Oxidative stress, radiation-induced damage and the potential role of N-acetylcysteine as a radioprotector

Year 2008, Volume: 23 Issue: 4, 200 - 207, 01.05.2008

Sevil Kılçıksız Can Demirel

Abstract

Many of the regulatory changes in cells after irradiation may be mediated through the production and interaction of classical signal transduction, free radicals, and DNA damage. The protection of normal tissues may provide an increase in tumor control by providing an increase in the radiation dose. Nacetylcysteine (NAC) is a potent free radical scavenger and may be beneficial in conditions of glutathione (GSH) depletion and free radical formation during oxidative stress. NAC has been shown to prevent radiation-induced DNA breaks and to have a place in cancer prevention. It may be suggested that NAC decreases irradiation-induced genocytotoxicity. NAC has not yet been widely used clinically for this purpose; further experimental studies are needed for determining its radioprotector effect. In the current review, we aimed to discuss the radioprotective potential of NAC.

Keywords

Oxidative Stress, Radiation Injuries, Radiation-Protective Agents, Acetylcysteine, Glutathione, DNA Damage

Oksidatif stres, radyasyona bağlı hasar ve radyokoruyucu olarak N-asetil-sistein'in potansiyel rolü

Abstract

Radyasyon sonrası hücre içi birçok düzenleyici değişiklik serbest oksijen radikalleri, DNA ve DNA çift kırığı (DSB) arasındaki klasik sinyal uyumlulaştırıcılarının etkileşimi aracılığıyla gerçekleşir. Normal dokuların korunabilmesi radyasyon dozunda yükselmeye olanak sağlayıp tümör kontrolünü arttırabilir. N-asetil-sistein (NAS) potent serbest oksijen radikalleri temizleyicisi olup azalmış vücut glutatyon depolarını destekler ve oksidatif streste serbest radikal oluşumu durumunda yaralı olabilir. Radyasyona bağlı DNA hasarını azaltabildiği ve kanserden korunmada yeri olduğu gösterilmiştir. NAS'nin radyasyona bağlı genositotoksisiteyi azalttığı söylenebilir. NAS klinikte bu amaçla henüz pek kullanılmamaktadır ve daha ileri çalışmalarla radyokoruyucu etkisinin doğrulanması gereklidir. İncelememizde, NAS'nin radyokoruyucu olarak güncel rolü değerlendirildi.

Keywords

Glutatyon, N-asetil-sistein, oksidatif stres, radyasyon hasarı

References

• 1 . B e rgendi L, Benes L, Duracková Z, Ferencik M. C h e m i s t r y, physiology and pathology of free radicals. Life Sci 1999;65(18-19):1865-74.
• 2 . Stohs SJ, Bagchi D. Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med 1 9 9 5 ; 1 8 ( 2 ) : 3 2 1 - 3 6 .
• 3 . Klatt P, Lamas S. Regulation of protein function by Sglutathiolation in response to oxidative and nitrosative stress. Eur J Biochem 2000;267(16):4928- 4 4 .
• 4 . Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 2 0 0 6 ; 1 6 0 ( 1 ) : 1 - 4 0 .
• 5 . Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007;39(1):44-84.
• 6 . Neal R, Matthews RH, Lutz P, Ercal N. Antioxidant role of N-acetyl cysteine isomers following high dose irradiation. Free Radic Biol Med 2003;34(6):689-95.
• 7 . Akkufl ‹. Serbest radikaller ve fizyopatolojik etkileri. Konya: Mimoza Yay›nlar›; 1993. s. 38.
• 8 . Steel GG (editor). Basic clinical radiobiology. 3rd ed. Oxford University Pres Inc., 198 Madison Av e n u e , New York, and NY10016. Edward Arnold Ltd.; 2002; p. 2-4.
• 9 . Weiss JF. Pharmacologic approaches to protection against radiation-induced lethality and other damage. Environ Health Perspect 1997;105 Suppl 6:1473-8.
• 1 0 .Cooke MS, Evans MD, Dizdaroglu M, Lunec J Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 2003;17(10):11 9 5 - 2 1 4 .
• 11 . G ö r p e A, Cantez S. Pratik nükleer t›p. ‹stanbul: ‹stanbul T›p Fakültesi Vakf›, Nobel T›p Kitabevi; 1992. s. 14-7.
• 1 2 . Machlin LJ, Bendich A. Free radical tissue damage: protective role of antioxidant nutrients. FASEB J 1 9 8 7 ; 1 ( 6 ) : 4 4 1 - 5 .
• 1 3 . Mc Clellan RO. In the control of exposure of the public to Ionizing radiation in the event of accident or attack. Bioi effect of low-level rad 1983;288-301.
• 14. Barker S, Weinfeld M, Zheng J, Li L, Murray D. Identification of mammalian proteins cross-linked to DNA by ionizing radiation. J Biol Chem 2 0 0 5 ; 2 8 0 ( 4 0 ) : 3 3 8 2 6 - 3 8 .
• 1 5 . De Flora S, Izzotti A, D'Agostini F, Balansky RM. Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points. Carcinogenesis 2 0 0 1 ; 2 2 ( 7 ) : 9 9 9 - 1 0 1 3 .
• 1 6 . Hofer M, Mazur L, Pospísil M, Weiterová L, Znojil V. Radioprotective action of extracellular adenosine on bone marrow cells in mice exposed to gamma rays as assayed by the micronucleus test. Radiat Res 2 0 0 0 ; 1 5 4 ( 2 ) : 2 1 7 - 2 1 .
• 1 7 . Lloyd DC, Edwards AA, Prosser JS, Corp MJ. The dose response relationship obtained at constant irradiation times for the induction of chromosome aberrations in human lymphocytes by cobalt-60 gamma rays. Radiat Environ Biophys 1984;23(3):179-89.
• 1 8 . Edwards AA, Lloyd DC, Purrott RJ. Dicentric chromosome aberration yield in human lymphocytes and radiation quality; A resume including recent results using alpha-particles. In: Booz J, Ebert HG, Hartfiel HD, editors Seventh Symposium on Microdosimetry, Report EUR7147, Harwood Academic Publishers, C h u r. 1980. p. 1263-73.
• 1 9 . Tawn EJ, Whitehouse CA, Martin FA. Sequential chromosome aberration analysis following radiotherapy - no evidence for enhanced genomic instability. Mutat Res 2000;465(1-2):45-51.
• 2 0 .Bump EA, Brown JM. Role of glutathione in the radiation response of mammalian cells in vitro and in vivo. Pharmacol Ther 1990;47(1):11 7 - 3 6 .
• 2 1 .Beckman KB, Ames BN. Oxidative decay of DNA. J Biol Chem 1997;272(32):19633-6.
• 2 2 . Marnett LJ. Lipid peroxidation-DNA damage by malondialdehyde. Mutat Res 1999;424(1-2):83-95.
• 2 3 . Prasad NR, Srinivasan M, Pugalendi KV, Menon VP. Protective effect of ferulic acid on gamma-radiationinduced micronuclei, dicentric aberration and lipid peroxidation in human lymphocytes. Mutat Res 2 0 0 6 ; 6 0 3 ( 2 ) : 1 2 9 - 3 4 .
• 2 4 .Jagetia GC, Reddy TK. The grapefruit flavanone naringin protects against the radiation-induced genomic instability in the mice bone marrow: a micronucleus study. Mutat Res 2002;519(1-2):37-48.
• 2 5 . Mansour HH, Hafez HF, Fahmy NM, Hanafi N. Protective effect of N-acetylcysteine against radiation induced DNA damage and hepatic toxicity in rats. Biochem Pharmacol 2008;75(3):773-80.
• 2 6 .Juránek I, Bezek S. Controversy of free radical hypothesis: reactive oxygen species-cause or consequence of tissue injury? Gen Physiol Biophys 2 0 0 5 ; 2 4 ( 3 ) : 2 6 3 - 7 8 .
• 2 7 .Chandra Jagetia G, Rajanikant GK, Rao SK, Shrinath Baliga M. Alteration in the glutathione, glutathione peroxidase, superoxide dismutase and lipid peroxidation by ascorbic acid in the skin of mice exposed to fractionated gamma radiation. Clin Chim Acta 2 0 0 3 ; 3 3 2 ( 1 - 2 ) : 111 - 2 1 .
• 2 8 . Atkuri KR, Mantovani JJ, Herzenberg LA, H e r z e n b e rg LA. N-Acetylcysteine--a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol 2007;7(4):355-9.
• 2 9 . Prescott L. Oral or intravenous N-acetylcysteine for acetaminophen poisoning? Ann Emerg Med 2 0 0 5 ; 4 5 ( 4 ) : 4 0 9 - 1 3 .
• 3 0 . Tirouvanziam R, Conrad CK, Bottiglieri T, H e r z e n b e rg LA, Moss RB, Herzenberg LA. Highdose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis. Proc Natl Acad Sci U S A 2006;103(12):4628-33.
• 3 1 . Yuhas MJ, Philips TL. Parmacokinetics and mechanisms of action of WR-2721 and other protective agents. Radioprotector and Anticarciogenesis. New York: Academic Pres; 1982. p. 639–653.
• 3 2 . Utley JF, Seaver N, Newton GL, Fahey RC. Pharmacokinetics of WR-1065 in mouse tissue following treatment with WR-2721. Int J Radiat Oncol Biol Phys 1984;10(9):1525-8.
• 3 3 . Sjödin K, Nilsson E, Hallberg A, Tunek A. Metabolism of N-acetyl-L-cysteine. Some structural requirements for the deacetylation and consequences for the oral bioavailability. Biochem Pharmacol 1 9 8 9 ; 3 8 ( 2 2 ) : 3 9 8 1 - 5 .
• 3 4 . Halliwell B. Antioxidants in human health and disease. Annu Rev Nutr 1996;16:33-50.
• 3 5 . De Rosa SC, Zaretsky MD, Dubs JG, Roederer M, Anderson M, Green A, et al. N-acetylcysteine replenishes glutathione in HIV infection. Eur J Clin Invest 2 0 0 0 ; 3 0 ( 1 0 ) : 9 1 5 - 2 9 .
• 3 6 .Ratjen F, Wönne R, Posselt HG, Stöver B, Hofmann D, Bender SW. A double-blind placebo controlled trial with oral ambroxol and N-acetylcysteine for mucolytic treatment in cystic fibrosis. Eur J Pediatr 1 9 8 5 ; 1 4 4 ( 4 ) : 3 7 4 - 8 .
• 3 7 . Sölen G. Radioprotective effect of N-acetylcysteine in vitro using the induction of DNA breaks as endpoint. Int J Radiat Biol 1993;64(4):359-66.
• 3 8 . Spapen H. N-acetylcysteine in clinical sepsis: a diff icult marriage. Crit Care 2004;8(4):229-30.
• 3 9 . Prescott L. Oral or intravenous N-acetylcysteine for acetaminophen poisoning? Ann Emerg Med 2 0 0 5 ; 4 5 ( 4 ) : 4 0 9 - 1 3 .
• 4 0 . Sridharan S, Shyamaladevi CS. Protective effect of N-acetylcysteine against gamma ray induced damages in rats-biochemical evaluations. Indian J Exp Biol 2002;40(2):181-6.
• 4 1 . L a u t e r b u rg BH, Corcoran GB, Mitchell JR. Mechanism of action of N-acetylcysteine in the protection against the hepatotoxicity of acetaminophen in rats in vivo. J Clin Invest 1983;71(4):980-91.
• 4 2 . Sener G, Tosun O, Sehirli AO, Kaçmaz A, Arbak S, Ersoy Y, et al. Melatonin and N-acetylcysteine have beneficial effects during hepatic ischemia and reperfusion. Life Sci 2003;72(24):2707-18.
• 4 3 . Allameh A, Vansoun EY, Zarghi A. Role of glutathione conjugation in protection of weanling rat liver against acetaminophen-induced hepatotoxicity. Mech Ageing Dev 1997;95(1-2):71-9.
• 4 4 . Wagdi P, Fluri M, Aeschbacher B, Fikrle A, Meier B. Cardioprotection in patients undergoing chemoand/or radiotherapy for neoplastic disease. A pilot s t u d y. Jpn Heart J 1996;37(3):353-9.
• 4 5 . Logani MK, Davies RE. Lipid oxidation: biologic e ffects and antioxidants--a review. Lipids 1 9 8 0 ; 1 5 ( 6 ) : 4 8 5 - 9 5 .
• 4 6 . Koizumi A, Weindruch R, Walford RL. Influences of dietary restriction and age on liver enzyme activities and lipid peroxidation in mice. J Nutr 1 9 8 7 ; 11 7 ( 2 ) : 3 6 1 - 7 .
• 4 7 . Martínez M, Hernández AI, Martínez N. NAcetylcysteine delays age-associated memory impairment in mice: role in synaptic mitochondria. Brain Res 2000;855(1):100-6.
• 4 8 . Shechmeister IL, Fishman M. The effect of ionizing radiation on phagocytosis and the bactericidal power of the blood. I. The effect of radiation on migration of leucocytes. J Exp Med 1955;101(3):259-74.
• 4 9 .Balabanli B, Türközkan N, Balabanli S, Erdamar H, Akmansu M. The effect of vitamin A pretreatment on radiation induced alteration in neutrophil functions. Mol Cell Biochem 2006;286(1-2):103-5.
• 5 0 . Konkabaeva AE, Bazeliuk LT. Effects of ionizing radiation on catecholamine level in experimental animals. [Article in Russian] Gig Sanit 2001;(6):22-3. [ A b s t r a c t ]
• 5 1 . M a c Vittie TJ, Farese AM, Smith WG, Baum CM, Burton E, McKearn JP. Myelopoietin, an engineered chimeric IL-3 and G-CSF receptor agonist, stimulates multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression. Blood 2000;95(3):837-45.
• 5 2 . Stevenson MA, Pollock SS, Coleman CN, Calderwood SK. X-irradiation, phorbol esters, and H2O2 stimulate mitogen-activated protein kinase activity in NIH-3T3 cells through the formation of reactive oxygen intermediates. Cancer Res 1 9 9 4 ; 5 4 ( 1 ) : 1 2 - 5 .
• 5 3 . Masella R, Di Benedetto R, Varì R, Filesi C, Giovannini C. Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes. J Nutr Biochem 2005;16(10):577-86.
• 5 4 . Wanamarta AH, van Rijn J, Blank LE, Haveman J, van Zandwijk N, Joenje H. Effect of N-acetylcysteine on the antiproliferative action of X-rays or bleomycin in cultured human lung tumor cells. J Cancer Res Clin Oncol 1989;11 5 ( 4 ) : 3 4 0 - 4 .
• 5 5 .Reliene R, Fischer E, Schiestl RH. Effect of N-acetyl cysteine on oxidative DNA damage and the frequency of DNA deletions in atm-deficient mice. Cancer Res 2004;64(15):5148-53.
• 5 6 . Oda T, Iwaoka J, Komatsu N, Muramatsu T. Involvement of N-acetylcysteine-sensitive pathways in ricin-induced apoptotic cell death in U937 cells. Biosci Biotechnol Biochem 1999;63(2):341-8.
• 5 7 .Campain JA. Nicotine: potentially a multifunctional carcinogen? Toxicol Sci 2004;79(1):1-3.
• 5 8 . van Zandwijk N. N-acetylcysteine (NAC) and glutathione (GSH): antioxidant and chemopreventive properties, with special reference to lung cancer. J Cell Biochem Suppl 1995;22:24-32.
• 5 9 . Morley N, Curnow A, Salter L, Campbell S, Gould D. N-acetyl-L-cysteine prevents DNA damage induced by UVA, UVB and visible radiation in human fibroblasts. J Photochem Photobiol B 2003;72(1-3):55-60.
• 6 0 . He YY, Häder DP. UV-B-induced formation of reactive oxygen species and oxidative damage of the cyanobacterium Anabaena sp.: protective effects of ascorbic acid and N-acetyl-L-cysteine. J Photochem Photobiol B 2002;66(2):11 5 - 2 4 .
• 6 1 . Mantovani G, Macciò A, Madeddu C, Mura L, Gramignano G, Lusso MR, et al. Antioxidant agents are effective in inducing lymphocyte progression through cell cycle in advanced cancer patients: assessment of the most important laboratory indexes of cachexia and oxidative stress. J Mol Med 2 0 0 3 ; 8 1 ( 1 0 ) : 6 6 4 - 7 3 .
• 6 2 . Klingler W, Kreja L, Nothdurft W, Selig C. Influence of different radioprotective compounds on radiotolerance and cell cycle distribution of human progenitor cells of granulocytopoiesis in vitro. Br J Haematol 2 0 0 2 ; 11 9 ( 1 ) : 2 4 4 - 5 4 .