Hüseyin Avni EROĞLU, Mustafa MAKAV, YASEMEN ADALI, MEHMET ÇİTİL

Effects of Ozone and L-Carnitine on Kidney MDA, GSH, and GSHPx Levels in Acetaminophen Toxicity

This study aimed to determine the therapeutic effcts of medical ozone and L-carnitine therapy on acetaminophen (APAP)-induced kidney damage by evaluating malondialdehyde (MDA), glutathione (GSH), and GSHPx levels. In this study, 56 rats were randomized into 8 groups with 7 rats in each group. Kidney injury was induced by the administration of a single dose N-acetyl-p-aminophenol (1 g/kg) orally. Therapeutic ozone (0.7 mg/kg) and L-carnitine (500 mg/kg) were administered intraperitoneally. After the therapy, the rat kidneys were homogenized, and the tissue MDA, GSH, and GSHPx levels were measured. Compared to the control groups, there were higher MDA levels in the kidney tissues only in the “APAP,” “APAP + Ozone,” and “APAP + Ozone + L-carnitine” groups (P

Asetaminofen Toksisitesinde Ozon ve L-Karnitinin Böbrek MDA, GSH ve GSHPx Düzeylerine Etkisi

Bu çalışmada, malondialdehit (MDA), glutatyon (GSH) ve GSHPx seviyelerini değerlendirerek tıbbi ozonve L-Karnitin tedavisinin asetaminofen (APAP) kaynaklı böbrek hasarı üzerindeki terapötik etkilerinin belirlenmesi amaçlanmıştır. Çalışmada 56 adet rat her bir grupta 7 tane olmak üzere toplam 8 gruba ayrılmıştır. Böbrek hasarı N-acetyl-p-aminopenol’ün (1 g/kg) oral yolla tek doz uygulamasıyla oluşturulmuştur. Terapotik olarak kullanılan ozon (0.7 mg/kg) ve L-karnitine (500 mg/kg) intraperitoneal yolla uygulanmıştır. Daha sonra ratların böbrekleri homojenize edilerek doku MDA, GSH ve GSHPx değerleri ölçülmüştür. Çalışma gruplarında böbrek dokusu MDA düzeylerinin yalnızca APAP, APAP + Ozon ve APAP + Ozon + L-karnitin uygulanan gruplardaki artışlarının kontrol amaçlı kullanılan tüm gruplara göre istatistiksel olarak anlamlı (P

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1. Jung KY, Kim T, Hwang SY, Yoon H, Shin TG, Sim MS, Jo IJ, Cha WC: Availabilityof drug at convenient stores is not associated with an increased incidence of their poisoning. Pharmacoepidemiol Drug Saf, 28 (4): 536-543, 2019. DOI: 10.1002/pds.4760

2. Hussain Z, Khan JA, Arshad A, Asif P, Rashid H, Arshad MI: Protective effects of Cinnamomum zeylanicum L. (Darchini) in acetaminopheninduced oxidative stress, hepatotoxicity and nephrotoxicity in mouse model. Biomed Pharmacother, 109, 2285-2292, 2019. DOI: 10.1016/j. biopha.2018.11.123

3. Yan M, Huo Y, Yin S, Hu H: Mechanisms of acetaminophen-induced liver injuryand its implications for therapeutic interventions. Redox Biol, 17, 274-283, 2018. DOI: 10.1016/j.redox.2018.04.019

4. David Josephy P: The molecular toxicology of acetaminophen. Drug Metab Rev, 37 (4): 581-594, 2005. DOI: 10.1080/03602530500205200

5. Bessems JGM, Vermeulen NPE: Paracetamol (acetaminophen)- induced toxicity: Molecular and biochemical mechanisms, analogues and protective approaches. Crit Rev Toxicol, 31 (1): 55-138, 2001. DOI: 10.1080/20014091111677

6. Mazer M, Perrone J: Acetaminophen-induced nephrotoxicity: Pathophysiology, clinical manifestations, and management. J Med Toxicol, 4 (1): 2-6, 2008. DOI: 10.1007/BF03160941

7. Ucar F, Taslipinar MY, Alp BF, Aydin I, Aydin FN, Agilli M, Toygar M, Ozkan E, Macit E, Oztosun M, Cayci T, Ozcan A: The effects of N-acetylcysteine and ozone therapy on oxidative stress and inflmmation in acetaminophen-induced nephrotoxicity model. Ren Fail, 35 (5): 640- 647, 2013. DOI: 10.3109/0886022X.2013.780530

8. Marrocco I, Altieri F, Peluso I: Measurement and clinical significance of biomarkers of oxidative stress in humans. Oxid Med Cell Longev, 2017:6501046, 2017. DOI: 10.1155/2017/6501046

9. Ayala A, Muñoz MF, Argüelles S: Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev, 2014:360438, 2014. DOI: 10.1155/2014/360438

10. Shadyro O, Lisovskaya A: ROS-induced lipid transformations without oxygen participation. Chem Phys Lipids, 221, 176-183, 2019. DOI: 10.1016/j.chemphyslip.2019.03.013

11. Lei XG, Zhu JH, Cheng WH, Bao Y, Ho YS, Reddi AR, Holmgren A, Arnér ES: Paradoxical roles of antioxidant enzymes: Basic mechanisms and health implications. Physiol Rev, 96 (1): 307-364, 2016. DOI: 10.1152/ physrev.00010.2014

12. Liu YH, Huang QH, Wu X, Wu JZ, Liang JL, Lin GS, Xu LQ, Lai XP, Su ZR, Chen JN: Polydatin protects against acetaminophen-induced hepatotoxicity in mice via anti-oxidative and anti-apoptotic activities. Food Funct, 9 (11): 5891-5902, 2018. DOI: 10.1039/c8fo01078a

13. Blumberg J: Use of biomarkers of oxidative stress in research studies. J Nutr, 134 (11): 3188S-3189S, 2004. DOI: 10.1093/jn/134.11.3188S

14. Brass EP: Supplemental carnitine and exercise. Am J Clin Nutr, 72 (Suppl. 2): 618S-623S, 2000. DOI: 10.1093/ajcn/72.2.618S

15. Abu-El-Zahab HSH, Hamza RZ, Montaser MM, El-Mahdi MM, AlHarthi WA: Antioxidant, antiapoptotic, antigenotoxic, and hepatic ameliorative effcts of L-carnitine and selenium on cadmium-induced hepatotoxicity and alterations in liver cell structure in male mice. Ecotoxicol Environ Saf, 173, 419-428, 2019. DOI: 10.1016/j.ecoenv.2019.02.041

16. Al-Eisa RA, Al-Salmi FA, Hamza RZ, El-Shenawy NS: Role of L-carnitine in protection against the cardiac oxidative stress induced by aspartame in Wistar albino rats. PLoS One, 13 (11): e0204913, 2018. DOI: 10.1371/journal.pone.0204913

17. Yapar K, Kart A, Karapehlivan M, Atakisi O, Tunca R, Erginsoy S, Citil M: Hepatoprotective effct of L-carnitine against acute acetaminophen toxicity in mice. Exp Toxicol Pathol, 59 (2): 121-128, 2007. DOI: 10.1016/j. etp.2007.02.009

18. Zanardi I, Borrelli E, Valacchi G, Travagli V, Bocci V: Ozone: A multifaceted molecule with unexpected therapeutic activity. Curr Med Chem, 23 (4): 304-314, 2016. DOI: 10.2174/0929867323666151221150420

19. Re L, Mawsouf MN, Menéndez S, León OS, Sánchez GM, Hernández F: Ozone therapy: Clinical and basic evidence of its therapeutic potential. Arch Med Res, 39 (1): 17-26, 2008. DOI: 10.1016/j.arcmed. 2007.07.005

20. Ajamieh H, Merino N, Candelario-Jalil E, Menéndez S, MartinezSanchez G, Re L, Giuliani A, Leon OS: Similar protective effect of ischaemic and ozone oxidative preconditionings in liver ischaemia/ reperfusion injury. Pharmacol Res, 45 (4): 333-339, 2002. DOI: 10.1006/ phrs.2002.0952

21. Uysal B, Yasar M, Ersoz N, Coskun O, Kilic A, Cayc T, Kurt B, Oter S, Korkmaz A, Guven A: Efficacy of hyperbaric oxygen therapy and medical ozone therapy in experimental acute necrotizing pancreatitis. Pancreas, 39 (1): 9-15, 2010. DOI: 10.1097/MPA.0b013e3181bb5ae3

22. Guven A, Gundogdu G, Vurucu S, Uysal B, Oztas E, Ozturk H, Korkmaz A: Medical ozone therapy reduces oxidative stress and intestinal damage in an experimental model of necrotizing enterocolitis in neonatal rats. J Pediatr Surg, 44 (9): 1730-1735, 2009. DOI: 10.1016/j. jpedsurg.2009.01.007

23. Bocci V: Is it true that ozone is always toxic? The end of a dogma. Toxicol Appl Pharmacol, 216 (3): 493-504, 2006. DOI: 10.1016/j. taap.2006.06.009

24. Bocci VA: Scientific and medical aspects of ozone therapy. State of the art. Arch Med Res, 37 (4): 425-435, 2006. DOI: 10.1016/j. arcmed.2005.08.006

25. Demirbag S, Uysal B, Guven A, Cayci T, Ozler M, Ozcan A, Kaldirim U, Surer I, Korkmaz A: Effcts of medical ozone therapy on acetaminophen-induced nephrotoxicity in rats. Ren Fail, 32 (4): 493-497, 2010. DOI: 10.3109/08860221003646352

26. Gul H, Uysal B, Cakir E, Yaman H, Macit E, Yildirim AO, Eyi YE, Kaldirim U, Oztas E, Akgul EO, Cayci T, Ozler M, Topal T, Oter S, Korkmaz A, Toygar M, Demirbag S: The protective effects of ozone therapy in a rat model of acetaminophen-induced liver injury. Environ Toxicol Pharmacol, 34 (1): 81-86, 2012. DOI: 10.1016/j.etap.2012.02.006

27. Özgün E, Sayılan Özgün G, Eskiocak S, Yalçın Ö, Süer Gökmen S: Deneysel kolitte L-karnitinin serum paraoksonaz, arilesteraz ve laktonaz aktivitelerine ve oksidatif duruma etkisi. Turk J Biochem, 38 (2): 145-153, 2013.

28. Beutler E, Duron O, Kelly BM: Improved method for the determination of blood glutathione. J Lab Clin Med, 61, 882-888, 1963.

29. Yoshioka T, Kawada K, Shimada T, Mori M: Lipid peroxidation in maternal and cord blood and protective mechanism against activatedoxygen toxicity in the blood. Am J Obstet Gynecol, 135 (3): 372-376, 1979. DOI: 10.1016/0002-9378(79)90708-7

30. Tsikas D: Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: Analytical and biological challenges. Anal Biochem, 524, 13-30, 2017. DOI: 10.1016/j. ab.2016.10.021

31. El-Demerdash FM, Yousef MI, Radwan FME: Ameliorating effct of curcumin on sodium arsenite-induced oxidative damage and lipid peroxidation in diffrent rat organs. Food Chem Toxicol, 47 (1): 249-254, 2009. DOI: 10.1016/j.fct.2008.11.013

32. Reis R, Charehsaz M, Sipahi H, Doğan Ekici AI, Macit Ç, Akkaya H, Aydın A: Energy drink induced lipid peroxidation and oxidative damage in rat liver and brain when used alone or combined with alcohol. J Food Sci, 82 (4): 1037-1043, 2017. DOI: 10.1111/1750-3841.13662

33. Wu MM, Chiou HY, Wang TW, Hsueh YM, Wang IH, Chen CJ, Lee TC: Association of blood arsenic levels with increased reactive oxidants and decreased antioxidant capacity in a human population of northeastern Taiwan. Environ Health Perspect, 109 (10): 1011-1017, 2001. DOI: 10.1289/ ehp.011091011

34. Sepand MR, Razavi-Azarkhiavi K, Omidi A, Zirak MR, Sabzevari S, Kazemi AR, Sabzevari O: Effct of acetyl-l-carnitine on antioxidant status, lipid peroxidation, and oxidative damage of arsenic in rat. Biol Trace Elem Res, 171 (1): 107-115, 2016. DOI: 10.1007/s12011-015-0436-y

35. Barhwal K, Hota SK, Jain V, Prasad D, Singh SB, Ilavazhagan G: Acetyl-l-carnitine (ALCAR) prevents hypobaric hypoxia-induced spatial memory impairment through extracellular related kinase-mediated nuclear factor erythroid 2-related factor 2 phosphorylation. Neuroscience, 161 (2): 501-514, 2009. DOI: 10.1016/j.neuroscience.2009.02.086

36. Karalija A, Novikova LN, Kingham PJ, Wiberg M, Novikov LN: Neuroprotective effcts of N-acetyl-cysteine and acetyl-L-carnitine after spinal cord injury in adult rats. PLoS One, 7 (7): e41086, 2012. DOI: 10.1371/ journal.pone.0041086

37. Liu J, Li C, Qu W, Leslie E, Bonifant CL, Buzard GS, Saavedra JE, Keefer LK, Waalkes MP: Nitric oxide prodrugs and metallochemotherapeutics: JS-K and CB-3-100 enhance arsenic and cisplatin cytolethality by increasing cellular accumulation. Mol Cancer Ther, 3 (6): 709-714, 2004.

38. Sayed-Ahmed MM, Eissa MA, Kenawy SA, Mostafa N, Calvani M, Osman AM: Progression of cisplatin-induced nephrotoxicity in a carnitine-depleted rat model. Chemotherapy, 50 (4): 162-170, 2004. DOI: 10.1159/000080689

39. Virmani A, Gaetani F, Imam S, Binienda Z, Ali S: The protective role of L-carnitine against neurotoxicity evoked by drug of abuse, methamphetamine, could be related to mitochondrial dysfunction. Ann N Y Acad Sci, 965, 225-232, 2002. DOI: 10.1111/j.1749-6632.2002. tb04164.x

40. Dhibi S, Mbarki S, Elfeki A, Hfaiedh N: Eucalyptus globulus extract protects upon acetaminophen-induced kidney damages in male rat. Bosn J Basic Med Sci, 14 (2): 99-104, 2014. DOI: 10.17305/bjbms.2014.2272

41. Ilbey YO, Ozbek E, Cekmen M, Somay A, Ozcan L, Otünctemur A, Simsek A, Mete F: Melatonin prevents acetaminophen-induced nephrotoxicity in rats. Int Urol Nephrol, 41 (3): 695-702, 2009. DOI: 10.1007/ s11255-008-9503-z

42. Ito T, Watanabe S, Tsuruga K, Aizawa T, Hirono K, Ito E, Joh K, Tanaka H: Severe intrinsic acute kidney injury associated with therapeutic doses of acetaminophen. Pediatr Int, 57 (2): e53-e55, 2015.DOI: 10.1111/ ped.12607

43. Ozturk O, Eroglu HA, Ustebay S, Kuzucu M, Adali Y: An experimental study on the preventive effcts of N-acetyl cysteine and ozone treatment against contrast-induced nephropathy. Acta Cir Bras, 33 (6): 508-517, 2018. DOI: 10.1590/s0102-865020180060000005