Reactive oxygen species – sources, functions, oxidative...

124 K. Jakubczyk et al.

Reaktywne formy tlenu – źródła, funkcje, uszkodzenia oksydacyjne

Jakubczyk K1, Dec K1, Kałduńska J1, Kawczuga D2, Kochman J1,Janda K1.

1Katedra i Zakład Żywienia Człowieka i Metabolomiki, PomorskiUniwersytet Medyczny w Szczecinie, 2Instytut Biologii, UniwersytetSzczeciński

Reaktywne formy tlenu to cząsteczki zdolne do samodzielnej egzysten-cji, zawierające co najmniej jeden atom tlenu i jeden lub więcej niesparo-wanych elektronów. Do grupy tej zaliczane są wolne rodniki tlenowe np.anionorodnik ponadtlenkowy, rodnik hydroksylowy, rodnik wodoronadtlen-kowy, tlen singletowy, a także wolne rodniki azotowe. W warunkach fizjo-logicznych powstają w niewielkiej ilości podczas procesów komórkowych,np. oddychania tlenowego czy procesach zapalnych, głównie w hepato-cytach oraz makrofagach. Reaktywne formy tlenu to przede wszystkimcząsteczki sygnałowe. Ponadto indukują różnicowanie komórek orazapoptozę, przez co biorą udział w fizjologicznym starzeniu się organi-zmu. Uczestniczą również w skurczach mięśni, regulacji napięcia na-czyniowego, warunkują aktywność bakteriobójczą i bakteriostatyczną.Nadmierną syntezę wolnych rodników wzbudza ekspozycja na promie-niowanie UV, nasilony stres, intensywny wysiłek fizyczny, nieprawidłowadiety oraz używki. W warunkach fizjologicznych istnieje równowaga po-między powstawaniem a usuwaniem wolnych związków wolnorodniko-wych z organizmu. Celem pracy był przegląd obecnego stanu wiedzydotyczącego stresu oksydacyjnego, funkcji wolnych rodników, a takżechorób o podłożu wolnorodnikowym. Wyszukiwania przeprowadzono wbazach PubMed i Google Scholar. Wykorzystano słowa kluczowe: wol-ne rodniki tlenowe, stres oksydacyjny, choroby wolnorodnikowe. Nad-mierna synteza wolnych rodników przyczynia się do powstania stresuoksydacyjnego, co wywołuje uszkodzenia na poziomie molekularnymoraz komórkowym. Reaktywne formy tlenu w warunkach in vitro wywołująchemiczne modyfikacje, a także uszkadzają białka (agregacja, denatu-racja), lipidy (peroksydacja), węglowodany i nukleotydy (zmiany w struk-turze DNA). Zmiany te przyczyniają się do rozwoju wielu chorób o cha-rakterze wolnorodnikowym. Stres oksydacyjny wywiera szczególnie nie-korzystny wpływ na układ krwionośny, oddechowy oraz nerwowy.

Słowa kluczowe: wolne rodniki tlenowe, stres oksydacyjny, chorobywolnorodnikowe

Pol Merkur Lekarski, 2020; XLVIII (284); 124–127

Reactive oxygen species – sources, functions, oxidative damage

Jakubczyk K1, Dec K1, Kałduńska J1, Kawczuga D2, Kochman J1,Janda K1.

1Department of Human Nutrition and Metabolomics, PomeranianMedical University, Szczecin, Poland; 2Institute of Biology, Universityof Szczecin, Poland

Reactive oxygen species (ROS) are molecules capable of independentexistence, containing at least one oxygen atom and one or more unpairedelectrons. This group includes oxygen free radicals, e.g. superoxideanion radical, hydroxyl radical, hydroperoxyl radical, singlet oxygen, aswell as free nitrogen radicals. Under physiological conditions, smallquantities of ROS are formed during cell processes, such as aerobicrespiration or inflammatory processes, mainly in hepatocytes andmacrophages. Reactive oxygen species are primarily signallingmolecules. In addition, they induce cell differentiation and apoptosis,thus contributing to the natural ageing process. They also participate inmuscle contractions, regulation of vascular tone, and determinebactericidal and bacteriostatic activity. Increased production of freeradicals is caused by excessive exposure to UV radiation, long-termstress conditions, intense physical exercise, improper diet and use ofstimulants. Under physiological conditions, there is a balance betweenthe generation and removal of free radicals from the body. The aim ofthe article was to review the current state of knowledge regarding oxidativestress, free radical function and free radical diseases. The search wasperformed using search engines such as PubMed and Google Scholar.The keywords used in the search included: oxygen radicals, oxidativestress, free radical-related diseases. Excessive formation of free radicalscontributes to oxidative stress, causing damage at the molecular andcellular level. Reactive oxygen species in vitro cause chemicalmodifications as well as damaging effects to proteins (aggregation,denaturation), lipids (peroxidation), carbohydrates and nucleotides(changes in the DNA structure). These changes contribute to thedevelopment of many free radical-mediated diseases. Oxidative stresshas a particularly adverse effect on the circulatory, respiratory andnervous systems.

Key words: oxygen radicals, oxidative stress, free radical-relateddiseases

Pol Med J, 2020; XLVIII (284); 124–127

Oxygen is vital for life. It is essential to respiration and othermetabolic processes. However, there is also another aspectto this element. Respiratory chain complexes I, III and IV transferan even number of electrons to oxygen [6]. The process isreferred to as a two-electron step, and when some of the elec-trons are lost at intermediate stages in the chain, reducing oxy-gen, the reaction is a one-electron step [15]. Electron leakageoccurs mainly at complex I with ubiquinone. The process leadsto the formation of reactive oxygen species [3,15]. Reactiveoxygen species (ROSs), also described as active oxygen forms,reactive oxygen compounds or reactive oxygen metabolites,are molecules or atoms capable of independent existence,containing at least one oxygen atom and one or more unpaired

electrons [3,15]. This study aims to summarise the currentstate of knowledge on oxidative stress, free radical functionand free radical diseases.

REACTIVE OXYGEN SPECIES

ROSs exhibit higher reactivity than triplet oxygen, the groundstate of molecular oxygen. The examples of reactive oxygenspecies include oxygen free radicals: superoxide anion radical– O

2•, hydroxyl radical – •OH, hydroperoxyl radical – HO

2•, singlet

oxygen, and nitrogen free radicals: NO•, NO•2. Hydrogen pero-

xide, peroxynitric acid, hypochlorous acid and hypothiocyanous

Reactive oxygen species – sources, functions, oxidativedamage

KAROLINA JAKUBCZYK1, KAROLINA DEC1, JUSTYNA KAŁDUŃSKA1, DOROTA KAWCZUGA2, JOANNA KOCHMAN1,KATARZYNA JANDA1

1Department of Human Nutrition and Metabolomics, Pomeranian Medical University, Szczecin, Poland; 2Institute of Biology, University of

Szczecin, Poland

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125Reactive oxygen species – sources, functions, oxidative damage

acid are regarded as non-radical species. Oxygen and ironcomplexes, e.g. ferryl and perferryl radicals, may also be cate-gorised as reactive oxygen species [3,15]. Adding a single elec-tron to an oxygen molecule leads to the formation of the super-oxide anion, the main type of oxygen free radicals found in thebody. Adding another electron produces hydrogen peroxide,one of the major precursors of free radicals. With the additionof the third electron, hydroxyl radical is formed, and the fourthleads to the synthesis of a water molecule, a neutral compoundnon-reactive with other cellular elements [5,15,37,51].

SOURCES OF REACTIVE OXYGEN SPECIES

Under physiological conditions, small quantities of oxygen freeradicals are synthesised during cellular metabolism in severalprocesses, including aerobic respiration or inflammatory pro-cesses [19,24]. Reactive oxygen compounds are synthesisedmainly in the mitochondrial respiratory chain, as by-productsof electron transport by enzymes, including: NADPH oxidase,superoxide dismutases and flavoprotein oxidases. In the re-spiratory chain, nearly 2% of molecular oxygen is transformedinto superoxide anion radical. The rate of free radical productionis elevated in damaged or ageing mitochondria [35]. Anotherintracellular source of those molecules are macrophages. Inthose cells, the release of free radicals is induced by cyclo-oxygenases (COX-1, COX-2), respiratory chain enzymes,NADPH-dependent oxidase, aldehyde oxidase and cytochromeP450 [2,59]. The endogenous sources of those molecules alsoinclude pulmonary endothelial cells, eosinophils, neutrophils andmonocytes. As a result of detoxification processes, e.g. duringxenobiotic metabolism, more free radicals are generated [15].

BIOLOGICAL FUNCTION OF REACTIVE OXYGEN

SPECIES

ROSs act as intracellular signalling molecules in the body. Su-peroxide and hydrogen peroxide, due to their low reactivity,selectiveness and ubiquitous distribution in the cell, are invo-lved in cell-to-cell signal transduction. In the signalling path-way of adenylyl cyclase and phospholipase C, radicals act assecondary messengers or modulators [12,58,61]. Radicals playa part in inhibiting several receptors, mainly those containingthiol groups, while the activity of certain proteins, includingguanylate cyclase and 5-lipoxygenase (LOX-5), may be upregu-lated in their presence. During the oxidation of polyunsaturatedfatty acids by LOX-5, the emerging radicals maintain the intra-cellular redox homeostasis, activating signalling pathways andgene expression [7,42,61]. Low concentrations of H

2O2 play a

part in activating the nuclear factor �B (NF-�B), which stimula-tes the expression of many genes, e.g. IL-1b, IL-6, thioredoxinand superoxide dismutase [40]. In addition, these reactivemolecules induce cell differentiation and apoptosis. They par-ticipate in muscle contractions, regulate vascular tone, anddetermine bactericidal and bacteriostatic activity of saliva. Theyare involved in eliminating xenobiotics, e.g. medicines, fromthe body [15]. The synthesis of reactive oxygen molecules byimmune cells, e.g. macrophages, monocytes or granulocytes, isa fundamental phenomenon in fighting infection and tissue re-pair following damage caused by pathogens. Radicals enhancecapillary permeability, which is necessary in a normal inflam-matory process [61]. It entails a significant increase in oxygenconsumption, in a process referred to as the respiratory (or oxi-dative) burst. It is associated with the use of oxygen in enhan-ced synthesis of superoxide anion radical and the activationof macrophages and granulocytes as the first-line defenceagainst infection. The activation of macrophages and neutro-phils leads to the release of large amounts of superoxide anionradical and its derivatives with the use of NADPH oxidase [52].Reactive oxygen metabolites are involved in the process ofeliminating parasites and pathogens in the oral cavity [25,52].

It was demonstrated that these molecules participate in theregulation of immunological processes. They upregulate lym-phocyte T activation and initiate endothelial adhesion of leuko-cytes, which helps them migrate from the blood stream to thesite of inflammation [7, 17,42,58,61]. Oxygen free radicals alsoplay an important role in the ageing process [20]. They contributeto the acceleration of this process, as well as determining celldeath or survival. Low doses of ROSs activate transcriptionfactors, which stimulates cell differentiation and helps cells adaptto different conditions [61]. On the other hand, high levels of freeradicals steer cells towards the apoptotic pathway, making itpossible to eliminate cells which have been seriously damagedand could pose a risk to the body, e.g. cancer cells [58,60,61].Maintaining a homeostasis between these processes is ne-cessary for normal body function.

OXIDATIVE STRESS

ROSs may be generated in the body under physiological con-ditions, in strictly controlled processes involving enzymatic andnon-enzymatic defence mechanisms [38,55]. Excessive andaccelerated synthesis of oxygen free radicals may be causedby exogenous factors, e.g. UV radiation, ionising radiation,stress, stimulants (alcohol, drugs or tobacco smoking),unhealthy diet, intense physical exertion or environmentalpollution [15,38]. Under normal conditions, there is a carefullymaintained balance between the production and elimination ofROSs, and the effects of ROSs depend on both the level andexposure time. In small quantities, they perform physiologicalfunctions, while elevated levels upset redox homeostasis[58,61]. Increased production of oxygen free radicals coupledwith reduced amounts of small-molecule antioxidant enzymescreate a situation where the body’s defence mechanisms failto effectively remove these molecules [50]. Inadequate antioxidantcapacity, when the body is not capable of rapid detoxificationof ROS or repair of free radical damage, disturbs the delicatebalance in favour of oxidation, leading to the so-called oxidativestress. The respirator system, circulatory system, brain andeyes are particularly susceptible to oxidative stress [1].

DAMAGE CAUSED BY REACTIVE OXYGEN SPECIES

Excessive production of free radicals contributes to their patholo-gical activity, affecting all types of molecules found in the bodyand causing damage at the molecular and cellular level. Reactiveoxygen species in vitro cause chemical modifications as well asdamage to proteins (aggregation, denaturation), lipids (peroxida-tion), carbohydrates and nucleotides (changes in the DNA struc-ture leading to mutations or cytotoxic effects) [1,55]. ROSs maynot only damage cell components, but also participate in celldifferentiation, signal transduction, or initiate apoptosis andnecrosis [38].

Oxidative stress may lead to mitochondrial damage, glycolysissuppression by inhibiting glyceraldehyde 3-phosphate dehy-drogenase, and ATP depletion. In cells, oxidized glutathione(GSSG) levels in cells go up, while the content of reduced glu-tathione (GSH) goes down. Enhanced release of oxidised glu-tathione from the liver into the blood stream is one of the mar-kers of oxidative stress. The shift in the redox balance in favourof oxidation leads to increased lipid peroxidation and a dropin the levels of reduced glutathione, which upregulates theactivity of enzymes involved in the arachidonic acid pathway,one of the main regulators of inflammatory response (cyclo-oxygenases and lipoxygenases), and causes an influx of cal-cium ions into the cell, resulting in damage to the cell mem-brane and its receptors. Free radical production is alsoconducive to depolarisation of the cell membrane, increasingits permeability.

With regard to the ROSs capacity as signalling molecules,their excessive synthesis may cause damage by inducing



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apoptosis or signalling its premature initiation. Increased per-meability of the inner mitochondrial membrane and cytochro-me C release from mitochondria to the cytosol is observed asa result of this process. An upswing in the amounts of malon-dialdehyde (MDA), a product of lipid peroxidation, alters cellmembrane permeability and uncouples oxidative phosphory-lation in mitochondria, which may ultimately stimulate the pro-grammed cell death process [50].

Disruptions in redox homeostasis may lead to protein oxi-dation [18,58,57]. This may involve cleavage of polypeptidechains, creation of dimers or aggregate proteins, or the emer-gence of altered amino acid residues. As a consequence, thesechanges may lead to the loss of functional activity of enzymes,membrane transporters or regulatory proteins [10,27,43]. Themolecules affected by irreversible change are selectively re-moved by proteases, however in the course of the cell ageingprocess proteolytic activity becomes diminished, and alteredproteins may aggregate in cells [16,56,54,61].

Nucleic acids constitute another cellular component whichis damaged by ROSs, even though – unlike proteins and lipids– they are characterised by greater stability. ROSs may da-mage purine and pyrimidine bases or cleave phosphodiesterbonds between nucleotides [29,47,61]. Additionally, mitochon-drial DNA is more exposed to the effects of oxidative stressbecause of the close proximity of the mitochondrial respiratorychain and lack of protection by chromatin [14,29,45,61]. Thisleads to the damage of mitochondrial DNA and mtDNA-enco-ded components of the electron-transport chain and apopto-sis [50]. Insufficient repair mechanisms and increased syn-thesis of ROSs cause cell membrane oxidation, structuralchanges, functional modifications in proteins, as well as DNAdamage and acceleration of ageing processes, which maytrigger mutations. The above processes may initiate carcino-genesis [50].

ROSs also play an important role in enzymatic and non-enzymatic lipid peroxidation processes. These involve the oxi-dation of polyunsaturated fatty acid residues. Lipid peroxidationis a chain reaction, which changes the physicochemical pro-perties of cell membranes. The process impairs transmem-brane transport, respiratory chain activity and signal trans-duction [52]. The end-products of peroxidation are modified,damaged lipid molecules [61]. The lipid peroxidation process,with its stages of initiation, propagation and termination, leadsto the formation of free radicals which then react with proteins.Lipid oxidation products (LOPs) inhibit the activity of membraneenzymes and transport proteins, at the same time alteringthe physical properties of cell membranes. It was also demon-strated that LOPs may induce the expression of cyclooxyge-nase 2 (COX-2) in macrophages and initiate inflammation inthese cells [39,61].

FREE RADICAL MEDIATED DISEASES

Oxidative stress plays an important role in the development ofmany diseases, including those of the circulatory system (athero-sclerosis), nervous system, lungs, eyes, as well as hepatitisand pancreatitis, diabetes, neurodegenerative diseases, obesi-ty and also in the ageing process and inflammatory conditions[13,21,31,44]. Oxidative stress is implicated in hepatitis C, al-tering the dynamics of HCV-RNA replication, which is inhibitedin hepatocytes by the reduction of NS3 and NS5A proteins [50].

With regard to HIV infection, ROSs activate HIV-RNA repli-cation, inducing nuclear factor kappa B (NF-�B). The condi-tion caused by HIV infection is observed to present with animbalanced redox status, depressed levels of total glutathioneand cysteine [4,25,32]. People infected with HIV develop disor-ders of the enzymatic system, presenting with reduced activityof SOD and GSH-Px and increased catalase activity [14].

The shift in the redox balance in favour of oxidation andalterations in the GSH/GSSG ratio are also observed in neurode-generative disorders, e.g. Parkinson’s disease and Alzheimer’s

disease [49], hepatitis B [33], influenza infection or bacterialinfections (e.g. Helicobacter pylori), as well as metabolic disor-ders (diabetes, atherosclerosis) [12,22,23,28,34]. During tissueischaemia or sepsis, ROS production is increased, leading totissue damage and complications, m.in.: shock, stroke, chroniccirculatory failure or arterial hypertension [52].

Oxidative stress also plays an important role in the patho-physiology of asthma and chronic obstructive pulmonary disease(COPD) [52]. A surplus of reactive oxygen species may alsopromote carcinogenetic processes [14].

Moreover, oxidative stress is one of the factors underlyingthe pathomechanism of neurodegenerative diseases [41,46,48].The accumulation of protein deposits (amyloid) in nerve cellsmay increase oxidative stress [10]. The activity of superoxidedismutase was observed in patients. Neurons have been demon-strated to be highly sensitive to oxidative stress, respondingwith elevated lipid peroxidation and significantly decreasedactivity of antioxidant enzymes [11,52]. Free radicals are indi-sputably involved in the atherosclerotic process.

ROSs are key mediators in the signalling pathways lying atthe root of vascular inflammation in atherosclerosis, startingfrom the initiation of the pathological process, through its pro-gression, to the ultimate atherosclerotic plaque rupture, andantioxidant supplementation may be helpful both in treatmentand prevention [8,26,30,36,53]. In recent years, researchershave turned their attention to the role of oxidative stress in obe-sity. Elevated markers of oxidative stress have been found inobese people, and in obese mice increased levels of stresswere found in adipose tissue; the involvement of adipose tissuein the production of free radicals has also been confirmed. In-creased levels of systemic oxidative stress observed in obesitymay contribute to the development of obesity-related diseases,including diabetes, arterial hypertension and atherosclerosis[9,21,44].

CONCLUSIONS

Oxidative stress plays an important role in the development ofmany diseases, including those of the circulatory system (athe-rosclerosis), nervous system, lungs, eyes, as well as hepatitisand pancreatitis, diabetes, neurodegenerative diseases, obesityand also in the ageing process and inflammatory conditions.Investigation of the mechanisms behind free-radical reactionsoccurring in selected biological models may help us under-stand these processes and counteract their adverse effects.

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Conflict of Interest: The authors declare that they have no conflict of interest.

Funding: The project is financed from the program of the Minister of Scienceand Higher Education under the name „Regional Initiative of Excellence”in 2019-2022 project number 002/RID/2018/19 amount of financing12 000 000 PLN.

Received: 29.01.2020Revised: 03.02.2020Accepted: 11.03.2020

Address for correspondence:Katarzyna JandaDepartment of Human Nutrition and MetabolomicsPomeranian Medical University24 Broniewskiego Str., 71-460 Szczecin, Polandtel.: +48 091 441 4818,email: [email protected]



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