as a result of heating, especially in the Western diet. MRPs are Maillard reaction products;
classified as into three stages: initial, intermediate, and final stages, indicative of increased complexity and metabolomics
size, incurring different flavor, aroma, and texture. MRPs presence is known to reduce the nutritional quality
of foods, particularly by reducing protein digestibility. Early reports have linked MRPs, especially advanced
glycation end-products (AGEs) present in high concentration in the typical Western diet, to health
conditions and diseases. However conflicting data has since been reported, and only a few (acrylamide,
heterocyclic amines and 5-Hydroxymethylfurfural) MRPs have documented potential toxic or carcinogenic
effects. High molecular weight MRPs are not available for direct absorption in the higher gastrointestinal
tract, and are thus mostly metabolized by resident colonic microbes. MRPs have been the subject of sparse
research interest in comparison with other non-digestible dietary elements. In this review, we outline the
state of knowledge on MRPs in nutrition and health, and highlight the need to develop the limited
knowledge on their impact on the gut microbiota and which metabolites derive from MRPs fermentation.

Introduction (human and animal), with focus on cancer, inflammatory and

metabolic diseases, obesity and more recently cognition and neu-
Western diet is becoming the dominant diet worldwide, and this
rology. Surprisingly, MRPs and MRPs-rich food interaction with
trend is suspected to play an important role in the rise of west-
the gut microbiota have received little attention from researchers
ern diseases. Western diet is characterized by higher intakes of
in comparison with other dietary elements.
red meat, fast foods, high-fat dairy products, fried and baked
The purpose of this review is to outline the current knowl-
foods, high-sugar drinks, and a reduced intake of fibers and
edge on MRPs in the context of nutrition and health, and pro-
whole grains. While higher intake of simple sugars and fat are
vide an overview of the scarce knowledge on metabolic impacts,
well known to increase disease and health conditions risks, there
microbiota interaction and metabolomics. We will conclude by
are also specific dietary elements that have been reported as det-
summarizing the aspects for which extensive knowledge is avail-
rimental. In this review, we will focus on Maillard Reaction
able, and state the research directions that need to be undertaken
Products (MRP), a relatively large class of molecules formed by
to complete our knowledge of MRPs metabolic impacts.
linkage between carbohydrates and proteins/peptides. MRPs are
known to occur in high levels in typical Western diet foodstuffs
resulting from different food preparation methods, such as roast- The chemistry of Maillard reaction products
ing, frying, and toasting. While early studies on MRPs have
Maillard reaction in food
pointed to their role as biomarkers of Western diet consumption
and potential correlation with diseases risk; there is currently no Maillard reaction (MR) was first described by Louis Camille
consensus on the role of MRPs in human health. Maillard in 1912, as the non-enzymatic chemical reaction
Although it has been known for decades that a symbiotic between the carbonyl group of reducing sugar molecules with
relationship exists between the host and microbiota, it is only the amino group of amino acids occurring during processing
recently that analytic tools have allowed for precise characteriza- and storage of foods. This reaction depends on physical param-
tion of both microbiota members but also their metabolites. It eters, such as heating, hydration, pH, and NH2 requirements in
is now well established that colonic microbes play an essential order to form complex compounds that are not naturally in
role in degrading undigested dietary elements and produce a foods and are responsible for a range of colors, odors, flavors,
vast array of metabolites. Diet-microbiota interactions are and palatability. Thus, these molecules have positive or negative
increasingly investigated in the context of health and disease biological actions.

CONTACT Franck Carbonero [email protected] Department of Food Science, University of Arkansas, 2650 North Young Avenue, Fayetteville, AR 72704, USA.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/bfsn.
© 2017 Taylor & Francis Group, LLC
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 475

MR is divided into three stages: initial, intermediate, and (Somoza 2007). MR can also affect the texture of food through
final stage (HODGE 1953) as described in Figure 1. In the ini- protein cross-linking (Gerrard 2002).
tial stage, colorless products such as sugar-amine condensation
and Amadori rearrangement products are produced. In the
Generation of Maillard reaction products in vivo
intermediate stage, yellow or colorless (with strong UV absorp-
tion) compounds are produced, including 5-Hydroxymethyl- In this review, we will focus on dietary MRPs. However, it is
furfural, reductone, and dicarbonyl compounds. In the final worth noting that MRPs have also been shown to be produced
stage, brown color compounds are produced, such as melanoi- endogenously in humans. The knowledge on endogenous MR
dins. The coloration occurs during heat pyrolysis of sugar, due is reviewed extensively in (Tessier 2010). The first report of MR
to pH reaction on carbonyl group of sugar, while amino acids in vivo was the glycation of aging proteins (MONNIER and
are not directly responsible for coloration (Adrian 1974). The CERAMI 1981). In biological systems, this reaction is mainly
characteristic color in foodstuff, such as coffee, malt, bread, implicated in protein modification, and divided into early and
cocoa, and other roasted foods is the result of melanoidins, advance reaction stages. In the early stage, the formation of the
which are brown nitrogen-containing high molecular weight Schiff base occurs, which is the interaction between the amine
pigments (Bastos et al. 2012). In addition to desirable color, the group of proteins with the reducing sugar, which generates
intermediate and final stages are the most important to develop a-dicarbonely compounds, or rearranges into the Amadori
flavor and aroma, through Strecker degradation (Ames 1990) product. In the advance stage, the Amadori product undergoes

Sugar-CHO+ Amino acids- N-substituted Ketosamines

NH2 glycosylamine
Reaction A Reaction B Amadori Rearrangement

Reaction H

Reaction D Reaction C Reaction C

Reaction C

5-HMF or Furfural Fission Products Reductones Dicarbonyl Compounds

Reaction E Reaction E
Reaction F Reaction F
Reaction E
Stecker Dehydroreductones Acrylamide
Aldehyde
s Hetreocyclic amines
Reaction F
Reaction F Advanced Glycation
Aldols and N-free End Products
polymers Low molecular weight

Low Reaction G
molecular + amino Reaction G
weight compound
+ amino
Reaction G
compounds compound Reaction G
+ amino
compound
Reaction G + amino
+ amino compound
compound

Melanoidins
Heterogenous, insoluble, nitrogen-containing high molecular weight molecules

Figure 1. Maillard Reaction Products stages (adapted from the initial description by Hodge in 1953 to reflect current knowledge). 1. Early stage: condensation of the car-
bonyl group of reducing sugar with the amino group of amino acids (Reaction A), resulting in N-substituted glycosylamine and water. 2. Intermediate stages: Conversion
of glycosylamine through Amadori rearrangement to form ketosamines (Reaction B) and other products. Amadori products are dehydrated and hydrolyzed to form 5-
Hydroxymethylfurfural (HMF) (Reaction C), which gives rise to either Aldose or N-free polymers (Reaction F). Reductones can be formed from either dehydration of sugars
or Amadori product (Reaction C) leading to Aldose and N-free polymers (Reaction F) or Stecker Aldehydes (Reaction E). Stecker aldehydes are formed by fragmentation of
amino acids, which enter browning reactions either by the aldehyde formed that can take part in aldol condensation which forms nitrogen-free polymers (Reaction F).
Amadori product and N-substituted glycosylamines can be fragmented fission products (Reaction D and H). In addition, fragments of MRPs produce reactive dicarbonyl
compounds that can act as precursors of acrylamide, heterocyclic amines, advanced glycation end products (AGEs), and low molecular weight compounds (Reaction C).
3. Advanced stages: Melanoidins include a wide array of heterogeneous colored molecules Dehydroreductones, fission and dicarbonyl compounds, furfural and Aldose
react with amino acids (Reaction G) to form melanoidins.
476 N. ALJAHDALI AND F. CARBONERO

rearrangements, which forms advanced glycation end products (Erbersdobler and Somoza 2007; Delgado-Andrade, Rufian-
(AGEs) (Brownlee, Vlassara, and Cerami 1984). The AGEs that Henares, and Morales 2005; Resmini, Pagani, and Pellegrino
have been detected in tissue protein are NeCarboxymethyllysine 1991). For example, low FL values may indicate a decrease in
(CML), Pentosidins, and Glucosepane, and CML was the first pasta quality due to exposure low temperatures (Garcia-Banos
AGEs isolated and characterized in vivo (Ahmed, Thorpe, and et al. 2004). Temperature and time play an important role in
Baynes 1986). The receptor of AGEs (RAGE) is a multi-ligand the rise or decline of FL content in foods. For example, FL levels
member of cell (Schmidt et al. 2000). Current studies demon- of soybean was high in extrusion treatments (66.55 mg/g) at
strated that CML/RAGE plays an important role in an induc- 140 C for 20–30s, followed by infrared heating (63.93 mg/g) at
tion the calcification cascade in diabetes (Wang et al. 2016). 110 C for 50s, and microwave heating (56.07 mg/g)
Thus, AGEs are known as metabolic products of glucose toxic- at 115C for 5 min (Zilic et al. 2014). Heating foods for a long
ity and play a significant role in the development of metabolic time decreases the level of FL which gives rise to other products
diseases (Wang et al. 2012). in the intermediate stage (Erbersdobler and Faist 2001).

5-Hydroxymethylfurfural (HMF)
Important Maillard reaction product molecules
5-Hydroxymethylfurfural (HMF) is produced in the intermedi-
Evidence indicates that the most important Maillard reaction ate stage of the Maillard reaction, and it forms in carbohydrate-
products in common diets are NeFructoselysine (furosine), rich food during acid-catalyzed dehydration of Schiff base of
5-Hydroxymethylfurfural (HMF), acrylamide, heterocyclic furfural (HODGE 1953) (Figure 1). HMF is a widely used
amines, advanced glycation end products (AGEs), and mela- marker of nutritional quality of foods, such as baked diets and
noidins. They all impact the nutritional quality of foodstuffs coffee, and it is not present in raw and fresh foods (Erbersdo-
and biological systems either positively or negatively, as bler and Somoza 2007). The concentration of HMF increases as
reviewed by (Tuohy et al. 2006). Table 1 summarizes the exam- thermal treatments or storage time of foodstuffs increase. Spe-
ple of MRPs content of commonly consumed foods. cifically, a positive correlation has been found between HMF
content and the development of browning color so that reduc-
NeFructoselysine (Furosine) (FL) ing the heating period might be possible to reduce the concen-
The a-amino and e-amino group of lysine interact with reduc- tration of HMF (Capuano et al. 2008). In addition to
ing sugar, such as glucose, fructose, and maltose to form glyco- temperature, increasing pH plays an important role in decreas-
sylamine that undergo Amadori rearrangement products ing the quantity of HMF in bakery products (Gokmen et al.
(ARP) in the early stage of Maillard reaction (HODGE 1953). 2007). Moreover, the type of sugar results in various quantities
Amadori products are measured as Nefructoselysine because it of HMF molecules. For example, hexose produce 4 to 5 times
was the first MRPs identified in foods, and is used as an indica- more HMF than pentose in baked foods. In addition to the
tor of the nutritional quality of foods. Moreover, FL amount is type of sugars, the presence of certain amino acids, such as leu-
used to estimate protein damage caused by heating in the initial cine, valine, and methionine can be linked to the concentration
stage of MR in cereal products, such as pasta and bread of HMF molecules in food products (Adrian 1974). HMF is

Table 1. Examples of MRPs content of commonly consumed foods.

MRP type Food item Average MRP concentration References
e
N Fructoselysine (FL) Soybean 66.55mg/g (Zilic et al. 2014)
Fresh Pasta 16–18.8 mg/100 g of protein (Garcia-Banos et al. 2004)
Dried Pasta 44.4–462 mg/100 g of protein
5-Hydroxymethylfurfural (HMF) Soluble Coffee 110 mg/kg (Arribas-Lorenzo and Morales 2010)
Cookies (sucrose) 19 mg/g for 10 min at 230C (Gokmen et al. 2007)
Cookies (glucose) 38 mg/g for 10 min at 230C
Acrylamide Potato Chips 628 mg/kg (Capuano and Fogliano 2011)
French Fries 350 mg/kg
Biscuits 317 mg/kg
Heterocyclic amines (HCAs) Fried Bacon 17 ng/g (Puangsombat et al. 2012)
Fried Tilapia 16.29 ng/g
Fried Pork 13.91 ng/g
Fried Beef 8.92 ng/g
Advanced Glycation End products (AGEs) Butter 100 KU/g (Goldberg et al. 2004)
Mayonnaise (fats) 265 KU/g (Van Nguyen 2006)
American Cheese (proteins) 87 KU/g
Pancakes (carbohydrates) 10 KU/g
NeCarboxymethyllsine (CML) Sterilized Milk 2066 nM of protein (Ahmed et al. 2005)
Pasteurized Milk 887 nM of protein
Raw Milk 337 nM of protein
White Bread Crust 382 mg/kg of protein (Assar et al. 2009)
Wholemeal Bread Crust 329 mg/kg of protein
Doner Kebab 2357.87 mg/kg of protein (Hull et al. 2012)
Melanoidins Sourdough Loaves 30 g/100 g of crust (Fogliano and Morales 2011)
Soluble Coffee 22 g/100 g
Roasted Barley 4.15% of 0.7 to 1.0 kg (MILIC et al. 1975)
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 477

also formed through the caramelization of sugars (Capuano [4,5-f]quinoxaline (DiMeIQx) (Knize et al. 1994; Puangsombat
and Fogliano 2011). HMF has been found in different quanti- et al. 2012).
ties in various foods. The concentration of HMF in dried fruits The levels of HCAs in cooked meat depends on the type of
and caramel are high, but bakery foods and coffee are the major meat and meat preparation methods. It has been reported that
sources of HMF intake (Capuano and Fogliano 2011; Murkovic well done cooked beef had higher concentration of HCAs,
and Pichler 2006). It has been reported that coffee is the main compared to medium cooked beef. Moreover, the highest level
source of HMF; the concentration of HMF in natural, blend, of total content of HCAs was quantified in fried bacon
roasted and soluble coffee was 110, 625, 1734, 2480 mg HMF/ (17.59 ng/g), compared to fried pork (13.91 ng/g), fried beef
kg, respectively (Arribas-Lorenzo and Morales 2010). (8.92 ng/g), or fried chicken (7.06 ng/g) (Puangsombat et al.
2012). In addition to total content of HCAs, high concentra-
Acrylamide tions of PhIP were found in fried Tilapia (10.89 ng/g), followed
Acrylamide, which is generated in intermediate stage of Mail- by MeIQx (4.00 ng/g) and DiMeIQx (3.57 ng/g) in fried bacon,
lard reaction, results from interaction between asparagine and but IQ was not identified (Puangsombat et al. 2012). However,
reducing sugars such as fructose and glucose in heat treated another study found the high levels of IQ was in well-done fried
bakery products and starchy foods (HODGE 1953) (Figure 1). bacon (10.5 ng/g), which had high content of fat (Johansson
A diversity of chemical pathways lead to the formation of acryl- and J€agerstad 1994). It has also been reported that fried meat
amide in carbohydrate-rich foods (Granvogl and Schieberle produced the highest concentration of HCAs, compared to
2006; Granvogl and Schieberle 2007). However, the major path- baked meat (Puangsombat et al. 2012).
ways are through Amadori products that degrade to form
dicarbonyl compounds, which react with asparagine via
Strecker degradation; or by the interaction of reducing sugar Advanced Glycation End products (AGEs)
and asparagine to form the Schiff base without Amadori prod- The interaction between glucose and protein or glucose and
uct (Granvogl and Schieberle 2007; Granvogl and Schieberle lipid generate advanced glycation end products (AGEs) that are
2006). Like HMF, the formation of acrylamide is dependent on also known as advanced Maillard reaction products (OBRIEN
the type and concentrations of sugars, amino acids, tempera- and MORRISSEY 1989). AGEs are generated in the intermedi-
ture, and time. A positive correlation has been found between ate stage of the Maillard reaction. The degradation of Amadori
acrylamide levels and heating-time during baking of biscuits at products generate reactive dicarbonyl compounds that react
200 degrees C and in potato chips that were fried at more than further with amino acids to form irreversible and highly stable
248 F (Nguyen et al. 2016; Tareke et al. 2002). Moreover, the advance glycation end products (AGEs) (Tuohy et al. 2006;
interaction between glucose and asparagine generated the high- Cho et al. 2007) (Figure 1). AGEs are also produced endoge-
est concentration of acrylamide, compared to fructose and nously through the glycation metabolic pathways (MONNIER
asparagine (Capuano and Fogliano 2011). Indeed, adding and CERAMI 1981). It has been found that Western diet is rich
asparginase might control acrylamide content in potato prod- in AGEs, so this review concentrates on food-derived AGEs
ucts (Zyzak et al. 2003). Unlike microwaved and boiled foods, that have been detected and measured in more than 200 food
the highest acrylamide concentration is formed through roast- items (Goldberg et al. 2004). The highest content of AGEs was
ing, frying, and baking methods. The highest level of acrylam- found in fat food items, such as butter with, a mean of
ide was found in fried potato products. For instance, the 100 § 19 kilounits (kU)/g, compared to carbohydrate diet that
average level of acrylamide found in potato crisps was 628 mg/ contained the lowest levels of AGEs with a mean of
kg, compared to biscuits, bread, and coffee, which were 3.4 § 1.8kU/g (Goldberg et al. 2004). Moreover, the heating
317 mg/kg, 136 mg/kg, and 253 mg/kg, respectively (Capuano period and preparation methods appear to be more critical to
and Fogliano 2011). form AGE. For example, the highest content of AGE was found
in grilled foods at temperatures of 230 C for short time, com-
Heterocyclic amines (HCAs) pared to boiled foods at 100 C for long periods (Goldberg et al.
Heterocyclic amines (HCAs), produced in the intermediate 2004). There are many types of AGEs, and the most common
stage of Maillard reaction, result from the reaction between studied are NeCarboxymethyllsine (CML) (non-cross-linking),
reducing sugar, amino acids, and their precursor creatine pyrraline and pentosidine (cross-linking), which are most
(a nitrogenous organic acid found naturally in muscles). To widely used as indicators of the nutritional quality of foodstuffs
illustrate, the fragmentation of Amadori products can form (Erbersdobler and Somoza 2007).
various dicarbonyl compounds that can act with amino acids NeCarboxymethyllsine (CML) is the most important bioac-
and creatine to form HCAs (JAGERSTAD et al. 1991; Tuohy tive markers of MRPs and a commonly measured AGE not
et al. 2006) (Figure 1). Increasing temperature and time play an only in food items (Goldberg et al. 2004) but also in biospeci-
important role in generating HCAs, which are mainly found in mens (Uribarri et al. 2003; Hofmann et al. 2002; Tessier et al.
muscles food, such as beef, pork, chicken, and fish. The most 2016). CML can be produced by the reaction of the carbonyl
common of HCAs found and studied in foods are 2-amino-1- group of glyoxal from dicarbonyl componds with an epsilon-
methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), 2-amino-3- amino group of the lysine or by Amadori rearrangement prod-
methyl-imidazo [4,5-f]quinoline (IQ), 2-amino-3-methylimi- ucts that act as a precursor of CML (HODGE 1953; Tuohy
dazo [4,5-f]quinoxaline (IQx), 2-amino-3,4-dimethylimidazo et al. 2006). Besides furosine, CML was found to be a useful
[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylimidazo [4,5-f] indicator of protein damage during the late stage of the
quinoxaline (MeIQx) and 2-amino-3,4,8-trimethyl-imidazo Maillard reaction (Van Nguyen 2006). Hull et al determined
478 N. ALJAHDALI AND F. CARBONERO

the CML content in 257 foods that are typically consumed in potato crisps (based on a 3-day food record) was 0.053 mg/kg
Western style diets (Hull et al. 2012). body weight for the adult population (17–60 years) and
0.142 mg/kg body weight for children (7–12 years), similar to
Melanoidins other European countries (Arribas-Lorenzo and Morales 2009).
Melanoidins, which are the final products of MR, are heteroge- CML exposure from a MRP-high diet was shown to be
neous, insoluble, nitrogen-containing high molecular weight 11.28 mg/day, while a MRP-low diet resulted in exposure of
molecules that generate in the advanced stage of MR. Melanoi- 5.36 mg/day in adolescents aged 11–14 years old (Delgado-
dins are formed by dehydration, rearrangements, isomeriza- Andrade et al. 2012). Dietary melanoidins represent the most
tion, and condensation of low molecules of MRPs formed in abundant MRP the human diet and ranges between 10–12 g
the intermediate stage (HODGE 1953). To illustrate, during the per day for individuals consuming a typical western diet
intermediate stage, dicarbonyl compounds, aldehydes, and fur- (Fogliano and Morales 2011; Pastoriza and Rufian-Henares
fural are generated, which react with each other to form aldol 2014). For example, the estimation of dietary melanoidins from
condensation products that react with amino acid to give rise coffee ranged between 0.5 to 2.0 g per day. The intake of bread
to low molecular weights of MRPs, leading to the high molecu- and dry biscuits melanoidins ranged between 1.8–15 g and 3.2–
lar weights of melanoidins (HODGE 1953) (Figure 1). Temper- 8.5 g per day, respectively (Fogliano and Morales 2011).
ature and time appear to be significant factors affecting When foodstuffs undergo MR, the nutritional value of food
molecular weight, while pH plays an essential role in the chemi- is reduced, and some proteins are lost or become non-digest-
cal structure of melanoidins (Wang, Qian, and Yao 2011). The ible, as reviewed by (Tuohy et al. 2006). For example, exposing
color of melanoidins that are found in coffee, malt, bread crust, glucose and lysine to different heating periods caused loss of
cocoa, and honey, derive from the polymerization of MRPs lysine (Adrian 1974). Moreover, protein efficiency ratio (PER)
(Hofmann 1998; Hofmann 1999). The highest amount of mela- decreases during MR, for example, the interaction between gly-
noidins was found in sourdough loaves (30 g per 100 g of cine and glucose reduced the PER by 22%, which reduced
crust), compared to soluble coffee (22.8 g per 100 g of coffee), digestibility of nitrogen and metabolism of proteins measured
but the quantity of melanoidins depends on the type of bread in animals (Adrian 1974). Increased amount of nitrogen in
and the degree of roasting in coffee (Fogliano and Morales stool samples was also measured in young people who con-
2011). sumed MRPs-rich diet (Seiquer et al. 2006). MRPs presence
also affects trace elements bioavailability. In an in-vitro study,
the presence of MRPs in the diet (brown diet) reduced iron bio-
Maillard reaction products impact on nutrition and availability (Mesias Garcia et al. 2009). MRPs decreased the
health digestion of magnesium in MRP-fed rats by 13%, compared to
non-MRP-fed animals (Delgado-Andrade, Seiquer, and Nav-
Consequences of the Maillard reaction in nutrition
arro 2007). Moreover, phosphorus bioavailability was linked to
Western diet, also known as the American standard diet, is the consumption of a diet rich in MRPs (Delgado-Andrade
characterized by higher intakes of red meat, high-fat dairy et al. 2011). However, some reports indicate that melanoidins
products, fried and baked foods, high-sugar drinks, and a are likely to play a significant role in the binding of dietary met-
reduced intake of fibers and whole grains. Maillard reaction als thereby leading to antioxidant and antimicrobial properties
products (MRPs), which are not naturally present in foods, are (Morales, Somoza, and Fogliano 2012). In particular, melanoi-
common in the Western diet (Hull et al. 2012). More than 200 dins that were prepared from glucose and glycine (GG) had a
staple food items of the typical Western diet contain measur- high chelating affinity towards copper (iron II) (32%), com-
able MRPs. These MRPs are the result of different food prepa- pared to melanoidins obtained from lactose and lysine (LL)
ration methods, such as roasting, frying, and toasting, which and lactose N-acetyllysine (LLa) (Borrelli et al. 2002).
are responsible for the aromas, colors, and tastes of foods
(Goldberg et al. 2004; Hull et al. 2012; Zilic et al. 2014). For
Effect of Maillard reaction products on health
example, coffee and bread are the major source of Melanoidins
(Fogliano and Morales 2011), fried chicken and broiled beef are The major concern arising from the Maillard reaction is the
rich in AGEs (Van Nguyen 2006), and HCAs are found at the formation of compounds that are not naturally present in food-
high concentration in cooked meat (Tamanna and Mahmood stuff. Time, high temperature, and other parameters generate
2015). products that may have detrimental health effects such as
The typical exposure to several dietary MRPs has been mutagenicity, carcinogenicity, cytotoxicity, and metabolic dis-
reported by different survey-based studies. The estimation of eases, or beneficial impacts such as antioxidant, antimicrobial,
dietary exposure to HMF from coffee was 5.26 mg HMF/day and antihypertensive properties.
(Arribas-Lorenzo and Morales 2010). The mean daily HCAs
intake from meat products in a typical western diet was esti- Toxicity and carcinogenicity
mated at 450 ng per day¡1, including mainly PhIP, MeIQx and The MRPs that have been reported to possess toxic and carci-
DiMeIQx (Keating, Layton, and Felton 1999). The average daily nogenetic properties are HMF, Acrylamide, HCAs, and AGEs
intake level of HCAs in Malaysia population was 553.7 ng per (Tuohy et al. 2006).
capita day¡1, and the highest level was PhIP followed by MeIQx HMF is considered a toxicological compound because it can
and MeIQ (Jahurul et al. 2010). Based on the Spanish National be converted into 5-sulphooxymethylfurfural (SMF) by sulfo-
consumption database, dietary exposure to acrylamide from transferase (SURH et al. 1994) and into 5-chloromethylfurfural
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 479

(CMF) via allylic chlorination (SURH and TANNENBAUM and Fukami 2015). However, the pathological implications
1994). Both compounds are known to possess toxic and muta- regarding the dietary AGEs and development of colorectal can-
genic compound. The highest daily exposure to dietary HMF cer risks have become more controversial. Elevated glyceralde-
was estimated as 8.57 mg HMF/day (Arribas-Lorenzo hyde –AGEs levels were associated with the risk of
and Morales 2010), and since the oral LD50 was found to be rectal cancer but were not linked to the risk of colon cancer
3.1 g/kg body weight in rats (Ulbricht, Northup, and Thomas based on 1,055 colorectal cancer cases (Kong et al. 2015).
1984), it can be considered that normal HMF intake may only Increased risk of pancreatic cancer was found to correlate with
represent a long term health risk. HMF was also shown to dietary CML-AGE consumption, particularly in male pancre-
induce aberrant crypt foci of colon, in experimental animals atic cancer patients (Jiao et al. 2015). In contrast, melanoidins,
(Archer et al. 1992). Skin papillomas caused by HMF have been mainly from coffee, have generally been reported as potentially
reported in studies on rodents (SURH et al. 1994). Moreover, protective against cancer (Vitaglione, Fogliano, and Pellegrini
DNA damage, cytotoxicity of kidney, and mutagenicity of liver 2012; Gasscht, Dicato, and Diederich 2015; Ludwig et al. 2014).
have been reported for HMF in mammalian cells (Schoental, In vitro studies have shown significant anti-proliferative effects
Hard, and Gibbard 1971; Janzowski et al. 2000; Capuano and of melanoidins from heated potato fiber (Langner et al. 2013;
Fogliano 2011; LEE et al. 1995). Specifically, HMF decreased Langner et al. 2011), miso and soy sauce(Kamei et al. 1997)
the amount of glutathione, which is an important antioxidant and coffee(Vitaglione, Fogliano, and Pellegrini 2012). However,
that prevents damage to cellular components by reactive oxy- because melanoidins are likely to behave similarly to fiber in
gen species (LEE et al. 1995). the colonic microbial ecosystem, it has been suggested that
Acrylamide was listed as a food-borne toxicant in 2002 by most anti-cancer properties may derive from microbial fermen-
the Swedish National Food Administration, and it is considered tation metabolites (Ludwig et al. 2014; Jaquet et al. 2009).
a potentially carcinogenic and toxic compound (Tareke et al.
2002). As summarized in a review by Capuano et al, several Metabolic and cardiovascular diseases
studies demonstrated that acrylamide possesses cytotoxic, gen- The more common emerging evidence of MRPs in the patho-
otoxic, and tumorigenic activities (Capuano and Fogliano genesis of metabolic and cardiovascular diseases are dietary
2011). In a study using rodents, the exposure of acrylamide in AGEs through their binding with the receptor for advanced gly-
different amounts led to an increase in the risk of developing cation end products (RAGEs) (Goldin et al. 2006; Grillo and
cancer in the lung, thyroid, skin, and pancreas (Beland et al. Colombatto 2008; Hartog et al. 2007). The binding of AGE-
2013). Previous studies indicated that the metabolism of acryl- RAGE in the endothelial cells activates the transcription
amide further converted to N-acetyl-S-(3-amino-3-oxopropyl)- nuclear factor-kappa B (NF-kB), which induces pro-inflamma-
cysteine (AAMA), and the oxidation of AAMA into AAMA- tory cytokines and up regulates inflammation, notably in asso-
sulfoxide induced kidney and bladder toxicity (Ramu et al. ciation with the development of diabetes and cardiac
1995; Capuano and Fogliano 2011). However, the actual mech- dysfunction (Hartog et al. 2007; Goldin et al. 2006). AGEs have
anisms responsible for dietary acrylamide carcinogenicity are been used as health biomarkers of several human diseases and
still not well documented (Capuano and Fogliano 2011; Tuohy conditions (Tessier and Birlouez-Aragon 2012), such as inflam-
et al. 2006). matory processes (Van Puyvelde et al. 2014), cardiovascular
Because heterocyclic amines (HCAs) are known as muta- and metabolic diseases (Prasad, Bekker, and Tsimikas 2012;
genic and carcinogenic compounds, several studies indicated Yamagishi, Nakamura, and Matsui 2017; de Vos et al. 2016)
that red meat might be a risk factor for colorectal cancer (Cross and aging (Wagner et al. 2016). Cai et al found that a high-
and Sinha 2004). HCAs are converted into genotoxic com- AGE diet enhanced low-density lipoprotein (LDL) induces vas-
pounds by hepatic cytochrome P-450 1A2 enzyme (CYP1A2), cular toxicity through protein kinase stimulant in diabetic
which is activated by many factors, such as HCAs-rich diet. patients (Cai et al. 2004). In addition to heart failure, dietary
Specifically, CYP1A2 converted dietary HCAs into MeIQx and AGEs were shown to induce Type 1 diabetes in non-obese-dia-
PhIP that are found in human urine (Boobis et al. 1994). In betic mice (Peppa et al. 2003). A diet high in AGEs induced
1993, MeIQ, MeIQx, and PhIP were categorized as carcino- inflammatory mediators such as TNF-a, which contributes to
genic compounds by the International Agency for Research on develop diabetes (Vlassara et al. 2003). In addition, a reduction
Cancer, and IQ might also be a human carcinogen. PhIP, but in dietary AGE intake led to lower levels of circulating AGE
not IQ, has been shown to induce colon tumors in rodents and improved insulin sensitivity in db/db mice (Hofmann et al.
(Canzian et al. 1994). Moreover, liver tumors were induced in 2002) and reduce possibly cardiovascular associated mortality
mice fed 0.06% of MeIQx that was extracted from foods in renal failure patients (Uribarri et al. 2003). AGEs were found
(Ohgaki et al. 1987), and 0.03% of MeIQ that was isolated from to be involved in aging and in neurodegenerative pathways are
broiled sardines induced tumors in various organs, such as the reviewed by (Grillo and Colombatto 2008).
Zymbal gland, oral cavity, colon, skin, and mammary gland of CML has been identified in tissues (Wang et al. 2012),
rat (Kato et al. 1989). Intestinal tumors were found in Nagase plasma (Teerlink et al. 2004), urine, and feces (Delgado-
analbuminemic rats that were fed 0.04% to 0.01% of PhIP Andrade et al. 2012). Although, CML is produced within the
(Ochiai et al. 1991). Colonic aberrant crypt (AC) was found in organism endogenously (Ahmed, Thorpe, and Baynes 1986),
the large intestine of rodents after 12 weeks of PhIP oral admin- several studies indicate that a significant correlation exists
istration (Takahashi et al. 1991). between dietary AGE content and CML serum in health people,
The potential role of endogenous AGEs and RAGE receptors as reviewed by (Uribarri et al. 2005). A recent study carried out
in cancer risk has been extensively studies (Yamagishi, Matsui, by Tessier et al found that the accumulation of dietary
480 N. ALJAHDALI AND F. CARBONERO

CML-fed mice was high in the kidney, intestine, and lungs, MRPs and gut microbiome/metabolome
compared to native CML-fed mice. (Tessier et al. 2016). Serum
Human gut microbiome and metabolome
levels of CML were found significantly higher in patients with
diabetes, compared to healthy subjects (Jara et al. 2012). Pyrra- In the last decade, the human microbiome/microbiota has
line was found in the extracellular matrix of glomerular and received extreme attention from basic and medical scientists,
arteriolar renal tissues from both diabetic and aged nondiabetic and it is now well established that the human body hosts up to
people (MONNIER et al. 1992). The highest level of pentosi- 100 trillion (1014) microbes. The vast majority of them are
dine was found in lens proteins of diabetic and uremic patients located in the human gastrointestinal tract (GIT), which has
(MONNIER et al. 1992). become the most investigated microbial ecosystem (Ley, Peter-
son, and Gordon 2006). While microbiota composition is sub-
Antioxidant, antimicrobial and antihypertensive activities ject to strong individuality, a core human gut microbiota can
The beneficial effects of antioxidant properties of MRPs have be defined (Turnbaugh et al. 2009; Arumugam et al. 2011). The
been detected in some compounds, such as FL, HMF, and mel- vast majority of colonic microorganisms depend on undigested
anoidins. Amadori compounds might exert a moderate effect dietary elements to support their metabolic needs, but some
on the antioxidant activity of dehydrated onion and garlic dur- genera have also evolved to utilize other microbial by-products
ing storage (Moreno et al. 2006). The pro-oxidant properties or host-derived compounds (Carbonero et al. 2012). The
were observed in the early stages (FL) of pasta (Anese et al. potential involvement of the gut microbiome has been exten-
1999). Beside other wide range of products, HMF was found to sively studied and reviewed for diseases such as intestinal can-
play an important role of the antioxidant capacity of honey cer (Candela et al. 2014; O’Keefe et al. 2015), inflammatory
(Gheldof, Wang, and Engeseth 2002). Although the early and bowel diseases (Wehkamp and Frick 2017), diabetes and meta-
intermediate MRPs were shown to exert moderate antioxidant bolic syndrome, obesity (Delzenne et al. 2015; Kahn and Flier
activity (Rufian-Henares and Delgado-Andrade 2009), mela- 2000) and more recently brain diseases (Fung, Olson, and
noidins are believed to be the major antioxidant MRPs Hsiao 2017).
(Rufian-Henares and Morales 2007b). Studies revealed a high level of variability in microbiota due
Melanoidins are known as antioxidants, thus, several studies to dietary habits, including short and long term dietary habits
point out that food melanoidins could prevent gastrointestinal that impact the gut microbiome (Ley, Peterson, and Gordon
tract cancers (Morales, Somoza, and Fogliano 2012). Melanoi- 2006). For example, it has been reported that long-term diets
dins, extracted from different foods, such as roasted barley were associated with the type of enterotypes of gut microbiota,
(malts) (MILIC et al. 1975), cocoa (Hofmann 1999), bread crust, but short-term diets were correlated with gut microbiota com-
and coffee (Fogliano and Morales 2011), have been shown to position (Wu et al. 2011). Wu et al found that the prevalence of
enhanced antioxidant capacity (Somoza et al. 2005). For exam- Bacteroides enterotype was strongly associated with the con-
ple, a significant increase of antioxidant activity was reported in sumption of animal protein and saturated fats, but the domi-
the plasma of healthy people after intake of 200 ml coffee nance of the Prevotella enterotype was linked to a
(Natella et al. 2002). This result was in agreement with those carbohydrate-based diet (Wu et al. 2011). Consequently, the
reported by Vitaglione et al, demonstrating a decrease in liver interaction between diet and gut microbiome have been
damage in rodents fed melanoidins extracted from coffee involved in both etiology and preservation from diseases (Louis
(Vitaglione et al. 2010). In addition to coffee, malt and bread et al. 2007; O’Keefe 2016; O’Keefe 2008).
crust were found to increase the activity of chemopreventive Gut bacteria degrade undigested foods by two main meta-
enzymes of the kidney and liver and to decrease oxidative stress bolic pathways: saccharolytic and proteolytic. On the one hand,
levels in the plasma of rodents (Somoza et al. 2005). The benefi- saccharolytic bacterial species, such as Bacteroides spp, Bifido-
cial effects of MRPs on the antimicrobial and antihypertensive bacterium spp, Ruminococus spp, Peptostreptococcus spp and
properties have been studied with melanoidins (Rufian-Henares Roseburia intestinalis hydrolyze non-digestable carbohydrates
and Morales 2007a; Wang, Qian, and Yao 2011). Coffee mela- into monomeric sugars that convert to beneficial products,
noidins demonstrasted higher antimicrobial activities towards such as short-chain fatty acids (SCFAs), principally acetate,
Geobacillus stearothermophylus var. calidolactis (Rufian-Henares propionate, and butyrate (GIBSON and ROBERFROID 1995;
and Morales 2006). Melanoidins fractions were shown to sup- Duncan et al. 2002). On the other hand, microbial metabolism
press Helicobacter pylori infection in vitro and in vivo studies of proteins, such as Bacteroides spp, Propionbacterium spp,
(Hiramoto et al. 2004). Moreover, water-soluble melanoidins Eubacterium spp, and Peptococcus spp degrade peptide and
were shown to possess antimicrobial properties towards patho- amino acids into a variety of products including short or
genic E.coli strains by disrupting their membranes (Rufian- branched-chain fatty acids, and other metabolites compounds,
Henares and Morales 2008). Data from vitro and vivo studies some of which are potentially toxic, such as uremic toxins
indicated that melanoidins fractions from bread crust and coffee (Evenepoel et al. 2009; Macfarlane, Cummings, and Allison
have a prebiotic activity similar to that of dietary fiber (Wang, 1986), phenols and amines. While metabolites from these two
Qian, and Yao 2011, Jaquet et al. 2009). For example, bread pathways are arguably dominant in terms of abundance, the
crust stimulated growth of beneficial bacteria, such as Bifidobac- complete metabolome comprises at least tens of thousands of
terium spp (Borrelli and Fogliano 2005). The antihypertensive different molecules (42,003 in the most recent version of the
activity of melanoidins isolated from coffee and beer has been Human Metabolome Database) (Wishart et al. 2016). Since
investigated only through in vitro ACE-inhibitory activity MRPs are molecules with both carbohydrate and proteic struc-
(Rufian-Henares and Morales 2007b). tures, it is likely that there are less bacterial members able to
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 481

degrade them, and that microbial consortia are probably acrylamide formation in wheat biscuits by lactic acid bacteria
needed to fully metabolize them to end-products. fermentation, including Lactobacillus sakei, Pediococcus pento-
saceus and Pediococcus acidilactici (Bartkiene et al. 2016). In a
recent review, several studies indicated that acrylamide was cat-
Known microbial interactions between microbes and MRPs alyzed to ammonia and acrylic acid by some microorganisms,
Impact of MRPs on food-associated microbes which produce amidases (an enzyme found in some microbes)
The impact of MRPs and associated environmental parameters (Duda-Chodak et al. 2016). In addition to above, data from
on microorganisms has been studied mostly by culture-depen- microorganism studies found that some gram- positive and
dent studies, as reviewed in (Helou et al. 2014). The first study gram- negative bacteria could detoxify HCAs by binding of
was by Hachisuka, describing the impact of heat treatments on HCAs to the peptidoglycan layer and the outer membrane of
germination spores of bacteria. The germination time of Bacil- microbes under physiologically conditions, which have been
lus subtilis spores decreased after exposing media to heat treat- reviewed in details by (Knasmuller et al. 2001).
ments (HACHISUKA et al. 1955). This finding was in In the advanced products of MR, the reduction of AGEs and
agreement with the study reported by Viswanathan et al, melanoidins levels were 37% and 15% respectively after incu-
describing an inhibitory growth of Lactobacillus bulgaricus in bating with Salmonella Typhimurium in batch cultures
heated milk powders (VISWANATHAN and SARMA 1957). (Chalova et al. 2012). Inhibition of microbial growth by MRPs
On the contrary, Foster observed the growth of lactic acid bac- has been studied (Einarsson, Snygg, and Eriksson 1983). High
teria in heated milk (FOSTER 1952). Lately, some studies have molecular weight MRPs inhibited the growth of Bacillus subti-
attempted to shed light on the effect of MRPs on microorgan- lis, Escherichia coli, and Staphylococcus aureus, compared to
isms. For instance, Stecchini et al found that MRPs inhibited low molecular weight MRPs (Einarsson, Snygg, and Eriksson
the growth of food-poisoning microorganism, such as Staphylo- 1983). These results are in agreement with studies by Rufian-
coccus aureus, Salmonella typhimurium, and Salmonella enteri- Henares et al, demonstrating higher antimicrobial activity was
tidis (STECCHINI et al. 1991). Several studies indicated found in high molecular weight of melanoidins, such as coffee
microorganisms that were isolated from different environments (Rufian-Henares and Morales 2006). This approach was suc-
were able to degrade and use MRPs from different stages as cessfully tested with darker coffee that exhibited high antimi-
shown in Table 2. crobial activity against E.coli, and report that melanoidins can
FL was shown to be preferentially used as a carbon source by damage both inner and outer membranes of the pathogenic
Salmonella Typhimurium in batch cultures, compared to AGEs bacteria strain (E.coli) (Rufian-Henares and Morales 2008).
and melanoidins (Chalova et al. 2012). Moreover, Escherichia Other studies showed that the antimicrobial activity of mela-
coli were found to use FL as an energetic substrate. Escherichia noidins were higher towards gram-positive microorganisms
coli has fructoselysine-6-phosphate deglycase enzyme that cata- compared to gram-negative microbes (Rufian-Henares and
lyzed the ATP-dependent phosphorylation of fructoselysine to Morales 2006; Rufian-Henares and Morales 2007a; Rufian-
fructoselysine 6-phosphate, and subsequently to lysine and glu- Henares and Morales 2007b).
cose 6-phosphate. Thus, this enzyme reached high activity lev-
els during fructoselysine utilization (Wiame et al. 2002). Known microbial metabolites of MRPs
Another study identified glucoselysine-6-phosphate deglycase
produced by Enterococcus faecium to convert fructoselysine Metabolite of amadori products. The available data for metab-
into lysine and glucose 6-phosphate, which then used as an olism of early MRPs found that the urinary excretion of
energy source (Wiame et al. 2005). ingested fructolysine was 60–80% in rats and 3–10% in humans
Among intermediate MRPs, it was found that SMF and (Faist and Erbersdobler 2001). It has been reported that the
CMF, which derived from HMF, had direct mutagenicity intestinal absorption rate of e-fructoselysine was higher than
towards Salmonella typhimurium (Sommer et al. 2003). In a-fructoselysine (Erbersdobler et al. 1981). Another study
addition to HMF, the formation of acrylamide during French found that excretion of NeFructoselysine in urine and feces was
fries deep-frying can be effectively lowered by prior lactic acid very low 3.68% in humans and 11.2%, rats (Erbersdobler and
fermentation carried out by Lactobacillus plantarum (Baardseth Faist 2001). Thus, several studies indicated that the rest of
et al. 2006). Moreover, a recent study described the reduction of NeFructoselysine was more likely to be degraded by intestinal

Table 2. Previous reports on the impact of MRPs on microorganisms.

MRP type Microorganisms The result of Study References

FL Salmonella Typhimurium Utilization 95% of FL as carbon and energy sources (Chalova et al. 2012)
E.coli Conversion FL into lysine and glucose 6 phosphate (Wiame et al. 2002)
Enterococcus faecium Conversion FL into lysine and glucose 6 phosphate
HMF (SMF)(CMF) Salmonella Typhimurium Mutagenicity in Salmonella Typhimurium (Sommer et al. 2003)
Acrylamide Lactobacillus plantarum Reducing the levels of acrylamide (Baardseth et al. 2006)
Lactobacillus sakei, Pediococcus Reducing the levels of acrylamide (Bartkiene et al. 2016)
pentosaceus and P. acidilactici
AGEs Salmonella Typhimurium Utilization 37% of AGEs as carbon and energy sources (Chalova et al. 2012)
Melanoidins Salmonella Typhimurium Utilization 15% of Melanoidins as carbon and energy sources (Chalova et al. 2012)
E.coli Inhibition the growth rates (Rufian-Henares and Morales 2008)
482 N. ALJAHDALI AND F. CARBONERO

microorganisms or accumulate in different tissues, according to As stated previously, excretion of NeFructoselysine (FL) in
a review by Faist et al (Faist and Erbersdobler 2001). urine and feces is very low (Erbersdobler and Faist 2001), and
it has been shown that the human colonic microbiota can
Metabolite of advance MRPs (Pre-Melanoidins). HMF is con- degrade FL after 4 hours of anaerobic incubation with human
verted to 5-hydroxymethyl-2-furoic acid (HMFA), during its fecal samples (Hellwig et al. 2015). Moreover, gut bacteria
metabolism and is excreted through urine in mammals related to Intestinimonas AF211 were found to contain genes
(Godfrey et al. 1999; Husoy et al. 2008). Acrylamide is con- coding for a butyrate-acetoacetyl-CoA transferase that can con-
verted into other substances, such as glycidamide or conjugated vert Amadori products into butyrate in the human intestine
with glutathione (GSH). Both glycidamide and GSH are further (Bui et al. 2015). A negative correlation between the fecal of
converted into N-acetyl-S-(3-amino-3-oxopropyl)-cysteine bifidobacteria counts and Amadori product was found in study
(AAMA) and other substances that are excreted with urine using human fecal samples, but no correlations were discovered
(Boettcher et al. 2006). The excretion of CML in feces was high between cecal Bifidobacteria numbers of rats and Amadori
for rich-MRP 3.52 mg/day, compared to low-MRP1.23 mg/day. product (Seiquer et al. 2014).
However, the elimination CML in urine was not significant dif- Fecal suspensions of NeCarboxymethyllsine (CML) and pyr-
ference between high and low MRPs (Delgado-Andrade et al. raline (PYR), the type of AGEs produce from the intermediate
2012). The large amounts of dietary CML recovered in urine stage, were degraded by human gut microbiota after 24 hours
(accounting for 26–29%) and in feces (accounting for 15–22%), (Hellwig et al. 2015). However, CML did not impact the growth
but more than 50% of CML was not yet accounted for, which rates of three strains of E.coli that were isolated from human
might be degraded by the intestinal microbiota (Ames 1990). and piglet feces, and there was no degradation of CML
observed in the presence of E.coli (Helou et al. 2014). The num-
Metabolites of melanoidins. The urinary excretion rate of mel- ber of lactobacilli and CML intake correlated negatively for
anoidins depends on molecular weight. To clarify, the rate of both humans and animal studies (Seiquer et al. 2014). In addi-
excretion of high molecular weight (HMW) melanoidins was tion to CML, negative correlations were found between
4.3%, compared to low molecular weight (LMW), which was Hydroxymethylfurfural (HMF) intake and lactobacilli, Escheri-
27% (FINOT and MAGNENAT 1981). Importantly, several chia, and Shigella counts both in vivo (animal) and vitro
studies indicated that major dietary sources of melanoidins (human) studies (Seiquer et al. 2014). Moreover, HMF was
remain in the gastrointestinal tract where they have biological converted into furfural alcohol, which is less toxic after it was
action, according to review by Tagliazucchi et al (Tagliazucchi incubated with enteric bacteria, such as Klebsiella, Enterobacter,
and Bellesia 2015). and Escherichia in short time incubations. According to
authors, these biotransformations might be valuable in the
The limited knowledge on the impact of MRPs on gut detoxification of furfural compounds (Boopathy, Bokang, and
microbiota Daniels 1993). IQ, a known HCA as mutagenic compound, was
Most research focused on impact of dietary MRPs using in vitro converted into innocuous metabolites structure after incuba-
assays using fermentation with human fecal samples or in vivo tion with human fecal samples (Bashir et al. 1987). Contrast-
models by means of animal studies. In the early observation of ingly, activation of IQ by Eubacterium and Clostridium into
the effect of MRPs on the gut microorganism in vitro study, potentially mutagenic 7-hdroxy “IQ” compounds has also been
Jemmali (1969) observed increase growth rates of three Lacto- shown in Salmonella (Vantassell, Kingston, and Wilkins 1990).
bacilli strains, but no effect on E.coli growth in batch cultures Data from animal studies show that melanoidins escape
of MRPs (Jemmali 1969). Moreover, Horikoshi et al detected digestion and pass into the lower gastrointestinal tract (FINOT
the impact of browning products, prepared from D-glucose and MAGNENAT 1981). Subsequently, they are likely to be
and glycine, on the growth both aerobic and anaerobic lactoba- degraded by gut microorganisms (Faist and Erbersdobler
cilli in the microflora of rats (HORIKOSHI et al. 1981). From 2001). Indeed, melanoidins have been shown to have potential
the small number of in vitro studies, it appears that MRPs prebiotic activity (Wang, Qian, and Yao 2011). For instance, an
stages influence the response of gut microbiota members increase in the number of gut bacteria was observed during fer-
(Table 3). mentation with bread melanoidins, which could be used as

Table 3. Current available data of the effect of MRPs on colonic microbiota.

The type of MRPs The type of Gut bacteria The results of study References

FL Viable microbiota (stability) Use as carbon source after 4 hours (Hellwig et al. 2015)
Intestinimonas AF211 Conversion FL into butyrate (Bui et al. 2015)
Bifidobacteria counts Decrease growth rates (Seiquer et al. 2014)
CML/PYR Viable microbiota (stability) Use as carbon source for 24 hours (Hellwig et al. 2015)
CML E.coli No effect on growth rates (Helou et al. 2014)
CML Lactobacilli counts Decrease growth rates (Seiquer et al. 2014)
HMF lactobacilli, Escherichia, and Shigella counts Decrease growth rates (Seiquer et al. 2014)
HMF Klebsiella, Enterobacter, and Escherichia Conversion HMF into furfural alcohol (BOOPATHY et al. 1993)
HCAs (IQ) Gut microbiota Conversion IQ into innocuous metabolites (Bashir et al. 1987)
IQ Eubacterium and Clostridium Conversion IQ into7-hdroxy (VANTASSELL et al. 1990)
Melanoidins Bifidobacteria Use as carbon source and increase growth rates (Borrelli and Fogliano 2005)
Melanoidins Bacteroides-prevotella Increase growth rates (Reichardt et al. 2009)
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 483

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This work was supported in part by an Arkansas Biosciences Institute catalyzed conversion of dietary heterocyclic amines to their proxi-
grant to FC. The authors want to thank Drs Pauline Anton-Gay and Pas- mate carcinogens is their major route of metabolism in humans.
cale Gadonna at LaSalle University for constructive discussions that helped Cancer Res 54:89–94.
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