Oxidative stress: Clinical diagnostic significance

JMB 2008; 27 (4) DOI: 10.2478/v10011-008-0024-1 UDK 577.1 : 61 ISSN 1452-8258 JMB 27: 409–425, 2008 Review article Pregledni ~lanak OXIDATIVE STRESS – CLINICAL DIAGNOSTIC SIGNIFICANCE Mirjana \uki}1, Milica Ninkovi}2, Marina Jovanovi}2 1Faculty of Pharmacy at the University of Belgrade 2Institute for Medical Research, Military Medical Academy, Belgrade Summary: Elevated free radical production and/or insufficient antioxidative defense results in cellular oxidant stress responses. Sustained and/or intense oxidative insults can overcome cell defenses resulting in accumulated damage to macromolecules, leading to loss of cell function, membrane damage, and ultimately to cell death. Oxidative stress (OS) can result from conditions including excessive physical stress, exposure to environmental pollution and xenobiotics, and smoking. Oxidative stress, as a pathophysiological mechanism, has been linked to numerous pathologies, poisonings, and the ageing process. Reactive oxygen species and reactive nitrogen species, endogenously or exogenously produced, can readily attack all classes of macromolecules (proteins, DNA, unsaturated fatty acid). The disrupted oxidative-reductive milieu proceeds via lipid peroxidation, altered antioxidative enzyme activities and depletion of non-enzymatic endogenous antioxidants, several of which can de detected in the pre-symptomatic phase of many diseases. Therefore, they could represent markers of altered metabolic and physiological homeostasis. Accordingly, from the point of view of routine clinical-diagnostic practice, it would be valuable to routinely analyze OS status parameters to earlier recognize potential disease states and provide the basis for preventative advance treatment with appropriate medicines. Keywords: oxidative stress, free radicals, antioxidants Reactive species and oxidative stress Reactive species (RS), a diverse group of heterogenic chemical compounds, consist of free radicals (FR) and non-radicals. Non-radical compounds, such as hydrogen peroxide (H2O2) and peroxynitrite Address for correspondence: Prof. dr Mirjana \uki} Institute for Toxicology Faculty of Pharmacy at the University of Belgrade Tel: 011 3951 308 e-mail: mirjana.djukicªpharmacy.bg.ac.yu Kratak sadr`aj: Pove}ano stvaranje slobodnih radikala i/ili nedovoljna antioksidativna za{tita dovodi do oksidativnog stresa (OS) u }eliji. Produ`eni i/ili sna`an oksidativni insult prevazilazi }elijski antioksidativni odbrambreni kapacitet, dolazi do o{te}enja makromolekula, gubi se }elijska funkcija, o{te}uju se membrane, {to sve zajedno dovodi do smrti }elije. Stanja organizma kao {to su pove}ana fizi~ka aktivnost, izlo`enost zaga|enju ~ovekove okoline, ksenobioticima, pu{enje itd. rezultiraju OS. Oksidativni stres, kao patofiziolo{ki mehanizam, je potvr|en u brojnim patologijama, trovanjima i starenju. Reaktivne kiseoni~ne vrste i reaktivne azotove vrste, endogenog ili egzogenog porekla, mogu lako da napadnu sve klase biomolekula (proteni, DNK, nezasi}ene masne kiseline). Naru{en oksido-reduktivni milje, koji posreduje pove}anju lipidne peroksidacije, promeni aktivnosti direktnih ili indirektnih antioksidativnih enzima, kao i smanjenom sadr`aju neenzimskih antioksidanasa, mo`e biti prepoznat u presimptomatskoj fazi brojnih bolesti. U tom smislu mo`e biti pokazatelj izmenjenih metaboli~kih i funkcionalnih zbivanja. U svakodnevnoj klini~ko-dijagnosti~koj praksi analize parametara OS u biolo{kom materijalu bi trebalo da imaju svoje mesto, radi rane dijagnoze bolesti, prevencije i unapre|ivanja terapije. Klju~ne re~i: oksidativni stres, slobodni radikali, antioksidansi (ONOO–) ions, do not have unpaired electrons in their outer orbit but react similarly to FR and support red-ox reactions of RS in the body (1–3). However, FR represent the main class of RS (4). Depending on which atom is in the active centre, RS are divided into categories: reactive oxygen species (ROS); reactive nitrogen species (RNS); reactive carbon species (RCS) and reactive sulfur species (RSS) (Table I). Free radicals are molecules, atoms or ions with unpaired electrons in the outer orbit, which act as oxidants due to their tendency to couple such electrons. The electrophillic properties of FR form the basis for 410 \uki} et. al.: Oxidative stress – clinical diagnostic significance Table I Reactive species. Radicals . ROS O2– Non radicals superoxide H2O2 hydrogen peroxide acid . anion radical HOCl hypochlorous HO hydroxyl radical O3 ozone . ROO peroxyl radical 1O2 singlet oxygen . RO alkoxyl radical HOO. hydroperoxyl radical RNS NO. nitric oxide radical NO2– nitrogen dioxide . anion NO2 nitrogen dioxide N2O 3 nitrogen trioxide radical NO2+ nitronium ion ONOO – peroxynitrite anion ROONO alkyl peroxynitrite NO– (singlet) nitroxyl anion NO+ nitrosyl cation NO2Cl nitryl chloride . alkyl radical RCS R . alkoxyl RO radical . ROO peroxyl radical . thiyl radical RSS RS . glutathyl GS radical . GSSG – diglutathione-disulfide anion radical unpaired electron electron transfer + »target« molecule oxidized »target« molecule + Under physiological conditions, FR concentrations are kept at low concentrations. However, their concentrations can acutely increase during numerous cell processes including erythropoesis, respiratory control and during signal transduction pathways stimulated by diverse growth factors and cytokines. When present at high concentrations FR can directly (and indirectly) affect proteins, lipids and chromatin and can alter signal transduction pathways and gene expression. As their effects are diverse they can contribute to promote pathophysiological processes in the body. Oxidative stress is a condition caused by an imbalance in RS production and the biological system’s ability to detoxify the reactive intermediates and repair the resulting damage (10). Increased FR generation which exceeds the capacity of the antioxidative defense system (ADS) results in OS. Depletion of energy and reductive equivalents is a consequence of increased ADS activity during OS (11). Oxidative stress often causes the disintegration of cell membranes, changes cellular morphology and function and is a prelude to cell death. A growing body of evidence concerning oxidative damage to macromolecules by highly reactive FR underlines the contribution of OS as a component in pathophysiological mechanisms (12–14). The involvement of RS has been identified in many pathologies (degenerative diseases, malignancy, diabetes mellitus, cardiovascular diseases based on atherosclerotic changes, and chemical poisoning), but also in physiological processes of ageing and apoptosis (12–17). Free radical Antioxidative defense system The ADS consists of several levels of protection Figure 1 Mechanism of free radical effects. their high reactivity. In reactions with FR, bio-molecules undergo oxidation and, through donation of their own electrons, they themselves become new »secondary« radicals that continue radic (...truncated)