Hasan Gazi UYAR, Aysegül BAYIR, Hasan KARA, Pınar KARABAĞLI, Abdullah SİVRİKAYA, Ali UNLU

Tavşanlarda Yapılan Asetaminofen Toksikoloji Modelinde N-Asetilsistein ve Resveratrol Tedavilerinin Karşılaştırılması

Amaç: Asetaminofen güvenli bir analjezik ilaçtır fakat yüksek dozlarda akut karaciğer hasarına neden olmaktadır. Asetaminofen intoksikasyonunda tedavisinde N-asetil sistein (NAC) kullanılmaktadır. Resveratrolun (RES), asetaminofen intoksikasyonu modellerinde kullanılabileceği gösterilmiştir. Çalışmamızda amaç, asetaminofen intoksikasyonunda NAC ile resveratrol tedavilerinin etkinliğinin karşılaştırmaktır.Araçlar ve Yöntem: Çalışmamızda 6’sı kontrol grubunda olmak üzere, 28’ i 4 farklı çalışma grubunda olmak üzere toplam 34 tavşan kullanıldı. Asetaminofen (APAP) (n=7) grubunda hayvanlara 2 gr/kg asetaminofen orogastrik tüp aracılığıyla verildi. Asetaminofen+N-asetilsistein (APAP+NAC) (N=7) grubunda hayvanlara 2 gr/kg asetaminofen orogastrik tüp aracılığıyla verildi ve takibinin 1. saatinde 150 mg/kg NAC intramüsküler (i.m) uygulandı. Asetaminofen+resveratrol (APAP+RES) (N=7) grubunda hayvanlara 2 gr/kg asetaminofen orogastrik tüp aracılığıyla verildi ve takibinin 1. saatinde orogastrik tüple 100 mg/kg resveratrol verildi. Asetaminofen+Nasetilsistein+Resveratrol (APAP+NAC+RES) (N=7) grubunda ise hayvanlara 2 gr/kg asetaminofen oro-gastrik tüp aracılığıyla verildi ve takibinin 1. saatinde orogastrik tüple 100 mg/kg resveratrol verildi ve 150 mg/kg NAC i.m uygulandı. ALT, AST, total GSH ve kan asetaminofen düzeyleri çalışıldı. Hayvanlar 24. saatte sakrifiye edildi. Karaciğer dokusu histopatolojik inceleme için kullanıldı.Bulgular: Sonuçlarımızda 12 saat GSH düzeyi APAP+NAC grubunda APAP+RES grubuna göre istatiksel olarak anlamlı bulundu (p=0.007). Histopatolojik çalışmada, apoptozis için kullandığımız HSCORE düzeyi kontrol grubunda APAP grubuna göre istat-iksel olarak daha düşük tespit edildi (p=0.007). Bu sonuç asetaminofen toksisisitesi karaciğer hücrelerinde apoptozisi tetiklediğini gösteriyor.Sonuç: Resveratrol asetaminofen toksisitesi tedavisinde NAC’a alternatif bir tedavi seçeneği olabilir.

Anahtar Kelimeler:

Asetamınofen, parasetamol, NAC, Toksisite, Resveratrol

Comparison of N-Acetyl Cysteine and Resveratrol Treatments in Acetaminophen Toxicity Model in Rabbits

Purpose: Acetaminophen is safe analgesic drug but it may cause hepatic failure in high doses. N-acetyl cysteine (NAC) is used in the treatment of acetaminophen intoxication. Resveratrol may be used in experimental acetaminophen intoxication models. Purpose, compare the efficacy of NAC and resveratrol treatments in acetaminophen intoxication.Materials and Methods: We used 34 rabbits. Six rabbits were included in control group, and 7 rabbits were enrolled in other groups Asetaminophen (APAP) (N=7) group. The animals were administered 2 g/kg of acetaminophen by an orogastric tube. Asetaminophen+N-acetylcysteine (APAP+NAC) (N=7) group, 150 mg/kg NAC was administered intramuscular (i.m) to animals at 1st hour following 2 g/kg of acetaminophen administration by orogastric tube. Asetaminophen+resveratrol (APAP+RES) (N=7) group, animals received 100 mg/kg resveratrol by orogastric tube at 1st hour following oral administration of 2 g/kg of acetaminophen by orogastric tube. e. Asetaminophen+N-acetyl cysteine+resveratrol (APAP+NAC + RES) (N=7) group, animals received 100 mg/kg resveratrol by orogastric tube and 150 mg/kg NAC i.m at 1st hour following oral administration of 2 g/kg of acetaminophen by orogastric tube. ALT, AST, GSH, and acetaminophen levels were measured. Animals were sacrificed at the 24th hour. Liver samples were obtained for histopathological examination.Results: According to our results, the GSH level at 12th hour was significantly different between APAP+NAC group and APAP+RES group (p=0.007). In histopathological examination, HSCORE level we used for apoptosis was statistically significantly lower in control group than in APAP group (p=0.007). Its supports that acetaminophen toxicity triggers apoptosis in liver cells.Conclusion: Resveratrol may be an alternative treatment option to NAC in the treatment of acetaminophen toxicity.

Keywords:

Resveratrol, Acetaminophen, paracetamol, NAC, Toxicity,

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1. Bessems JG, Vermeulen NP. Paracetamol (acetaminophen) induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches. Crit. Rev. Toxicol. 2001;31(1):55-138.
2. Bonkovsky HL, Kane RE, Jones DP, Galinsky RE, Banner B. Acute hepatic and renal toxicity from low doses of acetaminophen in the absence of alcohol abuse or malnutrition: evidence for increased susceptibility to drug toxicity due to cardiopulmonary and renal insufficiency. Hepatology. 1994;19(5):1141-1148.
3. De La Lastra CA, Villegas I. Resveratrol as an antioxidant and pro-oxidant agent: mechanısms and clinical implications Biochem Soc Trans. 2007;35(5):1156-1160.
4. Dernek S, İkizler M, Erkasap N, et al. Cardioprotection with resveratrol pretreatment: improved beneficial effects over Standard treatment in rat hearts after global ischemia. Scand Cardıovasc J. 2004;38(4):245-254.
5. Robb EL, Page MM, Wiens BE, Stuart JA. Moleculer mechanısms of oxidative stress resistance induced by resveratrol: Specıfıc and progressive induction of MnSOD. Biochem Biophys Res Commun. 2008;367 (2):406-412.
6. Baur JA, Pearson KJ, Price NL, et al. 2006. Resveratrol improves health and survival of mice on a highcalorie diet. Na-ture. 2006;444(7117):337-342.
7. Lagouge M, Argmann C, Gerhart-Hines Z, et al. 2006. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006;127(6):1109-1122.
8. Saiko P, Szakmary A, Jaeger W, et al. Resveratrol and its analog: defense against cancer, coronary disease and neurodegerative maladies or just a fad? Mutat Res. 2008;658(1-2):68-94.
9. Mann CD, Neal CP, Garcea G, et al. Phytochemicals as potential chemopreventive and chemotherapeutic agents in hepatocarcinogenesis. Eur J Cancer Prev. 2009;18(1):13-25.
10. Muriel P. NF-kB in liver diseases: a target for drug therapy. J Appl Toxicol. 2009;29(2):91-100.
11. Pendurthi UR, Williams JT, Rao LV. Resveratrol, a polyphenolic compound found in wine, inhibits tissue facto rexpression in vascular cells: a possible mechanism for the cardiovascular benefits associated with moderate consumption of wine. Arterioscler Thromb Vasc Biol. 1999;19(2):419-426.
12. Kuo D, Mitchell R, McGill Yuchao X, Mary LB, Hartmut J. Resveratrol prevents protein nitration and release of endonuclease from mitochondria during acetaminophen hepatotoxicity. Food Chem. Toxicol. 2015;81:62-70.
13. Wojnarova L, Kutinova N, Farghali H, Kucera T. Sirtuin. 1 Modulation in Rat Model of Acetaminophen-Induced Hepa-totoxicity. Physiol. Res. 2015;64 (4):477-487.
14. Bishayee A, Darvesh AS, Politis T, McGory R. Resveratrol and liver disease: from bench to bedside and community. Liver Int. 2010;30(8):1103-1114.
15. Wang Z, JiangY, Fan X, et al. Hepatoprotective effect of resveratrol against acetaminophen-induced liver injury is asso-ciated with inhibition of CYP-mediated bioactivation and regulation of SIRT-p53 signaling pathways. Toxicol Lett. 2015;236(2):82-89.
16. Farghali H, Kutinova Canova N, Lekic N. Resveratrol and related compounds as antioxidants with an allosteric mechanism of action in epigenetic drug targets. Physiol Res. 2013;62(1):1-13.
17. Černy D, Kutınova Canova N, Martinek J, et al. Effects of resveratrol pretreatment on tertbutylhydroperoxide induced hepatocytetoxicity in immobilized perifused hepatocytes: Involvement of inducible nitricoxidesynthase and hemoxygenase-1. Nitric Oxide. 2009;20(1):1-8.
18. Sener G, Toklu HZ, Sehirli AO, Velioglu-Oğunc A, Cetinel S, Gedik N. Protective effects of resveratrol against acetaminophen-induced toxicity in mice. Hepatol. Res. 2006;35(1):62-68.
19. Masubuchi Y, Suda C, Horie T. Involvement of mitochondria permeability transition in acetaminophen-induced liver injury in mice. J. Hepatol. 2005;42(1):110-116.
20. Wadsworth TL, Koop DR, Effects of the wine polyphenolics quercetin and resveratrol on proinflammatory cytokine expression in RAW 264.7 macrophages. Biochem Pharmacol. 1999;57(8):941-949.
21. Elbe H, Gul M, Çetin A, et al. Resveratrol reduces light and electron microscopic changes in acetaminophen-induced hepatotoxicity in rats: Role of Inos expression. Ultrastruct. Pathol. 2018;42(1):39-48.