1 s2.0 S0924224423000547 Main

Trends in Food Science & Technology 133 (2023) 219–230
Contents lists available at ScienceDirect
Trends in Food Science & Technology

journal homepage: www.elsevier.com/locate/tifs
Underlying mechanisms of synergistic antioxidant interactions during

lipid oxidation
Ipek Bayram *, Eric A. Decker
Department of Food Science, University of Massachusetts, 01003, Amherst, MA, United States
A R T I C L E I N F O A B S T R A C T
Handling Editor: Dr AR Jambrak Background: Unsaturated lipids undergo radical-initiated oxidative deterioration during lipid oxidation, which is
one of the most significant food quality and waste issues. Lipid oxidation results in off-flavors, toxic aldehydes,
Keywords: and the co-oxidation of proteins and color compounds. Various antioxidant strategies are utilized by the food
Tocopherol regeneration industry to reduce lipid oxidation and increase shelf-life. Combining antioxidants to achieve synergistic in
Metal chelation
teractions has been practiced for decades to improve oxidative stability. Nevertheless, underlying mechanisms of
Free radical scavenging
synergistic interactions between antioxidants are poorly understood and rarely studied.
Shelf-life
Food quality Scope and approach: This review examines the main hypothesized mechanisms of antioxidant synergism, which
Synergism include: 1) Regeneration of an oxidized antioxidant by another compound, 2) Differences in antioxidant parti
tioning in homogeneous and heterogeneous systems, 3) Combination of free radical scavenging and metal
chelating activities to provide two distinct protection pathways, and 4) Formation of additional antioxidant
compounds, such as phenolics, dimers, or adducts, upon oxidation which can further inhibit lipid oxidation.
Key findings and conclusions: In complex food systems, it is often difficult to predict which antioxidant combi
nations will work synergistically. Understanding the mechanisms of synergism will aid the food industry in the
production of effective antioxidant mixtures to improve oxidative stability and shelf-life, as well as in the
development of simple, rapid, and reliable methods for determining and evaluating synergism.
1. Introduction tissues have highly efficient endogenous antioxidant systems emerging

from the need to protect the aerobic organisms against oxygen and its
Despite more than 150 years of research, lipid oxidation remains a reactive species. However, many food processing operations can remove
major challenge for the food industry due to the complexity of food or degrade endogenous antioxidants in foods. For example, heating
products and the multiple elements that influence oxidation. Controlling destroys antioxidant enzymes, steam strips out phenolic antioxidants
lipid oxidation is crucial since it has a number of detrimental effects on and refining removes beneficial antioxidants from oil (Decker &
food quality. The lipid oxidation reactions produce volatile chemicals Bayram, 2021). Therefore, the incorporation of exogenous antioxidants
such as aldehydes, ketones, and alcohols, which cause rancidity into the food systems is often necessary, especially as food manufac
(Schaich, 2013). The free radicals and aldehydes produced by lipid turers try to make healthier products that are high in unstable unsatu
oxidation also promote co-oxidation of other molecules, particularly rated fatty acids. Consumer desires for clean labels and increase in
proteins, vitamins and pigments, influencing the nutritional quality, health concerns related to synthetic antioxidants have prompted the
texture and appearance of the product (Decker et al., 2010). Aside from food industry to find alternative ways to minimize lipid oxidation to
food quality concerns, it has also been suggested that lipid oxidation improve food quality and safety.
products can be toxic to biological tissues (Vieira, Zhang, & Decker, One of the most effective strategies used by the food industry is
2017). combining antioxidants. A combination of antioxidants results in three
Antioxidants are any molecules that can inhibit the deterioration of different types of interactions: synergism, additive effect, and antago
food products by minimizing lipid oxidation. Antioxidants can serve nism. Synergism refers to the concept where combination of antioxi
different actions in food, including scavenging free radicals, chelating dants enhances oxidative stability more efficiently than the sum of the
metal ions and quenching singlet oxygen (Choe & Min, 2009). Biological individual antioxidant effects. Antagonism, on the other hand, refers to
* Corresponding author.
E-mail addresses: [email protected] (I. Bayram), [email protected] (E.A. Decker).
https://doi.org/10.1016/j.tifs.2023.02.003
Received 13 December 2022; Received in revised form 29 January 2023; Accepted 5 February 2023
Available online 7 February 2023
0924-2244/© 2023 Elsevier Ltd. All rights reserved.
I. Bayram and E.A. Decker Trends in Food Science & Technology 133 (2023) 219–230
the concept that combining antioxidants makes them less effective than thermodynamically reduce the oxidized primary free radical scavenger
the sum of the individual compounds (Olszowy-Tomczyk, 2020). Ad back to its original form, a phenomenon called antioxidant regeneration.
ditive effect refers to the scenario in which combining antioxidants has However, just regenerating one antioxidant with another might not
no additional harm or benefit on the oxidative stability compared to the result in synergistic activity. This is because when antioxidants are
sum of the individual antioxidants. It should be noted that synergistic combined, the total antioxidant activity is related to the total number of
combinations are those in which one compound has little antioxidant antioxidant molecules in the system. Thus, if both antioxidants are
activity but can increase the activity of the second antioxidant (e.g., see equally effective at scavenging free radicals, their combination should
phospholipid-tocopherol combinations in section 2.2). Combinations produce an additive effect. One way to achieve synergistic regeneration
where both compounds have antioxidant activity can also be synergistic reactions is for one antioxidant to partition into the site of lipid oxida
(e.g., see myricetin-tocopherol combinations in section 2.1). While the tion (e.g., cell membrane) and the second antioxidant to regenerate the
former may show stronger synergism, the latter can produce better antioxidant that is preferentially oxidized in the lipid. This is the case for
overall antioxidant activity because both antioxidants provide protec ascorbic acid and tocopherols in phospholipid bilayers, including cell
tion. Therefore, calculation of synergism by formulas such as interaction membranes. The reaction scheme of α-tocopherol regeneration by
index (Culler et al., 2022; Panya et al., 2012), does not always indicate ascorbic acid is shown in Fig. 1. This reaction involves the formation of
which antioxidant combinations are the most effective. Obtaining the α-tocopheroxyl radical due to lipid radical scavenging (Step 1),
antioxidant synergism is beneficial for the food industry as effective followed by the hydrogen transfer from the most acidic hydroxyl group
combinations could: (1) prolong shelf-life; (2) protect foods with lower of ascorbic acid to α-tocopheroxyl radical, resulting in the formation of
antioxidant concentrations which could lower costs, especially where α-tocopherol and semihydroascorbate radical (Step 2) (Fujisawa et al.,
one of the antioxidants may already be present in the food (e.g., to 2006).
copherols) and, (3) improve nutritional quality and food safety. There Ascorbic acid’s ability to reduce and regenerate α-tocopheroxyl
fore, the food industry is testing variety of antioxidant mixtures to radical has been demonstrated using pulse radiolysis (Packer et al.,
obtain synergistic interactions. 1979) and electron spin resonance spectroscopy (Niki et al., 1982). In
Synergism is influenced by multiple factors, including type of food heterogeneous systems, such as soybean phosphatidylcholine liposomes,
matrix, pH, antioxidant type/concentration/ratio, interactions with Niki et al. (1985) and Thomas et al. (1992) demonstrated the synergistic
other food components, and processing conditions. Therefore, it is very activity of ascorbic acid and α-tocopherol, emerging from the different
difficult to determine which antioxidant combinations will exhibit partitioning of the antioxidants within the liposome structure.
synergistic effects in a given food system. Hundreds of papers on anti α-Tocopherol is lipid-soluble, but its hydroxyl group and phytol chain
oxidant synergism have been published so far, but the majority of them gives it amphiphilic properties. Therefore, α-tocopherol partitions at the
either fail to explain the reason for the synergistic activity or only sug interface of biological tissue cell membranes to provide protection
gest underlying mechanisms without providing experimental evidence. against oxidation and membrane disfunction. When free radicals are
A few examples from research articles in which authors identified syn present within the membrane, α-tocopherol is oxidized to form more
ergistic interactions but failed to provide an explanation for their polar α-tocopheroxyl radical, which can interact with water-soluble
occurrence include catechin/resveratrol (Skroza et al., 2015), kaemp ascorbic acid and initiate the electron transfer required to regenerate
ferol/myricetin (Hidalgo et al., 2010), and lycopene/vitamin E (Shi α-tocopherol back to its original form (Fukuzawa et al., 1993) (Fig. 2).
et al., 2007). It is essential to understand the underlying mechanisms of Water soluble ascorbic acid may not be an effective antioxidant in bio
synergism and the factors that can produce this synergism as this will logical tissues in this case because water soluble free radicals, such as
facilitate the identification of which antioxidant combinations will work hydroxyl radicals, are difficult to scavenge due to their high energy,
in different food systems versus conducting numerous studies to screen which allows them to oxidize the first molecule they encounter. Ascorbic
antioxidant mixtures. Therefore, the aim of this article is to provide acid is synergistic although it is not very effective on its own due to its
detailed insights into the mechanisms of synergistic antioxidant in inability to penetrate through the membrane to inhibit lipid oxidation
teractions, which include the regeneration of an oxidized antioxidant by but can maintain the antioxidant activity of α-tocopherol in the phos
another compound, the differences in antioxidant partitioning within pholipid bilayer. In addition, oxidized ascorbic acid is regenerated
the food matrix, the combination of free radical scavenging and metal enzymatically by glutathione and NAD(P)H in biological tissues, which
chelating activities, and/or the formation of an additional antioxidant maintain ascorbic acid concentrations to further regenerate more
compound from primary antioxidants upon oxidation. α-tocopherol (Pullar et al., 2017).
Niki et al. (1984) also reported a synergistic interaction between
2. Mechanisms of synergistic antioxidant interactions α-tocopherol and ascorbic acid during the oxidation of methyl linoleate
in tert-butyl alcohol/methanol solution. This discovery is intriguing
2.1. Antioxidant regeneration due to redox cycling because if both antioxidants were equally effective in a homogenous
system, the number of electrons to interact with the fatty acid radicals
Free radical scavenging antioxidants are widely used in the food would be expected to produce an additive effect. It is possible that the
industry because of their ability to slow down the initiation and prop methyl linoleate system is not homogeneous and instead has physical
agation stages of lipid oxidation. Their ability to inhibit lipid oxidation is structures like association colloids that partition the α-tocopherol and
determined by their reduction potential and structure, which influence ascorbic acid into different phases, allowing them to behave as they do
their ability to reduce lipid radicals as well as the energy of the anti in phospholipid bilayers. It is also possible that antioxidants regenerate
oxidant radical, which is typically reduced in phenolic antioxidants due each other in stoichiometries that are not 1:1, resulting in synergistic
to resonance delocalization. Antioxidants with low redox potentials (e. antioxidant interactions in homogeneous systems. An antioxidant with
g., <600 mV) (Decker et al., 2010) are thermodynamically capable of multiple redox active groups, for instance, may regenerate more than
donating hydrogens to convert alkyl, alkoxyl and peroxyl free radicals to one primary antioxidant, or the oxidation product of an antioxidant may
nonradical species such that the free radicals are not able to further still possess reduction potential, allowing it to reduce another primary
oxidize unsaturated lipids. Thus, free radical scavengers, such as to antioxidant.
copherols, are depleted during storage as they scavenge free radicals by Ascorbic acid-tocopherol synergism may be applicable to foods
hydrogen donation, and hence, lose their ability to protect unsaturated where oxidation occurs in the cell membrane (e.g., muscle foods).
fatty acids. If a secondary free radical scavenger with a substantially However, in muscle foods, ascorbic acid levels are typically low and
lower redox potential than that of the primary antioxidant (e.g., to decrease rapidly during post-mortem (Decker & Hultin, 1990). Supple
copherols) exists in the food matrix, it may be able to menting livestock with vitamin E (Delosière et al., 2019) and adding
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Fig. 1. Reaction scheme of α-tocopherol regeneration by ascorbic acid. Step 1: Formation of α-tocopheroxyl radical, Step 2: Reduction of α-tocopheroxyl radical by
ascorbic acid.
Fig. 2. Schematic representation of α-tocopherol regeneration by ascorbic acid in heterogenous systems due to differences in antioxidant partitioning.
exogenous ascorbic acid to muscle foods (Ham et al., 2019) have been to α-tocopherol regeneration. This logic is consistent with previous
found to effectively inhibit oxidation; but it is unknown what role studies that found synergistic interactions between α-tocopher
ascorbic acid/tocopherol synergism plays in these antioxidant strate ol/quercetin in methyl linoleate tert-butyl alcohol solution (Pedrielli &
gies. Ascorbic acid/tocopherol synergism might not be effective in other Skibsted, 2002), α-tocopherol/myricetin in stripped sunflower oil
food systems due to the insolubility of ascorbic acid in bulk oils, and the (Marinova et al., 2008), and α-tocopherol/EGCG in linoleic acid tert-
ability of ascorbic acid to increase the prooxidant activity of transition butyl alcohol/water solution (Jia et al., 1998). The synergistic interac
metals by redox cycling in oil-in-water emulsions (Jacobsen et al., tion between α-tocopherol and green tea extract was also observed
1999), thus making ascorbic acid-tocopherol combinations less effective during oxidation of linoleic acid in sodium dodecyl sulfate (SDS) mi
than in biological tissues where iron reactivity is tightly controlled by celles (Dai et al., 2008), where the synergism was attributed to
chelation to proteins (Decker & Bayram, 2021). EGCG-mediated α-tocopherol regeneration. This system resembles the
It is possible for combinations of antioxidants other than ascorbic ascorbic acid and α-tocopherol synergism in that EGCG is highly
acid-tocopherols to be synergistic through redox cycling. The ability of water-soluble and, like ascorbic acid, is a potentially weak antioxidant
antioxidants to regenerate each other can be estimated by comparing on its own due to its inability to interact with lipid radicals formed in the
their one electron reduction potential (E◦ ), which explains the potential lipid phase. The analysis of α-tocopherol degradation rates revealed that
of substances to transfer electrons. E◦ of antioxidants have been widely EGCG, like ascorbic acid, can reduce α-tocopheroxyl radical, resulting in
documented in the literature (Decker et al., 2010) utilizing various synergism. On the other hand, the regeneration of α-tocopherol is
techniques such as flash photolysis, pulse radiolysis, or cyclic voltam thermodynamically infeasible by antioxidants with E◦ greater than 500
metry. It is critical to note that E◦ of an antioxidant derived by different mV, such as kaempferol (750 mV), rutin (600 mV), catechin-epicatechin
approaches should be compared carefully due to differences in notating (570 mV), chlorogenic acid (550 mV), and caffeic acid (534 mV) (Decker
the results (e.g., potential versus half-potential). Similarly, E◦ is strongly et al., 2010). This logic is consistent with previous studies that reported
influenced by system characteristics such as pH, ionic strength, and antagonistic/additive interactions between α-tocopherol and caffeic
solvent type; thus, comparing E◦ values of antioxidants requires iden acid in aqueous dispersions of linoleic acid (Peyrat-Maillard et al.,
tical experimental conditions. The ability of ascorbic acid to regenerate 2003), α-tocopherol and catechin/epicatechin in stripped sunflower oil
α-tocopherol is due to its lower redox potential (ascorbate monoanion, (Yin et al., 2012), and α-tocopherol and chlorogenic acid in phosphati
AscH-/semidehydroascorbate radical, Asc•-, 282 mV) than α-tocopherol dylcholine liposomes (Neunert et al., 2015), where additive effect occurs
(α-tocopherol, TOH/α-tocopheroxyl radical, TO•, 500 mV) (Buettner, due to the absence of any interaction between antioxidants, and
1993). Therefore, it is possible to estimate the likelihood of antioxidant antagonism may result from the regeneration of a less potent antioxidant
regeneration by comparing E◦ of different antioxidants. by a more potent antioxidant.
Quercetin-quercetagetin-fisetin (330 mV), myricetin (360 mV), and Although E◦ provides a decent approximation, it does not always
epigallocatechin (EGC)-epigallocatechin gallate (EGCG) (430 mV), for guarantee that antioxidant combination will result in regeneration re
example, have lower redox potentials than α-tocopherol (500 mV) actions. Some reactions that are thermodynamically favorable may not
(Decker et al., 2010), which could produce synergistic interactions due be kinetically feasible. Combinations of water- and lipid-soluble
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antioxidants, for instance, may not always be synergistic if emulsifiers at bulk oils, emulsions, and low moisture food products.
the lipid-water interface reduce the ability of antioxidants to undergo
electron transfer due to their charge, which could repel oppositely 2.2. Antioxidant regeneration through other mechanisms
charged antioxidants, or the thickness of the interface, which could
sterically hinder antioxidant interactions (Barouh et al., 2022). Also, the Phospholipids are amphiphilic lipids composed of two fatty acids and
structure of an antioxidant may be such that the antioxidant radical is a phosphate group attached to a glycerol backbone. Phosphatidyletha
sterically protected, making it difficult to interact with a regenerating nolamine (PE), phosphatidylserine (PS), phosphatidylcholine (PC),
antioxidant. These could explain why contradictory results were re phosphatidylethanolinositol (PI), and phosphatidic acid (PA) are major
ported for the same antioxidant pairs in similar food systems. For phospholipid types found in food systems. During the degumming pro
example, while Dai et al. (2008) discovered synergistic antioxidant in cess, the majority of phospholipids are removed from bulk oil to prevent
teractions between α-tocopherol and EGCG during the oxidation of cloudy appearance and darkening at high temperatures, and eliminate
linoleic acid in sodium dodecyl sulfate (SDS) micelles, Durand et al. contamination with excess metal ions carried by phospholipids (Weng &
(2015) discovered non-synergistic interactions between α-tocopherol Gordon, 1993). However, due to their amphiphilic properties, phos
and EGCG during the oxidation of methyl eleostearate in sodium pholipids are added to food systems for their emulsifying and crystal
caseinate-stabilized emulsions. This may be due to differences in inter modifying properties. In recent years, the synergistic interactions be
facial properties as well as variations in tocopherol-EGCG proximity, as tween phospholipids and tocopherols have been a promising research
tocopherol can interact with EGCG at the micelle interface much more area for the enhancement of oxidative stability, but the mechanisms
readily than in emulsions due to the micelle’s smaller interfacial thick underlying these interactions are unclear. Some researchers claimed
ness compared to an emulsion stabilized by a large protein, such as simple electron transfer between these compounds (Hudson & Lewis,
casein. 1983a) similar to the ascorbic acid/α-tocopherol system, while others
Another approach to estimate the antioxidant regeneration would be claimed due to the phospholipids having metal chelating activity
to compare bond dissociation enthalpy (BDE), which is a thermody (Dacaranhe & Terao, 2001), or regenerating lipid radicals with their
namic property showing the energy required for bond cleavage. acidic protons. Weng and Gordon (1993) demonstrated that PE was
Numerous experimental measurements and theoretical calculations capable of converting α-tocopherylquinone to α-tocopherol, resulting in
have been performed to determine the BDE of wide range of phenolic synergistic interactions in lard. Prior to this discovery, only the regen
antioxidants (Decker et al., 2010). The comparison of these values may eration of α-tocopherol by ascorbic acid, which occurred through the
suggest the probability of hydrogen transfer from one antioxidant to reduction of α-tocopheroxyl radicals, was known (Packer et al., 1979).
another, analogous to E◦ ; thus, it may provide insight into the likelihood The process begins with the two-electron oxidation of α-tocopherol in
of antioxidant regeneration. However, the results of E◦ and BDE may food systems due to free radical scavenging activity, which results in the
differ depending on the system conditions. For example, quercetin and formation of α-tocopherylquinone (Fig. 3). Doert et al. (2012) demon
α-tocopherol have E◦ values of 330 and 500 mV, respectively (Decker strated that the reduction of α-tocopherylquinone by phospholipids is
et al., 2010), implying that quercetin could thermodynamically donate not caused by simple electron transfer due to differences in redox po
an electron to reduce oxidized α-tocopherol. However, quercetin and tentials, but rather by rearrangement reactions. The authors showed that
α-tocopherol have BDE values of 81.98 and 78.87 kcal/mol, respectively PE and PS form complexes with α-tocopherylquinone, which later
(Decker et al., 2010), implying that it is more difficult for quercetin to generate PE-PS-α-tocopherones through amino-carbonyl reactions.
donate hydrogen because more energy is required to break the bond. PE-PS-α-tocopherones then undergo a series of rearrangements,
Similarly, ascorbic acid has a lower E◦ (282 mV), but a higher BDE value including decarboxylation (for PS) and acid heterolysis (for PE),
(83.00 kcal/mol) than α-tocopherol (Decker et al., 2010). The observed resulting in regeneration of α-tocopherol (Fig. 3). On the other hand,
synergistic interactions between α-tocopherol and quercetin in methyl authors did not find any α-tocopherol regeneration with PC, which was
linoleate tert-butyl alcohol solution (Pedrielli & Skibsted, 2002) and associated with the absence of amine group. Studies analyzing the
α-tocopherol and ascorbic acid in methyl linoleate tert-butyl alcohol/ synergistic interactions between α-tocopherol and phospholipids in bulk
methanol solution (Niki et al., 1984) were attributed to α-tocopherol oils support this conclusion. For instance, Takenaka et al. (2007)
regeneration, indicating that E◦ might provide a more accurate estima demonstrated synergistic antioxidant activity between α-tocopherol and
tion than BDE. In addition, one-electron reduction potential (E◦ ) is PE in stripped bonito oil, whereas PC had no synergistic effect. Similarly,
reversible whereas bond dissociation enthalpy (BDE) is not, so it is Cui et al. (2015) found that the addition of PE to store-bought soybean
thought that reduction potentials may more accurately describe anti oil containing endogenous tocopherols increased shelf-life, whereas the
oxidant regeneration (Warren et al., 2010). These contradictory values addition of PC had the opposite effect. Xu et al. (2019) concluded the
may also result from different measurement techniques, type of solvent, same synergistic activity of tocopherols with PE in stripped soybean oil,
pH of the system, or the complexity of the calculation methods if the but they discovered an additive effect with PS. On the other hand,
estimation is theoretical. Samdani et al. (2018) discovered that while PS acts synergistically with
Besides thermodynamic estimations, the regeneration of antioxi α-tocopherol in stripped soybean oil-in-water emulsions, PE produced
dants can be directly measured using experimental techniques such as an additive effect, which is the exact opposite effect compared to bulk
cryogenic electron paramagnetic resonance or high performance liquid oils. This might be due to differences in partitioning at the emulsion
chromatography. The former can be employed by monitoring the loss of droplet interface because of varying phospholipid and surfactant in
the primary antioxidant radical signal in the presence of a secondary teractions. Synergisms in these systems occur because the phospholipids
antioxidant (Panya et al., 2012). The latter can be used if an oxidation themselves have little to no antioxidant activity; therefore, any increase
product of the primary antioxidant can be measured (e.g., quinone) and in tocopherol activity by PE or PS results in synergism.
then determining if a secondary antioxidant can convert the oxidation The vast majority of studies demonstrating PE and PS synergism with
product back to the original primary antioxidant structure (Cui et al., tocopherols employ research-grade phospholipids. The commercially
2015). There are many factors influencing the radical transfer between available lecithins are a mixture of various phospholipid types,
antioxidants, especially in complex food systems, such as anti including prooxidant PC. However, PC in lecithins can be transformed to
oxidant/prooxidant activity, thermodynamic properties, solubility and PE or PS by the enzyme phospholipase D through hydrolysis and
polarity of the antioxidants, and antioxidant distribution throughout the transphosphatidylation reactions. The resulting high-PE and high-PS
food matrix owing to the presence of micelles, membranes, and so on. As lecithins could be combined with tocopherols to obtain synergism. For
a result, it is critical to look for different antioxidant regenerating pairs instance, Arora et al. (2022) converted high-PC (94%) soybean lecithin
that may be suited for a variety of different food applications including to high-PS (92%) soybean lecithin, which showed synergistic
222
Fig. 3. Reaction scheme of α-tocopherol regeneration by phospholipids. Step 1: Formation of α-tocopherylquinone as a result of antioxidant activity, Step 2:
Reduction of α-tocopherylquinone by phosphatidylethanolamine (PE) and phosphatidylserine (PS) through series of rearrangement reactions. Adapted by Doert
et al. (2012).
interactions with α-tocopherol in stripped soybean oil-in-water emul systems in which antioxidants are modified with different alkyl chain
sions. Similarly, Culler et al. (2022) obtained synergistic activity both in lengths to alter their polarities and, consequently, their partitioning and
oil-in-water emulsions and stripped soybean oil when researchers con antioxidant activity. This has been observed in oil-in-water emulsions
verted high-PC (96%) soybean lecithin to high-PE (72%) soybean leci containing rosmarinic acid (Laguerre et al., 2010) and hydroxytyrosol
thin. Compared to the direct use of purified phospholipids, this (Medina et al., 2009). In general, while antioxidant activity increased in
conversion permits the food industry to produce more cost-effective emulsions with increasing hydrophobicity (C2 to C8 or C12 alkyl chain
methods for enhancing the oxidative stability of bulk oils and emulsions. length) as predicted by the polar paradox hypothesis, there was a
Phenolic antioxidants may also regenerate each other by forming "cut-off" effect for longer alkyl chains (>C8–C12), where antioxidant
stable complexes as a result of π-π stacking rather than simple redox activity decreased as molecules became more nonpolar. This cut-off ef
cycling, potentially resulting in synergism. This was observed between fect was caused by multiple factors, including 1) molecules becoming
rosmarinic acid and quercetin, where the formation of a stable complex extremely nonpolar after a certain alkyl chain length, resulting in par
between cinnamic acid and flavonol due to the π-π stacking of the aro titioning in the oil phase as opposed to the interface, and (2) more
matic ring of the phenolic and the B ring of the flavonol resulted in nonpolar antioxidants forming micelles with emulsifiers, thereby
synergistic activity (Peyrat-Maillard et al., 2003). This alters the struc migrating away from the emulsion droplets. From a synergism stand
ture and bonding between molecules, making the complex more stable point, Panya et al. (2012) demonstrated that only water soluble ros
than the parental compounds in terms of hydrogen-donating capacity for marinic acid devoid of a linked alkyl chain exhibited synergism with
regeneration reactions. α-tocopherol due to their maximum interaction, as observed by fluo
rescence quenching. This suggests that rosmarinic acid was only syn
ergistic when it was in the water phase versus coexisiting with
2.3. Differences in antioxidant partitioning within food tocopherol in the emulsion droplet. This demonstrates the importance of
using antioxidants to achieve synergistic antioxidant interactions based
The ability of antioxidants to interact synergistically may also occur not only on their polarities and efficacies, but also on their inter
as a result of their different partitioning within the food matrix. The action/physical contact with each other.
different localization of antioxidants in emulsions, micelles, liposomes, Until now, several water- and lipid-soluble antioxidants have been
or association colloids could promote antioxidant regeneration, hence studied in heterogeneous systems without taking the antioxidant parti
synergism, as observed in α-tocopherol/ascorbic acid combinations in tioning into consideration; consequently, contradictory results
heterogenous systems (Niki et al., 1985; Thomas et al., 1992). Therefore, regarding antagonistic and synergistic interactions have been published.
it is important to know the location and efficacy of antioxidants in order The interactions between antioxidants should be investigated individ
to design synergistic antioxidant interactions. ually in homogenous (e.g., solvents) and heterogeneous (e.g., liposomes,
It was first proposed in the 1980s that nonpolar antioxidants are micelles) systems, as the same antioxidants may function synergistically
more active in polar settings, such as oil-in-water emulsions, while polar in one system but antagonistically in another. For instance, it was found
antioxidants are more active in nonpolar environments, such as bulk oils that while quercetin and α-tocopherol had antagonistic interactions in
due to their distinct partitioning in the area where lipid oxidation is stripped sunflower oil, they acted synergistically in methyl linoleate
prevalent (Porter et al., 1989). Trolox, for example, was shown to be a emulsions (Becker et al., 2007). This may be due to the fact that the
stronger antioxidant in corn oil triacylglycerols than α-tocopherol due to presence of a lipid-water interface may have increased
its more polar nature, as suggested by the polar paradox (Huang et al., regeneration-induced synergism in comparison to a homogeneous sys
1996). This theory has been one of the most influential guidelines for tem. However, this could also be due to the fact that quercetin can
estimating the antioxidant activity in simple model systems. However, chelate metals (see section 2.4). This was also observed with other
multiple studies have demonstrated that the polar paradox theory does phenolic compounds, where heterogenous systems had higher
not always accurately predict antioxidant activity, particularly in
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α-tocopherol regeneration rates than in pure hexane due to their distinct water molecules to create micelle-like structures. Consequently, it is
partitioning (Iglesias et al., 2009). Therefore, it is essential to have anticipated that the oil-water interfaces are also the principal lipid
knowledge of the physical locations of antioxidants in heterogeneous oxidation sites for bulk oils, thus, interfacial antioxidants are good
systems to determine whether antioxidants could operate synergisti choices to inhibit oxidation. α-Tocopherol, for example, is an effective
cally. This could be accomplished by measuring the partition coefficient antioxidant in bulk oils because 73% of α-tocopherol partitions at the
of antioxidants (log P), which reflects a molecule’s tendency to partition interface and 26% in the hydrophobic phase (Gunaseelan et al., 2006).
in water or lipid phases, giving a notion of their hydrophilicity versus From synergism standpoint, interface-active antioxidants may have
lipophilicity. This is often performed using immiscible octanol-water more synergistic interactions compared to their non-interface active
systems. The partition coefficients of some antioxidants are summa counterparts due to their ease of interacting with other antioxidants
rized in Table 1. located in aqueous and lipid phases, which may lead to antioxidant
However, measuring hydrophilicity/lipophilicity alone is insuffi regeneration. On the other hand, if regenerating antioxidants could not
cient to estimate the partitioning site because some antioxidants have interact at all due to the partitioning at different phases (aqueous and
amphiphilic properties and preferentially locate at the oil-water inter lipid) rather than at the interface, an additive or antagonistic effect may
face, where most lipid oxidation reactions occur. Therefore, the “polar be observed. Therefore, knowing which antioxidants locate at the
paradox” theory was expanded to take into account the impact of anti interface can help predict whether an antioxidant combination will act
oxidants’ surface activity (Frankel et al., 1994). Since free radicals are synergistically. The antioxidants’ interfacial activity can be measured
mainly generated at oil-water interfaces due to interface-active lipid using fluorescence with the interfacial 1,2-dioleoyl-sn-glycero-3-phos
hydroperoxide decomposition, interfacial antioxidants may be better phoethanolamine-N-(7-nitro-2-1,3-benzoxadiazol-4-yl) (NBD-PE),
able to suppress lipid oxidation. This is especially true in emulsion where the change in NBD-PE intensity in the presence of antioxidants
systems, where interfacial antioxidants are far more powerful than demonstrates the ability of antioxidants to locate at the interface (Cui
water-soluble antioxidants partitioning directly into the aqueous phase. et al., 2015). Similarly, a 4-hexadecylarenediazonium ion probe, which
In oil-in-water emulsions, for example, amphiphilic ascorbyl palmitate partitions only at the interfacial layer of the emulsions and reacts with
and propyl gallate partitioned at higher concentrations at the interface the antioxidants located at the interface, can be used to determine the
than tocopherol, resulting in enhanced oxidative stability distributions of antioxidants (Gunaseelan et al., 2006). Interfacial ac
(López-Martínez & Rocha-Uribe, 2017). Similarly, even though bulk oil tivity of antioxidants can also be estimated by measuring the interfacial
appears to be a homogeneous system, the same hypothesis applies. Bulk tension using equipments such as the drop shape analyzer, which re
oils contain physical structures known as association colloids, which are cords the image of the drop in the absence and presence of an antioxi
formed when amphiphilic molecules, such as phospholipids, enclose dant to calculate the interfacial tension (Sasaki et al., 2010). The
Table 1
The partition coefficients (log P) of some antioxidants.
Compounds Log P References Compounds Log P References
Tocopherol 12.10a Jamshidian et al. (2012) Sesamol 1.34a Geetha et al. (2015)
589c Liao and Yin (2000) 1.29c Geetha et al. (2015)
Carnosol 4.58a Logan et al. (2015) Taxifolin 1.22a Dičkancaitė et al. (1998)
15.90b Huang et al. (1997) 1.12c Shatalin and Shubina (2014)
Carnosic Acid 5.13a Logan et al. (2015) EGCG 0.39c Shibusawa et al. (2005)
10.20b Huang et al. (1997) 1.67a Shibusawa et al. (2005)
1.41b Kajiya et al. (2001)
BHT 6.60a Jamshidian et al. (2012) Hydroxytyrosol 1.07c Peng et al. (2015)
Myricetin 5.27c Liao and Yin (2000) Caffeic Acid 0.56c Liao and Yin (2000)
3.18b Chuang et al. (2017) 1.30a Son and Lewis (2002)
1.29b Noubigh et al. (2009)
Trolox 3.83b Huang et al. (1997) Ferulic Acid 1.58a Son and Lewis (2002)
3.20a Son and Lewis (2002) 0.49c Sohn and Oh (2003)
Resveratrol 3.09a Yang et al. (2017) Propyl Gallate 1.20a Jamshidian et al. (2012)
0.85b Huang et al. (1997)
Quercetin 3.84c Liao and Yin (2000) Rutin 0.76b Chuang et al. (2017)
3.32b Chuang et al. (2017) 0.85c Pedriali et al. (2008)
2.74a Dičkancaitė et al. (1998)
Thymol 3.04c Schwarz et al. (1996) Catechin 0.32c Shibusawa et al. (2005)
0.86a Shibusawa et al. (2005)
BHA 3.40a Jamshidian et al. (2012) Epicatechin 0.13c Shibusawa et al. (2005)
2.95c Schwarz et al. (1996) 0.86a Shibusawa et al. (2005)
TBHQ 3.00a Jamshidian et al. (2012) EGC − 0.50c Shibusawa et al. (2005)
0.43a Shibusawa et al. (2005)
Rosmarinate 2.07a Logan et al. (2015) Gallic Acid 0.02b Huang et al. (1997)
0.48b Huang et al. (1997) − 0.89c Schwarz et al. (1996)
2.50c Huang et al. (2019)
ECG 1.06c Shibusawa et al. (2005) Chlorogenic Acid − 0.77a Maisuthisakul et al. (2006)
2.10a Shibusawa et al. (2005) − 0.90c Bonarska-Kujawa et al. (2015)
Vanillic Acid 1.43a Kamaya et al. (2005)
1.42b Noubigh et al. (2010)
a
Indicated the estimated log P obtained through computation.
b
Indicated the experimental log P obtained through chromatographic methods.
c
Indicated the experimental log P obtained through spectrophotometric analysis. Aside from the techniques, the log P values of the same compounds vary depending
on the type of solvent (octanol-water versus oil-water), pH and the presence of other components.
224
interfacial activity of some antioxidants is summarized in Table 2. The metals (Timoshnikov et al., 2022), supplying a steric effect to avoid
interfacial activity was determined by comparing the interfacial tensions direct contact between transition metals and hydroperoxides (Gulcin &
of the control group without antioxidants to the samples after antioxi Alwasel, 2022), modifying the partitioning of the metal ions within food
dant addition. The different antioxidant concentrations and their matrix (Yi et al., 2014), and reducing the metal ion solubility (Sun et al.,
resulting interfacial tensions were summarized. 2021). Organic acids (e.g., citric acid), ethylenediaminetetraacetic acid
(EDTA), polyphosphates, and proteins are common food chelators used
2.4. Combination of free radical scavenging and metal chelating activities in the food industry, and their efficiency is determined by the chelator:
metal ion ratio and food characteristics such as pH. EDTA is one of the
The food industry employs antioxidant combinations with different most effective chelators due to its high affinity for the majority of metal
mechanisms of action, such as free radical scavenging activity, metal ions, potent activity at low concentrations, and superior chelating ability
chelating ability and singlet oxygen quenching activity. Combining two under acidic conditions compared to most organic acids. Concerns exist
antioxidants with distinct molecular mechanisms can increase oxidative regarding clean labeling when EDTA is used, and other natural chelators
stability via synergistic effects. Two commonly used antioxidants in food (e.g., organic acids, proteins, peptides) are not as effective due to their
systems are free radical scavengers and metal chelators; therefore, it is low solubility in certain food systems and decreased activity at low pH as
critical to understand their synergistic/antagonistic interactions in order a result of protonation (Díaz et al., 2003). Therefore, it is crucial to
to develop systems with improved oxidative stability. examine the possibility of using other natural compounds, such as fla
In vivo and in vitro lipid oxidation occurs via free radical chain vonoids, as food chelators.
mechanism in which external factors produce free radicals that trigger The rate of metal-induced lipid oxidation reactions varies depending
the chain reactions. The presence of metal ions in food systems, on the nature of the food product; therefore, it is critical to determine
particularly iron and copper, is one of the primary external factors whether a metal chelator will be effective in a specific food system and,
forming the free radicals. Iron and copper are normally bound to pro if so, which concentrations or types of chelators will provide the best
teins in biological tissues; hence, their reactivity is typically under protection. For example, the rate of metal-promoted lipid oxidation is
control. However, these bound metal ions can be released during har significantly higher in emulsions than low moisture foods as the pres
vesting, slaughtering, salting, cooking and pH changes during food ence of water-oil interface increases the contact between lipid hydro
processing operations, resulting in more reactive free metal ions. peroxides and prooxidative metals. Some food systems, such as low
Released metal ions can partition into aqueous phase and promote lipid moisture crackers do not require the use of metal chelating agents. This
hydroperoxide decomposition into peroxyl or alkoxyl radicals at the is likely due to the inability of metal ions to diffuse into the lipids in low
interface, which promote further oxidation by reacting with more un moisture conditions. Barden et al. (2015) showed that iron addition into
saturated fatty acids. Although free radical scavengers are added to crackers had no effect on the lag phase of hydroperoxide and hexanal
deactivate these free radicals in food systems, they eventually become formation, nor did the addition of EDTA extend shelf-life.
depleted and antioxidant activity is lost. Decreasing radical generation Besides chelators, metal reactivity can be influenced by factors that
can be achieved by inhibiting metal activity with chelators. The inhi impact the ability of metals to interact with water-lipid interfaces. For
bition of prooxidant metal activity can slow down the depletion rate of example, using positively charged molecules at the interface such as
free radical scavengers, resulting in a longer shelf-life. cationic surfactants, carbohydrates, and proteins can repel positively
The food industry uses metal chelators as food additives to reduce the charged prooxidant metal ions and prevent contact with the oil phase,
metal ion-mediated lipid oxidation reactions. Metal chelators can slow thereby reducing oxidation. On the other hand, negatively charged in
lipid oxidation by varying the reduction potential of the transition terfaces attract positively charged metal ions and can increase oxidation.
Table 2
The interfacial activity of some antioxidants.
Interface-Active System Concentration Interfacial Tension of Interfacial Tension of References
Compounds (mmol/kg) Control (mN/m) Compounds (mN/m)
Tocopherol Hexadecane:water 1.0–5.0 43.3 41.5–35.0 Chaiyasit et al. (2007)

TBHQ Hexadecane:water 0.25–1.0 43.3 43.0–41.6 Chaiyasit et al. (2007)
Trolox Hexadecane:water 0.2–1.0 43.3 34.8–28.0 Chaiyasit et al. (2007)
Propyl Gallate Hexadecane:water 1.0 43.3 34.6 Chaiyasit et al. (2007)
Octyl Chlorogenic Acid Hexadecane:water 0.13–0.65 44.4 42.2–34.9 Sasaki et al. (2010)
Dodecyl Chlorogenic Hexadecane:water 0.13–0.65 44.4 39.1–17.8 Sasaki et al. (2010)
Acid
Catechin Refined olive oil:buffer 0.01–10.0 72.8 57.3–53.5 Di Mattia et al. (2010)
Quercetin Refined olive oil:buffer 0.01–10.0 72.8 59.1–56.1 Di Mattia et al. (2010)
Syringic Acid Extra virgin olive oil: 5.05 41.0 32.5 Katsouli et al. (2017)
water:Tween 20
Caffeic Acid Extra virgin olive oil: 5.55 41.0 36.4 Katsouli et al. (2017)
water:Tween 20
Vanillic Acid Extra virgin olive oil: 5.95 41.0 36.2 Katsouli et al. (2017)
water:Tween 20
Rutin Soybean oil:buffer:soy 0.08–0.32 7.4 6.5–5.1 Cui et al. (2014)
protein isolate
Non Interface-Active System Concentration Interfacial Tension of Interfacial Tension of References

Compounds (mmol/kg) Control (mN/m) Compounds (mN/m)
EGCG Corn oil:water 0.04–0.62 26.6 25.5–25.3 Mura et al. (2017)

BHT Hexadecane:water 1.0–5.0 43.3 43.7–43.7 Chaiyasit et al. (2007)
Chlorogenic Acid Hexadecane:water 0–0.65 44.4 44.4–44.3 Sasaki et al. (2010)
Gallic Acid Soybean oil:water 5.9–205.7 14.0 14.0–13.0 Gomes et al. (2016)
The interfacial tension of control groups varies based on the measurement technique and the presence of other compounds in the testing phase, such as emulsifiers (e.g.
Tween 20), proteins (e.g. soy protein isolate), or other antioxidant compounds (e.g. phenolics in extra virgin olive oil). The mmol/kg unit represents the mmol of added
antioxidants per kilogram of phase containing the solubilized antioxidants.
225
Since the majority of food emulsion droplets are negatively charged, analyzed by lipid hydroperoxide and volatile analysis in the absence and
metal chelating agents such as negatively charged proteins and peptides presence of the chelator. High performance liquid chromatography
can bind and remove metal ions away from the emulsion droplet surface might also be used to test the degradation rate of the free radical scav
thereby improving oxidative stability. enger in the absence and presence of the metal chelator, which is a good
If the food industry intends to combine free radical scavengers and indicator of how well the metal chelator spares the free radical scav
natural metal chelators to achieve synergistic interactions, it is crucial to enger. Given all of these considerations, developing an effective free
evaluate the ability of metal-chelator complexes to inhibit lipid oxida radical scavenger and natural metal chelator mixture could be a prom
tion, as metal chelating ability does not always guarantee the antioxi ising method for extending the shelf-life of lipid-based food products
dant effect. Natural metal chelators, such as phenolics and organic acids, through synergistic interactions.
may exhibit prooxidant effects following chelation if the chelated metal
ion is more soluble and reactive than the unchelated metal. Many 2.5. Formation of additional antioxidant compounds
phenolic compounds reduce ferric iron into more soluble ferrous iron to
be able to bind the metal ions (Mira et al., 2002). This could cause lipid Aside from the mechanisms described above, the interactions be
oxidation reactions to proceed much faster as reduced metals are more tween antioxidants may cause them to react with one another to form
prooxidative. For instance, caffeic acid addition led to prooxidant ac complexes/adducts or to degrade into smaller compounds, resulting in
tivity in fish oil-in-water emulsions as a result of the conversion of the formation of new antioxidant molecules. If the formed compounds
endogenous ferric ions to more reactive ferrous ions irrespective of pH such as intermolecular complexes, adducts, dimers, and/or phenolics
and type of the emulsifier (Sørensen et al., 2008). Given this prooxidant have a higher antioxidant activity in the food than the parental anti
activity, synergism with free radical scavengers is unlikely in these oxidants, it could retard the formation of rancidity and result in syner
systems unless other mechanisms are involved. This is due to the fact gistic interactions (Olszowy-Tomczyk, 2020). There has not been much
that faster lipid oxidation results in faster consumption of the free research done to determine whether synergism or antagonism in binary
radical scavenger, resulting in decreased protection. systems is caused by the formation of a tertiary compound. However,
Several researchers, on the other hand, believe that even if a metal this mechanism appears to be very likely because antioxidants go
ion is transformed to a more active state, the complex can retain anti through multiple chemical changes during lipid oxidation and can
oxidant activity as a result of chelation. For example, although Mira induce each other’s degradation and complexation processes especially
et al. (2002) showed iron reducing activity of quercetin and taxifolin, in complex food systems due to the presence of other compounds.
Hudson and Lewis (1983b) have reported antioxidant activity in lard, Antioxidants or their quinone forms may undergo breakdown pro
where authors explained reason to be the copper chelating ability. It is cesses and form new antioxidant molecules. This was previously
important to note, however, that the antioxidant/prooxidant activity of observed in oil-in-water emulsions containing α-tocopherol and ros
metal chelating phenolics is highly dependent on the system conditions. marinic acid, where rosmarinic quinone fragmented into caffeic acid,
Most phenolics, for example, have significantly higher iron reducing and the presence of α-tocopherol increased the caffeic acid formation
activity in acidic pH than in neutral pH; thus, antioxidants that act (Panya et al., 2012). The generation of caffeic acid resulted in synergism
synergistically in neutral pH due to metal chelating ability may act due to the presence of a third phenolic compound that could scavenge
antagonistically in acidic food formulations due to metal reduction. additional free radicals. Similarly, the synergism between butylated
Therefore, it may be possible to achieve synergistic interactions through hydroxytoluene (BHT) and butylated hydroxyanisole (BHA) has been
the combination of free radical scavenging and metal chelating activities attributed to the formation of adducts between compounds and the
only when the metal chelator can inhibit the prooxidant activity of metal subsequent formation of new phenolic compounds as a result of their
ions upon chelation. Yao et al. (2012) discovered synergistic antioxidant interaction (Omura, 1995).
interactions between quercetin and resveratrol, hypothesizing that In addition to the formation of an entirely new antioxidant com
metal chelating activity could be one of the mechanisms involved. pound, synergism may result from the formation of intermolecular
However, it is difficult to determine whether synergism is caused by the complexes, adducts, or dimers between antioxidant molecules. 2,2-
chelating ability of phenolics, as these molecules can also scavenge free diphenylpicrylhydrazyl (DPPH) radical scavenging activity was used
radicals. Metal chelators with no free radical scavenging activity, such as to determine synergistic antioxidant interactions between glutathione
EDTA, citric acid, or polyphosphates, could thus be combined with free and taxifolin/lutein/quercetin/catechin (Pereira et al., 2013). The syn
radical scavengers to better understand if this combination can result in ergism was found to be due to the formation of antioxidant mono
synergistic interactions. For example, Frankel et al. (1959) identified glutathionyl and diglutathionyl adducts from glutathione and the
antioxidant synergism between tocopherols and citric acid in soybean quinone methide on B ring of the phenolics. In these cases, if the
oil. Similarly, combining tocopherols and sodium polyphosphate resul resulting complex has diminished antioxidant properties, the formation
ted in increased antioxidant activity in heated palm oil when compared of an adduct or additional bonding between antioxidants may result in
to individual compounds (Chang, 1989). However, a similar synergism antagonistic activity. For example, the same authors discovered that the
was not observed when EDTA and tocopherols were combined. This complex formed between glutathione and galangin on ring A resulted in
combination is difficult to assess because EDTA is highly effective at antagonistic activity because the complex formation accelerated gluta
delaying lipid oxidation on its own, resulting in additive but not syn thione degradation (Pereira et al., 2013). Similarly, catechin and ellagic
ergistic interactions (Let et al., 2007). Fig. 4 gives schematic represen acid had antagonistic interactions during low density lipoprotein (LDL)
tation of combined actions of free radical scavenging and metal oxidation because hydrogen bonding between the carbonyl group of
chelating activities during inhibition of lipid oxidation. ellagic acid and the ortho-dihydroxy group of catechin blocked cate
Both synergism or antagonism are possible depending on the type of chin’s hydrogen donating capacity (Meyer et al., 1998). Pinelo et al.
metal chelator, type and oxidation state of the metal ion, and the matrix (2004) also observed antagonistic interactions between resveratrol,
used to perform the experiments. As a result, selecting the metal chelator catechin, and quercetin, as the polymerization reactions between anti
based on the features of the food system is critical for achieving oxidants decreased the availability of hydroxyl groups for hydrogen
enhanced oxidative stability as well as synergistic interactions with the transfer. Therefore, as a rule of thumb, it is possible to expect synergistic
free radical scavenger. This can be accomplished by determining the interaction if the resulting complex or adduct has more antioxidant
metal chelating activity in certain food systems using techniques such as activity than the parental compounds, possibly due to its higher stabil
UV-VIS spectroscopy, electrospray mass spectrometry, Raman spec ity. On the other hand, if complexation occurs through the hydroxyl
troscopy, and nuclear magnetic resonance. After assuring the metal groups on molecules, we would expect antagonism because they are the
chelating capacity of the compound, the oxidative stability can be main groups of hydrogen transfer during antioxidant protection.
226
Fig. 4. Synergistic antioxidant combinations of free radical scavenging and metal chelating activities during lipid oxidation in oil-in-water emulsions.
In addition to the formation of adducts between antioxidant mole chemical structure, concentration and ratio of antioxidants, type of food
cules, numerous studies have also examined the effect of antioxidant- system, interaction of antioxidants with other food components, storage
protein adducts on synergism. For instance, bovine serum albumin conditions, and external environmental factors may influence the type of
(BSA) demonstrated synergistic activity with green tea catechins in antioxidant interaction. As a result, understanding the mechanisms
stripped sunflower oil-in-water emulsions (Almajano et al., 2007). The underlying synergistic antioxidant interactions is critical for designing
researchers discovered that catechin can bind to BSA irreversibly, and food systems with increased antioxidant activity. Understanding the
that the resulting protein-catechin adducts have higher antioxidant ac mechanisms will assist the food industry in more rapidly developing
tivity than the parental compounds. The adduct, in this case, retained its effective antioxidant mixtures to extend shelf-life. Being better able to
antioxidant activity due to the presence of free hydroxyl groups even predict synergisms will aid in the development and production of foods
after complexation. However, depending on the system conditions, such with unstable lipids (e.g., omega-3 fatty acids) and thus could improve
as the type of antioxidant, protein, and food matrix, the formation of the health and wellness attributes of the food supply and decrease food
antioxidant-protein adducts may have antagonistic or additive effects as waste.
well. For example, researchers discovered that complexes formed be Although synergistic antioxidants are a promising approach for
tween casein and tea catechin masked the antioxidant activity of the tea reducing lipid oxidation in foods, some challenges must be addressed.
catechins due to the reduction of optimum free radical scavenging ac Because antioxidant interactions are extremely complex due to the
tivity (Arts et al., 2002). complexity of food, more extensive research in various food matrices is
In light of these interactions between antioxidant molecules, it is required to develop synergistic combinations suitable for a specific
essential to investigate the formation of additional compounds using product. Despite considerable number of research and advances in
experimental methods such as liquid chromatography coupled with antioxidant synergism, more detailed research in the following areas is
mass spectrometry. This will aid in the analysis of any unknown mole required to gain a better understanding of synergism mechanisms: (1)
cules in the matrix and possibly determine if they are the cause of the Development of new techniques and methodologies for analyzing the
synergistic interaction. Of course, it is impossible to detect and analyze antioxidant regeneration ability of a wide range of antioxidants in
every single component within the matrix for antioxidant activity; thus, different systems, such as bulk oils, emulsions, and low-moisture foods;
it is a smart approach to search for the chemistry and thermodynamics of (2) Screening and testing the metal chelating and reducing activities of a
the parental antioxidants to determine what the possible degradation wide range of natural plant phenolics in different food systems under
products or complexes/adducts are. In general, the most oxidizable varying system conditions (such as pH); (3) Creating fast and reliable
carbon on the molecule would be the most susceptible to breakdown as a techniques for assessing antioxidant interactions and the formation of
result of the electron-withdrawing effects exerted by neighboring atoms additional antioxidant compounds.
(Panya et al., 2012). This causes the closest bond to undergo scission
reactions, leading to the formation of new compounds. Therefore, it
could be possible to estimate the newly formed compound by looking at Declaration of competing interest
the molecular structures of the parental compounds.
The authors declare that they have no known competing financial
3. Conclusions and perspectives interests or personal relationships that could have influenced the work
reported in this paper.
Antioxidant interactions may have a positive or negative impact on
the oxidative stability of food systems, resulting in synergism or Data availability
antagonism. The most likely synergistic free radical scavenging antiox
idant combinations would be an antioxidant physically located at the No data was used for the research described in the article.
site of oxidation and a second antioxidant with a lower reduction po
tential capable of accessing and regenerating the antioxidant at the site Acknowledgment
of oxidation. In addition, free radical scavenger and metal chelator
combination can be effective if the chelator decreases free radical gen Ipek Bayram was supported by a Fulbright fellowship granted by the
eration and thus antioxidant degradation. Multiple factors, including the Turkish Fulbright Commission.
227
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Trends in Food Science & Technology 133 (2023) 219–230

Contents lists available at ScienceDirect

Trends in Food Science & Technology

Underlying mechanisms of synergistic antioxidant interactions during

1. Introduction tissues have highly efficient endogenous antioxidant systems emerging

Tocopherol Hexadecane:water 1.0–5.0 43.3 41.5–35.0 Chaiyasit et al. (2007)

Non Interface-Active System Concentration Interfacial Tension of Interfacial Tension of References

EGCG Corn oil:water 0.04–0.62 26.6 25.5–25.3 Mura et al. (2017)

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