New markers of oxidative damage to macromolecules

Journal of Medical Biochemistry, Jan 2008

The presence of free radicals in biological material has been discovered some 50 years ago. In physiological conditions, free radicals, in the first place the ones of oxygen and nitrogen, are continuously synthesized and involved in the regulation of a series of physiological processes. The excess of free radicals is efficiently eliminated from the body in order to prevent their toxic effects. Toxic effects of free radicals may be classified into three groups: a) change of intracellular redox potential, b) oxidative modification of lipids, proteins and DNA, and c) gene activation. Lipid peroxidation involving cell membranes, lipoproteins and other molecules leads to the production of primary high-reactive intermediaries (alkyl radicals, conjugated dienes, peroxy- and alkoxyl radicals and lipid hydroperoxide), whose further breakdown generates the secondary products of lipid peroxidation: short-chain evaporable hydrocarbons, aldehydes and final products of lipid peroxidation: isoprostanes, MDA, 4- hydroxy-2,3-transnonenal and 4,5-dihydroxydecenal which are important mediators of atherosclerosis, coronary disease, acute myocardial infarction, rheumatoid arthritis, systemic sclerosis and lupus erythematodes. Oxidative modification of proteins is manifested by changes in their primary, secondary and tertiary structures. Proteins have a specific biological function, and therefore their modification results in unique functional consequences. The nature of protein modification may provide valid information on the type of oxidants causing the damage. Chlorotyrosyl is a specific marker of oxidative damage to tyrosine caused by HOCl action, which most commonly reflects the involvement of neutrophils and monocytes in oxidative stress, while nitrotyrosyl indicates the presence of higher peroxy-nitrite synthesis. Methyonin and cysteine are the amino acids most sensitive to oxidative stress, carbonyl groups are markers of severe damage caused by free radicals, and di-tyrosyl is the most significant and sensitive marker of oxidative modification made by g rays. "Carbo-proteins, where reducing sugars non-enzymatically react with amino groups of proteins and lipids and give rise to the production of covalent compounds known as advanced glycosylated end products (AGE-products). A hydroxyl radical damages the DNA, leading to a loss of base and the formation of a basic sites (AP sites), break of DNA chain and sugar modification. Final lipid peroxidation products (MDA) may covalently bind to DNA, producing the "DNA radicals" which are responsible for mutations. Measurement of an adequate oxidative stress biomarker may not only point to an early onset of disease, its progression and assessment of therapy effectiveness, but can also help in the clarification of the pathophysiological mechanisms of tissue damage caused by oxidative stress, prediction of disease prognosis and choice of appropriate treatment in the early stages of disease.

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New markers of oxidative damage to macromolecules

JMB 2008; 27 (1) DOI: 10.2478/v10011-007-0049-x UDK 577.1 : 61 ISSN 1452-8258 JMB 27: 1–16, 2008 Review article Pregledni ~lanak NEW MARKERS OF OXIDATIVE DAMAGE TO MACROMOLECULES NOVI MARKERI OKSIDATIVNOG O[TE]ENJA MAKROMOLEKULA Emina ^olak Institute of Medical Biochemistry, CCS, Belgrade, Serbia Summary: The presence of free radicals in biological material has been discovered some 50 years ago. In physiological conditions, free radicals, in the first place the ones of oxygen and nitrogen, are continuously synthesized and involved in the regulation of a series of physiological processes. The excess of free radicals is efficiently eliminated from the body in order to prevent their toxic effects. Toxic effects of free radicals may be classified into three groups: a) change of intracellular redox potential, b) oxidative modification of lipids, proteins and DNA, and c) gene activation. Lipid peroxidation involving cell membranes, lipoproteins and other molecules leads to the production of primary high-reactive intermediaries (alkyl radicals, conjugated dienes, peroxy- and alkoxyl radicals and lipid hydroperoxide), whose further breakdown generates the secondary products of lipid peroxidation: short-chain evaporable hydrocarbons, aldehydes and final products of lipid peroxidation: isoprostanes, MDA, 4hydroxy-2,3-transnonenal and 4,5-dihydroxydecenal which are important mediators of atherosclerosis, coronary disease, acute myocardial infarction, rheumatoid arthritis, systemic sclerosis and lupus erythematodes. Oxidative modification of proteins is manifested by changes in their primary, secondary and tertiary structures. Proteins have a specific biological function, and therefore their modification results in unique functional consequences. The nature of protein modification may provide valid information on the type of oxidants causing the damage. Chlorotyrosyl is a specific marker of oxidative damage to tyrosine caused by HOCl action, which most commonly reflects the involvement of neutrophils and monocytes in oxidative stress, while nitrotyrosyl indicates the presence of higher peroxy-nitrite synthesis. Methyonin and cysteine are the amino acids most sensitive to oxidative stress, carbonyl groups are markers of severe damage caused by free radicals, and di-tyrosyl is the most significant and sensitive marker of oxidative modification made by g rays. »Carbo- Address for correspondence: ^olak Emina Institute of Medical Biochemistry Clinical Center of Serbia Vi{egradska 26 11000 Belgrade, Serbia tel: 3615 631 e-mail: eminacolakªsbb.co.yu Kratak sadr`aj: Prisustvo slobodnih radikala u biolo{kim materijalima je otkriveno pre ne{to vi{e od 50 godina. U fiziolo{kim uslovima, slobodni radikali, pre svega kiseonika i azota, stalno se sinteti{u i pri tom u~estvuju u regulaciji niza fiziolo{kih procesa. Vi{ak slobodnih radikala se efikasno uklanja iz organizma u cilju spre~avanja njihovih toksi~nih efekata. Toksi~ni efekti delovanja slobodnih radikala se mogu podeliti u tri grupe: a) pomeranje intra}elijskog redoks stanja, b) oksidativna modifikacija lipida, proteina i DNK i c) aktivacija gena. Lipidna peroksidacija koja zahvata }elijske membrane, lipoproteine i druge molekule dovodi do stvaranja primarnih visokoreaktivnih intermedijera (alkil radikala, konjugovanih diena, peroksi i alkoksi radikala i lipidnih hidroperoksida), koji daljom razgradnjom daju sekundarne produkte lipidne peroksidacije: kratkolan~ane isparljive ugljovodonike, aldehide i krajnje proizvode lipidne peroksidacije: izoprostane, MDA (malondialdehid), 4-hidroksi-2,3-transnonenal i 4,5-dihidroksidecenal, koji su zna~ajni medijatori ateroskleroze, koronarne bolesti, akutnog infarkta miokarda, reumatoidnog artritisa, sistemske skleroze, lupusa eritematodesa. Oksidativna modifikacija proteina manifestuje se promenama njihove primarne, sekundarne i tercijarne strukture. Proteini imaju specifi~nu biolo{ku funkciju, stoga njihova izmena ima jedinstvene funkcionalne posledice. Priroda proteinske modifikacije mo`e nam dati validan podatak o vrsti oksidansa koji je doveo do o{te}enja. Hlorotirozil je specifi~an marker oksidativnog o{te}enja tirozina dejstvom hipohlorita (HOCl), koji naj~e{}e reflektuje u~e{}e neutrofila i monocita u oksidativnom stresu, dok nitrotirozil ukazuje na prisustvo pove}ane sinteze peroksinitrita. Metionin i cistein su najosetljivije aminokiseline na dejstvo oksidativnog stresa, karbonilne grupe su markeri te{kog o{te}enja slobodnim radikalima, dok je di-tirozil najzna~ajniji i najosetljiviji marker oksidativne modifikacije dejstvom g-zraka. »Karbonilni stres« je zna~ajan vid sekundarne oksidacije proteina u kojem redukuju}i {e}eri neenzimski reaguju sa amino grupama proteina i lipida dovode}i do stvaranja kovalentnih jedinjenja poznatih kao uznapredovani proizvodi glikozilacije ili AGE-proizvodi (advanced glycosylated end products). Hidroksilni radikal o{te}uje i molekul DNK dovode}i do gubitka baze i stvaranja abazi~nih mesta (AP site-ova), cepanja lanca DNK i modifikacije {e}era. Krajnji proizvodi lipidne peroksidacije (MDA) mogu se kovalentno vezivati za DNK, stvara- 2 ^olak: New markers of oxidative damage to macromolecules nyl stress« is an important form of the secondary oxidation of proteins, where reducing sugars non-enzymatically react with amino groups of proteins and lipids and give rise to the production of covalent compounds known as advanced glycosylated end products (AGE-products). A hydroxyl radical damages the DNA, leading to a loss of base and the formation of abasic sites (AP sites), break of DNA chain and sugar modification. Final lipid peroxidation products (MDA) may covalently bind to DNA, producing the »DNA radicals« which are responsible for mutations. Measurement of an adequate oxidative stress biomarker may not only point to an early onset of disease, its progression and assessment of therapy effectiveness, but can also help in the clarification of the pathophysiological mechanisms of tissue damage caused by oxidative stress, prediction of disease prognosis and choice of appropriate treatment in the early stages of disease. ju}i »DNK radikale« koji su odgovorni za nastanak mutacija. Merenje adekvatnog biomarkera oksidativnog stresa mo`e nam ukazati ne samo na ranu pojavu bolesti, njenu progresiju i procenu efikasnosti terapije, ve} i pomo}i u rasvetljavanju patofiziolo{kih mehanizama o{te}enja tkiva dejstvom oksidativnog stresa, u predikciji prognoze bolesti i izboru adekvatnog le~enja u ranim stadijumima bolesti. Klju~ne re~i: oksidativna modifikacija, lipidi, proteini, DNK, biomarkeri, slobodni radikali, lipidna peroksidacija, karbonilni stres Keywords: oxidative modification of lipids, proteins, DNA, biomarkers, free radicals, lipid peroxidation, carbonyl stress Introduction The presence of free radicals in biological materials was discovered some 50 years ago (1). Soon after that discovery, Harman (2) reported his hypothesis that free radicals were the (...truncated)


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Čolak Emina. New markers of oxidative damage to macromolecules, Journal of Medical Biochemistry, 2008, pp. 1-16, Volume 1,