Elsevier

Food and Chemical Toxicology

Volume 51, January 2013, Pages 15-25
Food and Chemical Toxicology

Review
A review on antioxidants, prooxidants and related controversy: Natural and synthetic compounds, screening and analysis methodologies and future perspectives

https://doi.org/10.1016/j.fct.2012.09.021Get rights and content

Abstract

Many studies have been conducted with regard to free radicals, oxidative stress and antioxidant activity of food, giving antioxidants a prominent beneficial role, but, recently many authors have questioned their importance, whilst trying to understand the mechanisms behind oxidative stress. Many scientists defend that regardless of the quantity of ingested antioxidants, the absorption is very limited, and that in some cases prooxidants are beneficial to human health. The detection of antioxidant activity as well as specific antioxidant compounds can be carried out with a large number of different assays, all of them with advantages and disadvantages. The controversy around antioxidant in vivo benefits has become intense in the past few decades and the present review tries to shed some light on research on antioxidants (natural and synthetic) and prooxidants, showing the potential benefits and adverse effects of these opposing events, as well as their mechanisms of action and detection methodologies. It also identifies the limitations of antioxidants and provides a perspective on the likely future trends in this field.

Highlights

► Antioxidants and prooxidants have been intensively studied over the past few decades. ► Recently, controversy has intensified in this area due to conflicting results. ► Natural and synthetic antioxidants both have advantages and disadvantages. ► Many different methods are used to screen matrixes or to find specific antioxidants. ► Due to some limitations, new methodologies are being prepared.

Introduction

Biochemical reactions that take place in the cells and organelles of our bodies are the driving force that sustains life. The laws of nature dictate that one goes from childhood, to adulthood and finally enters a frail condition that leads to death. Due to the low number of births and increasing life expectancy, in the near future, worldwide population will be composed in a considerable number of elderly. This stage in life is characterized by many cardiovascular, brain and immune system diseases that will translate into high social costs (Rahman, 2007). It is therefore important to control the proliferation of these chronic diseases in order to reduce the suffering of the elderly and to contain these social costs. Free radicals, antioxidants and co-factors are the three main areas that supposedly can contribute to the delay of the aging process (Rahman, 2007). The understanding of these events in the human body can help prevent or reduce the incidence of these and other diseases, thus contributing to a better quality of life.

Free radicals are atoms, molecules or ions with unpaired electrons that are highly unstable and active towards chemical reactions with other molecules. They derive from three elements: oxygen, nitrogen and sulfur, thus creating reactive oxygen species (ROS), reactive nitrogen species (RNS) and reactive sulfur species (RSS). ROS include free radicals like the superoxide anion (O2radical dot), hydroperoxyl radical (HO2radical dot), hydroxyl radical (radical dotOH), nitric oxide (NO), and other species like hydrogen peroxide (H2O2), singlet oxygen (1O2), hypochlorous acid (HOCl) and peroxynitrite (ONOO). RNS derive from NO by reacting with O2radical dot, and forming ONOO. RSS are easily formed by the reaction of ROS with thiols (Lü et al., 2010). Regarding ROS, the reactions leading to the production of reactive species are displayed in Fig. 1. The hydroperoxyl radical (HO2radical dot) disassociates at pH 7 to form the superoxide anion (O2radical dot). This anion is extremely reactive and can interact with a number of molecules to generate ROS either directly or through enzyme or metal-catalyzed processes. Superoxide ion can also be detoxified to hydrogen peroxide through a dismutation reaction with the enzyme superoxide dismutase (SOD) (through the Haber–Weiss reaction) and finally to water by the enzyme catalase (CAT). If hydrogen peroxide reacts with an iron catalyst like Fe2+, the Fenton reaction can take place (Fe2+ + H2O2  Fe3+ + OHradical dot + OH) forming the hydroxyl radical HOradical dot (Flora, 2009). With regard to RNS, the mechanism forming ONOO is: NOradical dot + O2radical dot (Squadrito and Pryor, 1998). Finally, RSS derive, under oxidative conditions, from thiols to form a disulfide that with further oxidation can result in either disulfide-S-monoxide or disulfide-S-dioxide as an intermediate molecule. Finally, a reaction with a reduced thiol may result in the formation of sulfenic or sulfinic acid (Giles et al., 2001).

Internally, free radicals are produced as a normal part of metabolism within the mitochondria, through xanthine oxidase, peroxisomes, inflammation processes, phagocytosis, arachidonate pathways, ischemia, and physical exercise. External factors that help to promote the production of free radicals are smoking, environmental pollutants, radiation, drugs, pesticides, industrial solvents and ozone. It is ironic that these elements, essential to life (especially oxygen) have deleterious effects on the human body through these reactive species (Lobo et al., 2010).

The balance between the production and neutralization of ROS by antioxidants is very delicate, and if this balance tends to the overproduction of ROS, the cells start to suffer the consequences of oxidative stress (Wiernsperger, 2003).

It is estimated that every day a human cell is targeted by the hydroxyl radical and other such species and average of 105 times inducing oxidative stress (Valko et al., 2004). The main targets of ROS, RNS and RSS are proteins, DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) molecules, sugars and lipids (Lü et al., 2010, Craft et al., 2012) (Fig. 2). Regarding proteins, there are three distinct ways they can be oxidatively modified: (1) oxidative modification of a specific amino acid, (2) free radical-mediated peptide cleavage and (3) formation of protein cross-linkage due to reaction with lipid peroxidation products (Lobo et al., 2010). The damage induced by free radicals to DNA can be described both chemically and structurally having a characteristic pattern of modifications: Production of base-free sites, deletions, modification of all bases, frame shifts, strand breaks, DNA–protein cross-links and chromosomal arrangements. An important reaction involved with DNA damage is the production of the hydroxyl radical through the Fenton reaction. This radical is known to react with all the components of the DNA molecule: the purine and pyrimidine bases as well as the deoxyribose backbone. The peroxyl and OH-radicals also intervene in DNA oxidation (Dizdaroglu et al., 2002, Valko et al., 2004).

Regarding sugars, the formation of oxygen free radicals during early glycation could contribute to glycoxidative damage. During the initial stages of non-enzymatic glycosylation, sugar fragmentation produces short chain species like glycoaldehyde whose chain is too short to cyclize and is therefore prone to autoxidation, forming the superoxide radical. The resulting chain reaction propagated by this radical can form α and β-dicarbonyls, which are well known mutagens (Benov and Beema, 2003).

Lipid peroxidation is initiated by an attack towards a fatty acid’s side chain by a radical in order to abstract a hydrogen atom from a methylene carbon. The more double bonds present in the fatty acid the easier it is to remove hydrogen atoms and consequently form a radical, making monounsaturated (MUFA) and saturated fatty acids (SFA) more resistant to radicals than polyunsaturated fatty acids (PUFA). After the removal, the carbon centered lipid radical can undergo molecular rearrangement and react with oxygen forming a peroxyl radical. These highly reactive molecules can the abstract hydrogen atoms from surrounding molecules and propagate a chain reaction of lipid peroxidation. The hydroxyl radical is the one of the main radicals in lipid peroxidation, it is formed in biological systems, as stated above, by the Fenton reaction as a result of interaction between hydrogen peroxide and metal ions. This radical acts according to the following generic reaction: L–H + OHradical dot  H2O + Lradical dot, where L–H represents a generic lipid and Lradical dot represents a lipid radical. The trichloromethyl radical (CCl3O2radical dot) which is formed by the addition of carbon tetrachloride (CCl4) with oxygen also attacks lipids according to this equation: L–H + CCl3O2radical dot  Lradical dot + CCl3OH. Isolated PUFA’s can suffer damage from the hydroperoxyl radical through this equation: L–H + HO2radical dot  Lradical dot + H2O2. Finally, another way to generate lipid peroxides is through the attack on PUFA’s or their side chain by the singlet oxygen which is a very reactive form of oxygen. This pathway does not probably qualify as initiation because the singlet oxygen reacts with the fatty acid instead of abstracting a hydrogen atom to start a chain reaction, making this a minor pathway when compared to the hydroxyl one (Halliwell and Chirico, 1993).

Free radicals have different types of reaction mechanisms, they can react with surrounding molecules by: electron donation, reducing radicals, and electron acceptance, oxidizing radicals (a), hydrogen abstraction (b), addition reactions (c), self-annihilation reactions (d) and by disproportionation (e) (Slater, 1984).

  • (a)

    OH+RS-OH-+RS

  • (b)

    CCl3+RHCHCl3+R

  • (c)

    CCl3+CH2CH2CH2(CCl3)-CH2

  • (d)

    CCl3+CCl3C2Cl6

  • (e)

    CH3CH2+CH3CH2CH2CH2+CH3-CH3

These reactions lead to the production of ROS, RNS and RSS whom have been linked to many severe diseases like cancer, cardiovascular diseases including atherosclerosis and stroke, neurological disorders, renal disorders, liver disorders, hypertension, rheumatoid arthritis, adult respiratory distress syndrome, auto-immune deficiency diseases, inflammation, degenerative disorders associated with aging, diabetes mellitus, diabetic complications, cataracts, obesity, autism, Alzheimer’s, Parkinson’s and Huntington’s diseases, vasculitis, glomerulonephritis, lupus erythematous, gastric ulcers, hemochromatosis and preeclampsia, among others (Rahman, 2007, Lobo et al., 2010, Lü et al., 2010, Singh et al., 2010).

Halliwell and Gutteridge (1995) defined antioxidants as “any substance that, when present at low concentrations compared with that of an oxidizable substrate, significantly delays or inhibits oxidation of that substrate”, but later defined them as “any substance that delays, prevents or removes oxidative damage to a target molecule” (Halliwell, 2007). In the same year Khlebnikov et al. (2007) defined antioxidants as “any substance that directly scavenges ROS or indirectly acts to up-regulate antioxidant defences or inhibit ROS production”. Another property that a compound should have to be considered an antioxidant is the ability, after scavenging the radical, to form a new radical that is stable through intramolecular hydrogen bonding on further oxidation (Halliwell, 1990). During human evolution, endogenous defences have gradually improved to maintain a balance between free radicals and oxidative stress. The antioxidant activity can be effective through various ways: as inhibitors of free radical oxidation reactions (preventive oxidants) by inhibiting formation of free lipid radicals; by interrupting the propagation of the autoxidation chain reaction (chain breaking antioxidants); as singlet oxygen quenchers; through synergism with other antioxidants; as reducing agents which convert hydroperoxides into stable compounds; as metal chelators that convert metal pro-oxidants (iron and copper derivatives) into stable products; and finally as inhibitors of pro-oxidative enzymes (lipooxigenases) (Darmanyan et al., 1998, Heim et al., 2002, Min and Boff, 2002, Pokorný, 2007, Kancheva, 2009).

The human antioxidant system is divided into two major groups, enzymatic antioxidants and non-enzymatic oxidants (Fig. 3). Regarding enzymatic antioxidants they are divided into primary and secondary enzymatic defences. With regard to the primary defence, it is composed of three important enzymes that prevent the formation or neutralize free radicals: glutathione peroxidase, which donates two electrons to reduce peroxides by forming selenoles and also eliminates peroxides as potential substrate for the Fenton reaction; catalase, that converts hydrogen peroxide into water and molecular oxygen and has one of the biggest turnover rates known to man, allowing just one molecule of catalase to convert 6 billion molecules of hydrogen peroxide; and finally, superoxide dismutase converts superoxide anions into hydrogen peroxide as a subtract for catalase (Rahman, 2007). The secondary enzymatic defense includes glutathione reductase and glucose-6-phosphate dehydrogenase. Glutathione reductase reduces glutathione (antioxidant) from its oxidized to its reduced form, thus recycling it to continue neutralizing more free radicals. Glucose-6-phosphate regenerates NADPH (nicotinamide adenine dinucleotide phosphate – coenzyme used in anabolic reactions) creating a reducing environment (Gamble and Burke, 1984, Ratnam et al., 2006). These two enzymes do not neutralize free radicals directly, but have supporting roles to the other endogenous antioxidants.

Considering the non-enzymatic endogenous antioxidants, there are quite a number of them, namely vitamins (A), enzyme cofactors (Q10), nitrogen compounds (uric acid), and peptides (glutathione).

Vitamin A or retinol is a carotenoid produced in the liver and results from the breakdown of β-carotene. There are about a dozen forms of vitamin A that can be isolated. It is known to have beneficial impact on the skin, eyes and internal organs. What confers the antioxidant activity is the ability to combine with peroxyl radicals before they propagate peroxidation to lipids (Palace et al., 1999, Jee et al., 2006).

Coenzyme Q10 is present in all cells and membranes; it plays an important role in the respiratory chain and in other cellular metabolism. Coenzyme Q10 acts by preventing the formation of lipid peroxyl radicals, although it has been reported that this coenzyme can neutralize these radicals even after their formation. Another important function is the ability to regenerate vitamin E; some authors describe this process to be more likely than regeneration of vitamin E through ascorbate (vitamin C) (Turunen et al., 2004).

Uric acid is the end product of purine nucleotide metabolism in humans and during evolution its concentrations have been rising. After undergoing kidney filtration, 90% of uric acid is reabsorbed by the body, showing that it has important functions within the body. In fact, uric acid is known to prevent the overproduction of oxo-hem oxidants that result from the reaction of hemoglobin with peroxides. On the other hand it also prevents lysis of erythrocytes by peroxidation and is a potent scavenger of singlet oxygen and hydroxyl radicals (Kand’ár et al., 2006).

Glutathione is an endogenous tripeptide which protects the cells against free radicals either by donating a hydrogen atom or an electron. It is also very important in the regeneration of other antioxidants like ascorbate (Steenvoorden and Henegouwen, 1997).

Despite its remarkable efficiency, the endogenous antioxidant system does not suffice, and humans depend on various types of antioxidants that are present in the diet to maintain free radical concentrations at low levels (Pietta, 2000).

Vitamins C and E are generic names for ascorbic acid and tocopherols. Ascorbic acid includes two compounds with antioxidant activity: l-ascorbic acid and l-dehydroascorbic acid which are both absorbed through the gastrointestinal tract and can be interchanged enzymatically in vivo. Ascorbic acid is effective in scavenging the superoxide radical anion, hydrogen peroxide, hydroxyl radical, singlet oxygen and reactive nitrogen oxide (Barros et al., 2011). Vitamin E is composed of eight isoforms, with four tocopherols (α-tocopherol, β-tocopherol, γ-tocopherol and δ-tocopherol) and four tocotrienols (α-tocotrienol, β-tocotrienol, γ-tocotrienol and δ-tocotrienol), α-tocopherol being the most potent and abundant isoform in biological systems. The chroman head group confers the antioxidant activity to tocopherols, but the phytyl tail has no influence. Vitamin E halts lipid peroxidation by donating its phenolic hydrogen to the peroxyl radicals forming tocopheroxyl radicals that, despite also being radicals, are unreactive and unable to continue the oxidative chain reaction. Vitamin E is the only major lipid-soluble, chain breaking antioxidant found in plasma, red cells and tissues, allowing it to protect the integrity of lipid structures, mainly membranes (Burton and Traber, 1990). These two vitamins also display a synergistic behavior with the regeneration of vitamin E through vitamin C from the tocopheroxyl radical to an intermediate form, therefore reinstating its antioxidant potential (Halpner et al., 1998).

Vitamin K is a group of fat-soluble compounds, essential for posttranslational conversion of protein-bound glutamates into γ-carboxyglutamates in various target proteins. The 1,4-naphthoquinone structure of these vitamins confers the antioxidant protective effect. The two natural isoforms of this vitamin are K1 and K2 (Vervoort et al., 1997).

Flavonoids are an antioxidant group of compounds composed of flavonols, flavanols, anthocyanins, isoflavonoids, flavanones and flavones. All these sub-groups of compounds share the same diphenylpropane (C6C3C6) skeleton. Flavanones and flavones are usually found in the same fruits and are connected by specific enzymes, while flavones and flavonols do not share this phenomenon and are rarely found together. Anthocyanins are also absent in flavanone-rich plants. The antioxidant properties are conferred on flavonoids by the phenolic hydroxyl groups attached to ring structures and they can act as reducing agents, hydrogen donators, singlet oxygen quenchers, superoxide radical scavengers and even as metal chelators. They also activate antioxidant enzymes, reduce α-tocopherol radicals (tocopheroxyls), inhibit oxidases, mitigate nitrosative stress, and increase levels of uric acid and low molecular weight molecules. Some of the most important flavonoids are catechin, catechin-gallate, quercetin and kaempferol (Rice-Evans et al., 1996, Procházková et al., 2011).

Phenolic acids are composed of hydroxycinnamic and hydroxybenzoic acids. They are ubiquitous to plant material and sometimes present as esters and glycosides. They have antioxidant activity as chelators and free radical scavengers with special impact over hydroxyl and peroxyl radicals, superoxide anions and peroxynitrites. One of the most studied and promising compounds in the hydroxybenzoic group is gallic acid which is also the precursor of many tannins, while cinnamic acid is the precursor of all the hydroxycinnamic acids (Krimmel et al., 2010, Terpinc et al., 2011).

Carotenoids are a group of natural pigments that are synthesized by plants and microorganisms but not by animals. They can be separated into two vast groups: the carotenoid hydrocarbons known as the carotenes which contain specific end groups like lycopene and β-carotene; and the oxygenated carotenoids known as xanthophyls, like zeaxanthin and lutein. The main antioxidant property of carotenoids is due to singlet oxygen quenching which results in excited carotenoids that dissipate the newly acquired energy through a series of rotational and vibrational interactions with the solvent, thus returning to the unexcited state and allowing them to quench more radical species. This can occur while the carotenoids have conjugated double bonds within. The only free radicals that completely destroy these pigments are peroxyl radicals. Carotenoids are relatively unreactive but may also decay and form non-radical compounds that may terminate free radical attacks by binding to these radicals (Paiva and Russell, 1999).

Minerals are only found in trace quantities in animals and are a small proportion of dietary antioxidants, but play important roles in their metabolism. Regarding antioxidant activity, the most important minerals are selenium and zinc. Selenium can be found in both organic (selenocysteine and selenomethionine) and inorganic (selenite and selenite) forms in the human body. It does not act directly on free radicals but is an indispensable part of most antioxidant enzymes (metalloenzymes, glutathione peroxidase, thioredoxin reductase) that would have no effect without it (Tabassum et al., 2010). Zinc is a mineral that is essential for various pathways in metabolism. Just like selenium, it does not directly attack free radicals but is quite important in the prevention of their formation. Zinc is also an inhibitor of NADPH oxidases which catalyze the production of the singlet oxygen radical from oxygen by using NADPH as an electron donor. It is present in superoxide dismutase, an important antioxidant enzyme that converts the singlet oxygen radical into hydrogen peroxide. Zinc induces the production of metallothionein that is a scavenger of the hydroxyl radical. Finally zinc also competes with copper for binding to the cell wall, thus decreasing once again the production of hydroxyl radicals (Prasad et al., 2004).

In order to have a standard antioxidant activity measurement system to compare with natural antioxidants and to be incorporated into food, synthetic antioxidants have been developed. These pure compounds are added to food so it can withstand various treatments and conditions as well as to prolong shelf life. Table 1 reports the most important and widely available synthetic antioxidants as well as their uses, showing that the main focus of synthetic antioxidants is the prevention of food oxidation, especially fatty acids. Today, almost all processed foods have synthetic antioxidants incorporated, which are reported to be safe, although some studies indicate otherwise.

BHT (butylated hydroxytoluene) and BHA (butylated hydroxyanisole) are the most widely used chemical antioxidants. Between 2011 and 2012, the European food safety authority (EFSA) re-evaluated all the available information on these two antioxidants, including the apparently contradictory data that have been published. EFSA established revised acceptable daily intakes (ADIs) of 0.25 mg/kg bw/day for BHT and 1.0 mg/kg bw/day for BHA and noted that the exposure of adults and children was unlikely to exceed these intakes (EFSA, 2011, EFSA, 2012). TBHQ (tert-Butylhydroquinone) stabilizes and preserves the freshness, nutritive value, flavour and color of animal food products. In 2004 the EFSA published a scientific opinion reviewing the impact of this antioxidant on human health and stated that there was no scientific proof of its carcinogenicity despite previous conflicting data. They pointed out that dogs were the most sensitive species and allocated an ADI of 0–0.7 mg/kg bw/day (EFSA, 2004). Octyl gallate is considered safe to use as a food additive because after consumption it is hydrolysed into gallic acid and octanol, which are found in many plants and do not pose a threat to human health (Joung et al., 2004). NDGA (Nordihydroguaiaretic acid) despite being a food antioxidant is known to cause renal cystic disease in rodents (Evan and Gardner, 1979).

Singh et al. (2010) wrote that antioxidants have gone from “Miracle Molecules” to “Marvellous Molecules” and finally to “Physiological Molecules”. No doubt these molecules play a vital role in metabolic pathways and protect cells, but recently conflicting evidence has forced the academic community to dig deeper into the role of antioxidants and prooxidants. The latter are defined as chemicals that induce oxidative stress, usually through the formation of reactive species or by inhibiting antioxidant systems (Puglia and Powell, 1984). Free radicals are considered prooxidants, but surprisingly, antioxidants can also have prooxidant behaviour.

Vitamin C is considered a potent antioxidant and intervenes in many physiological reactions, but it can also become a prooxidant. This happens when it combines with iron and copper reducing Fe3+ to Fe2+ (or Cu3+ to Cu2+), which in turn reduces hydrogen peroxide to hydroxyl radicals (Duarte and Lunec, 2005).

α-Tocopherol is also known to be a useful and powerful antioxidant but in high concentrations it can become a prooxidant due to its antioxidant mechanism. When it reacts with a free radical it becomes a radical itself, and if there is not enough ascorbic acid for its regeneration it will remain in this highly reactive state and promote the autoxidation of linoleic acid (Cillard et al., 1980).

Although not much evidence is found, it is proposed that carotenoids can also display prooxidant effects especially through autoxidation in the presence of high concentrations of oxygen-forming hydroxyl radicals (Young and Lowe, 2001). Even flavonoids can act as prooxidants, although each one responds differently to the environment in which it is inserted. Dietary phenolics can also act as prooxidants in systems that contain redox-active metals. The presence of O2 and transition metals like iron and copper catalyze the redox cycling of phenolics and may lead to the formation of ROS and phenoxyl radicals which damage DNA, lipids and other biological molecules (Galati and O’Brien, 2004).

Yordi et al. (2012) published a list of fourteen phenolic acids, considered to be antioxidants but under certain conditions behaved as prooxidants.

Section snippets

Antioxidant activity screening assays

To date there are various antioxidant activity assays, each one having their specific target within the matrix and all of them with advantages and disadvantages. There is not one method that can provide unequivocal results and the best solution is to use various methods instead of a one-dimension approach. Some of these procedures use synthetic antioxidants or free radicals, some are specific for lipid peroxidation and tend to need animal or plant cells, some have a broader scope, some require

Controversy

In recent years, antioxidants and prooxidants have been extensively studied and it seems that most of the dietary antioxidants can behave as prooxidants; it all depends on their concentration and the nature of neighbouring molecules (Villanueva and Kross, 2012). The controversy around dietary antioxidants is because the capacity to display antioxidant and prooxidant behaviour depends on various factors. Numerous studies have shown the beneficial effects of antioxidants, in a few thousand

Future perspectives

During the past decades a lot of research has been carried out around antioxidants and their effects on health. There is a lack of a standard procedure to determine antioxidant activity across the majority of matrixes in order to produce consistent and undoubted results. The published results so far are conflicting and difficult to compare between each other. The antioxidant limitations and metabolism still pose a challenge to future research in this field, and researchers must try and overcome

Conflict of Interest

The authors declare that there are no conflicts of interest.

Acknowledgements

The authors thank to Fundação para a Ciência e a Tecnologia (FCT, Portugal) and COMPETE/QREN/EU for financial support to CIMO (strategic project PEst-OE/AGR/UI0690/2011).

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