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A Review on Antioxidants, Prooxidants and Related Controversy Natural

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A Review on Antioxidants, Prooxidants and Related Controversy Natural
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  Review A review on antioxidants, prooxidants and related controversy: Naturaland synthetic compounds, screening and analysis methodologies and futureperspectives Márcio Carocho, Isabel C.F.R. Ferreira ⇑ CIMO/Escola Superior Agrária, Instituto Politécnico de Bragança, Apartado 1172, 5301-855 Bragança, Portugal a r t i c l e i n f o  Article history: Received 19 July 2012Accepted 14 September 2012Available online 24 September 2012 Keywords: Free radicalsOxidative stressAntioxidantsProoxidantsFuture perspectives a b s t r a c t Many studies have been conducted with regard to free radicals, oxidative stress and antioxidant activityof food, giving antioxidants a prominent beneficial role, but, recently many authors have questioned theirimportance, whilst trying to understand the mechanisms behind oxidative stress. Many scientists defendthat regardless of the quantity of ingested antioxidants, the absorption is very limited, and that in somecases prooxidants are beneficial to human health. The detection of antioxidant activity as well as specificantioxidant compounds can be carried out with a large number of different assays, all of them withadvantages and disadvantages. The controversy around antioxidant  in vivo  benefits has become intensein the past few decades and the present review tries to shed some light on research on antioxidants (nat-ural and synthetic) and prooxidants, showing the potential benefits and adverse effects of these opposingevents, as well as their mechanisms of action and detection methodologies. It also identifies the limita-tions of antioxidants and provides a perspective on the likely future trends in this field.   2012 Elsevier Ltd. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161.1. From free radicals to oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161.1.1. Free radicals and oxidative stress mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161.1.2. Effects of oxidative stress. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171.2. Antioxidants and prooxidants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171.2.1. Natural antioxidants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171.2.2. Synthetic antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191.2.3. Prooxidants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192. Methodologies for antioxidant activity screening and antioxidants analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202.1. Antioxidant activity screening assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202.2. Antioxidant compounds analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223. Controversy and limitations among antioxidants and prooxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223.1. Controversy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223.2. Limitations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234. Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Conflict of Interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 0278-6915/$ - see front matter    2012 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.fct.2012.09.021 ⇑ Corresponding author. Tel.: +351 273 303219; fax: +351 273 325405. E-mail address:  iferreira@ipb.pt (I.C.F.R. Ferreira).Food and Chemical Toxicology 51 (2013) 15–25 Contents lists available at SciVerse ScienceDirect Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox  1. Introduction 1.1. From free radicals to oxidative stress Biochemical reactions that take place in the cells and organellesof our bodies are the driving force that sustains life. The laws of nature dictate that one goes from childhood, to adulthood and fi-nally enters a frail condition that leads to death. Due to the lownumber of births and increasing life expectancy, in the near future,worldwide population will be composed in a considerable numberof elderly. This stage in life is characterized by many cardiovascu-lar, brain and immune system diseases that will translate into highsocial costs (Rahman, 2007). It is therefore important to control theproliferationof these chronic diseases in order to reduce the suffer-ing of the elderly and to contain these social costs. Free radicals,antioxidants and co-factors are the three main areas that suppos-edly can contribute to the delay of the aging process (Rahman,2007). The understanding of these events in the human body canhelp prevent or reduce the incidence of these and other diseases,thus contributing to a better quality of life. 1.1.1. Free radicals and oxidative stress mechanisms Free radicals are atoms, molecules or ions with unpaired elec-trons that are highly unstable and active towards chemical reac-tions 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 (O 2   ),hydroperoxyl radical (HO 2  ), hydroxyl radical (  OH), nitric oxide(NO), and other species like hydrogen peroxide (H 2 O 2 ), singlet oxy-gen ( 1 O 2 ), hypochlorous acid (HOCl) and peroxynitrite (ONOO  ).RNS derive from NO by reacting with O 2   , and forming ONOO  .RSS are easily formed by the reaction of ROS with thiols (Lüet al.,2010). RegardingROS, the reactionsleading to the productionof reactive species are displayed in Fig. 1. The hydroperoxyl radical(HO 2  ) disassociates at pH 7 to form the superoxide anion (O 2   ).This anion is extremely reactive and can interact with a numberof molecules to generate ROS either directly or through enzymeor metal-catalyzed processes. Superoxideion can also be detoxifiedto hydrogen peroxide through a dismutation reaction with theenzyme superoxide dismutase (SOD) (through the Haber–Weiss Fig. 1.  Overview of the reactions leading to the formation of ROS. Green arrows represent lipid peroxidation. Blue arrows represent the Haber–Weiss reactions and the redarrows represent the Fenton reactions. The bold letters represent radicals or molecules with the same behavior (H 2 O 2 ). SOD refers to the enzyme superoxide dismutase andCAT refers to the enzyme catalase. Adapted from Ferreira et al. (2009) and Flora (2009). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) Fig. 2.  Targets of free radicals. Adapted from Dizdaroglu et al. (2002), Valko et al. (2004), Benov and Beema (2003), Halliwell and Chirico (1993) and Lobo et al. (2010). 16  M. Carocho, I.C.F.R. Ferreira/Food and Chemical Toxicology 51 (2013) 15–25  reaction) and finally to water by the enzyme catalase (CAT). If hydrogen peroxide reacts with an iron catalyst like Fe 2+ , the Fentonreaction can take place (Fe 2+ + H 2 O 2 ? Fe 3+ + OH  + OH  ) formingthe hydroxyl radical HO  (Flora, 2009). With regard to RNS, themechanism forming ONOO  is: NO  + O 2   (Squadrito and Pryor,1998). Finally, RSS derive, under oxidative conditions, from thiolsto form a disulfide that with further oxidation can result in eitherdisulfide- S  -monoxide or disulfide- S  -dioxide as an intermediatemolecule. Finally, a reaction with a reduced thiol may result inthe formation of sulfenic or sulfinic acid (Giles et al., 2001). 1.1.2. Effects of oxidative stress Internally, free radicals are produced as a normal part of metabolism within the mitochondria, through xanthine oxidase,peroxisomes, inflammation processes, phagocytosis, arachidonatepathways, ischemia, and physical exercise. External factors thathelp to promote the production of free radicals are smoking, envi-ronmental pollutants, radiation, drugs, pesticides, industrial sol-vents and ozone. It is ironic that these elements, essential to life(especially oxygen) have deleterious effects on the human bodythrough these reactive species (Lobo et al., 2010).The balance between the production and neutralization of ROSby antioxidants is very delicate, and if this balance tends to theoverproduction of ROS, the cells start to suffer the consequencesof oxidative stress (Wiernsperger, 2003).It is estimated that everyday a human cell is targeted by the hy-droxyl radical and other such species and average of 10 5 timesinducing oxidative stress (Valko et al., 2004). The main targets of ROS, RNS and RSS are proteins, DNA (deoxyribonucleic acid) andRNA (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 mod-ification of a specific amino acid, (2) free radical-mediated peptidecleavage and (3) formation of protein cross-linkage due to reactionwith lipid peroxidation products (Lobo et al., 2010). The damageinduced by free radicals to DNA can be described both chemicallyand 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 chromo-somal arrangements. An important reaction involved with DNAdamage is the production of the hydroxyl radical through the Fen-ton reaction.This radicalis knownto react with all the componentsof the DNA molecule: the purine and pyrimidine bases as well asthe deoxyribose backbone. The peroxyl and OH-radicals also inter-vene in DNA oxidation (Dizdaroglu et al., 2002; Valko et al., 2004).Regarding sugars, the formation of oxygen free radicals duringearly glycation could contribute to glycoxidative damage. Duringthe initial stages of non-enzymatic glycosylation, sugar fragmenta-tion produces short chain species like glycoaldehyde whose chainis too short to cyclize and is therefore prone to autoxidation, form-ing the superoxide radical. The resulting chain reaction propagatedby this radical can form a and  b -dicarbonyls, which are well knownmutagens (Benov and Beema, 2003).Lipid peroxidation is initiated by an attack towards a fatty acid’sside chain by a radical in order to abstract a hydrogen atom from amethylene carbon. The more double bonds present in the fatty acidthe easier it is to remove hydrogen atoms and consequently form aradical, making monounsaturated (MUFA) and saturated fattyacids (SFA) more resistant to radicals than polyunsaturated fattyacids (PUFA). After the removal, the carbon centered lipid radicalcan undergo molecular rearrangement and react with oxygenforming a peroxyl radical. These highly reactive molecules canthe abstract hydrogen atoms from surrounding molecules andpropagate a chain reaction of lipid peroxidation. The hydroxyl rad-ical is the one of the mainradicalsin lipid peroxidation, it is formedin biological systems, as stated above, by the Fenton reaction as aresult of interaction between hydrogen peroxide and metal ions.This radical acts according to the following generic reaction: L–H + OH  ? H 2 O + L   , where L–H represents a generic lipid and L   represents a lipid radical. The trichloromethyl radical (CCl 3 O 2  )which is formed by the addition of carbon tetrachloride (CCl 4 ) withoxygen also attacks lipids according to this equation: L–H + CCl 3- O 2  ? L   + CCl 3 OH. Isolated PUFA’s can suffer damage from thehydroperoxyl radical through this equation: L–H + HO 2  ? L   + H 2- O 2 . Finally, another way to generate lipid peroxides is throughthe attack on PUFA’s or their side chain by the singlet oxygenwhich is a very reactive form of oxygen. This pathway does notprobably qualify as initiation because the singlet oxygen reactswith the fatty acid instead of abstracting a hydrogen atom to starta chain reaction, making this a minor pathway when compared tothe hydroxyl one (Halliwell and Chirico, 1993).Free radicals have different types of reaction mechanisms, theycan react with surrounding molecules by: electron donation,reducing radicals, and electron acceptance, oxidizing radicals (a),hydrogen abstraction (b), addition reactions (c), self-annihilationreactions (d) and by disproportionation (e) (Slater, 1984).(a) OH  þ RS  !  OH  þ RS  (b) CCl  3  þ RH  !  CHCl 3  þ R   (c) CCl  3  þ CH 2 @ CH 2  !  CH 2 ð CCl 3 Þ  CH 2 (d) CCl  3  þ CCl  3  !  C 2 Cl 6 (e) CH 3 CH  2  þ CH 3 CH  2  !  CH 2 @ CH 2  þ CH 3   CH 3 These reactions lead to the production of ROS, RNS and RSSwhom have been linked to many severe diseases like cancer, car-diovascular diseases including atherosclerosis and stroke, neuro-logical disorders, renal disorders, liver disorders, hypertension,rheumatoid arthritis,adultrespiratorydistresssyndrome,auto-im-mune deficiency diseases, inflammation, degenerative disordersassociated with aging, diabetes mellitus, diabetic complications,cataracts, obesity, autism, Alzheimer’s, Parkinson’s and Hunting-ton’s diseases, vasculitis, glomerulonephritis, lupus erythematous,gastric ulcers, hemochromatosis and preeclampsia, among others(Rahman,2007;Loboet al., 2010;Lüet al., 2010;Singh et al., 2010). 1.2. Antioxidants and prooxidants1.2.1. Natural antioxidants Halliwell and Gutteridge (1995) defined antioxidants as ‘‘anysubstancethat,whenpresentatlowconcentrationscomparedwiththat of an oxidizable substrate, significantly delays or inhibits oxi-dation of that substrate’’, but later defined them as ‘‘any substancethat delays, prevents or removes oxidative damage to a target mol-ecule’’ (Halliwell, 2007). In the same year Khlebnikov et al. (2007) defined antioxidants as ‘‘any substance that directly scavengesROSorindirectlyactstoup-regulateantioxidantdefencesorinhibitROSproduction’’.Anotherpropertythatacompoundshouldhavetobeconsideredanantioxidantistheability,afterscavengingtherad-ical, to form a new radical that is stable through intramolecularhydrogen bonding on further oxidation (Halliwell, 1990). Duringhuman evolution, endogenous defences have gradually improvedto maintain a balance between free radicals and oxidative stress.The antioxidant activity can be effective through various ways: asinhibitors of free radical oxidation reactions (preventive oxidants)by inhibiting formation of free lipid radicals; by interrupting thepropagationoftheautoxidationchainreaction(chainbreakinganti-oxidants); as singlet oxygen quenchers; through synergism withother antioxidants; as reducing agents which convert hydroperox-ides into stable compounds; as metal chelators that convert metalpro-oxidants (iron and copper derivatives) into stable products;and finally as inhibitors of pro-oxidative enzymes (lipooxigenases) M. Carocho, I.C.F.R. Ferreira/Food and Chemical Toxicology 51 (2013) 15–25  17  (Darmanyanetal.,1998;Heimetal.,2002;MinandBoff,2002;Pok-orny´, 2007; Kancheva, 2009). The human antioxidant system is divided into two majorgroups, enzymatic antioxidants and non-enzymatic oxidants(Fig. 3). Regarding enzymatic antioxidants they are divided intoprimary and secondary enzymatic defences. With regard to the pri-mary defence, it is composed of three important enzymes that pre-vent the formation or neutralize free radicals: glutathioneperoxidase, which donates two electrons to reduce peroxides byforming selenoles and also eliminates peroxides as potential sub-strate for the Fenton reaction; catalase, that converts hydrogenperoxide into water and molecular oxygen and has one of the big-gest turnover rates known to man, allowing just one molecule of catalase to convert 6 billion molecules of hydrogen peroxide; andfinally, superoxide dismutase converts superoxide anions intohydrogen peroxide as a subtract for catalase (Rahman, 2007). Thesecondary enzymatic defense includes glutathione reductase andglucose-6-phosphate dehydrogenase. Glutathione reductase re-duces glutathione (antioxidant) from its oxidized to its reducedform, thus recycling it to continue neutralizing more free radicals.Glucose-6-phosphate regenerates NADPH (nicotinamide adeninedinucleotide phosphate – coenzyme used in anabolic reactions)creating a reducing environment (Gamble and Burke, 1984;Ratnam et al., 2006). These two enzymes do not neutralize freeradicals directly, but have supporting roles to the other endoge-nous antioxidants.Considering the non-enzymatic endogenous antioxidants, thereare quite a numberof 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 re-sults from the breakdown of   b -carotene. There are about a dozenforms of vitamin A that can be isolated. It is known to have bene-ficial impact on the skin, eyes and internal organs. What confersthe antioxidant activity is the ability to combine with peroxyl rad-icals 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 animportant role in the respiratory chain and in other cellular metab-olism. Coenzyme Q10 acts by preventing the formation of lipidperoxyl radicals, although it has been reported that this coenzymecan neutralize these radicals even after their formation. Anotherimportant function is the ability to regenerate vitamin E; someauthors describe this process to be more likely than regenerationof vitamin E through ascorbate (vitamin C) (Turunen et al., 2004).Uric acid is the end product of purine nucleotide metabolism inhumans and during evolution its concentrations have been rising.After undergoing kidney filtration, 90% of uric acid is reabsorbedby the body, showing that it has important functions within thebody. In fact, uric acid is known to prevent the overproduction of oxo-hemoxidantsthatresult fromthe reactionof hemoglobinwithperoxides. On the other hand it also prevents lysis of erythrocytesby peroxidation and is a potent scavenger of singlet oxygen andhydroxyl radicals (Kand’ár et al., 2006).Glutathione is an endogenous tripeptide which protects thecells against free radicals either by donating a hydrogen atom oran electron. It is also very important in the regeneration of otherantioxidants like ascorbate (Steenvoorden and Henegouwen,1997).Despite its remarkable efficiency, the endogenous antioxidantsystem does not suffice, and humans depend on various types of antioxidants that are present in the diet to maintain free radicalconcentrations at low levels (Pietta, 2000).Vitamins C and E are generic names for ascorbic acid and toc-opherols. Ascorbic acid includes two compounds with antioxidantactivity:  L  -ascorbic acid and  L  -dehydroascorbic acid which are bothabsorbed through the gastrointestinal tract and can be inter-changed enzymatically  in vivo . Ascorbic acid is effective in scav-enging the superoxide radical anion, hydrogen peroxide, hydroxylradical, singlet oxygen and reactive nitrogen oxide (Barros et al.,2011). Vitamin E is composed of eight isoforms, with four tocophe-rols ( a -tocopherol,  b -tocopherol,  c -tocopherol and  d -tocopherol)and four tocotrienols ( a -tocotrienol,  b -tocotrienol,  c -tocotrienol Fig. 3.  Natural antioxidants separated in classes. Green words represent exogenous antioxidants, while yellow ones represent endogenous antioxidants. Adapted from Pietta(2000), Ratnam et al. (2006) and Godman et al. (2011). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)18  M. Carocho, I.C.F.R. Ferreira/Food and Chemical Toxicology 51 (2013) 15–25

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