Resveratrol abrogates 5-flourouracil -induced hepatotoxicity: A preclinical study

Document Type: Original Article

Authors

1 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Nigeria

2 Department of Biochemistry, Faculty of Science, Madonna University Nigeria

10.30476/tips.2021.87868.1065

Abstract

The manifestation of acute hepatotoxicity caused by 5-fluorouracil could be characterized by asymptomatic elevations of liver enzymes, hepatic steatosis and fuminant hepatitis. Natural antioxidants have potential as excellent treatment strategy against diseases and drug-induced toxicities. This study assessed the potential of resveratrol (RSV) to abrogate the hepatotoxic effect of 5-FU in rats. Forty adult male albino rats (240g± 20g) were randomized and orally supplemented with RSV (10, 20 and 40 mg/kg/day) prior to the administration of 5-FU (20mg/kg/day) intraperitoneally for 5 days. On day 6, after weighing, the rats were anesthetized, blood samples were collected and centrifuged and sera obtianed. Liver tissues were harvested and weighed. Sera and liver samples were evaluated for biochemical parameters. Liver tissues were assessed for histology. Body weight was significantly (p <0.05) decreased where as liver weight was significantly (p <0.01) increased in 5-FU administered rats in relation to control. Serum and liver lactate dehydrogenase, aminotransferases (AST), alkaline phosphatase, gamma-glutamyl transferase, total bilirubin, conjugated bilirubin and malondialdehyde levels were significantly (p <0.001) increased in 5FU-administered rats in relation to control. Liver glutathione peroxidase, catalase, glutathione and superoxide dismutase levels were significantly (p <0.001) decreased in 5-FU administered rats in relation to control. The liver of 5-FU administered rats showed necrosis and steatosis. The hepatotoxic effect of 5-FU was abrogated in a dose-related fashion in RSV 10 mg/kg (p <0.05), 20mg/kg (p <0.01), and RSV 40mg/kg (p <0.001) supplemented rats in relation to 5-FU. RVS may be clinically effective against 5-FU-induced hepatotoxicity.

Keywords


1. Yousef HN, Aboelwafa HR. The potential protective role of taurine against 5-fluorouracil-induced nephrotoxicity in adult male rats. Exp Toxicol Pathol. 2017 Jun 14;69(5):265-274. doi: 10.1016/j.etp.2017.01.012. Epub 2017 Feb 8. PMID: 28189472.
2. Nadia R.A. Abou-Zeid. Ameliorative effect of vitamin C against 5-fuorouracil-induced hepatotoxicity in mice: A light and electron microscope study. J Basic Appl Zool. 2014;67:109-18
3. Focaccetti C, Bruno A, Magnani E, Bartolini D, Principi E, Dallaglio K, Bucci EO, Finzi G, Sessa F, Noonan DM, Albini A. Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes. PLoS One. 2015 Feb 11;10(2):e0115686. doi: 10.1371/journal.pone.0115686. PMID: 25671635; PMCID: PMC4324934.
4. Hajj A, Ghosn M, Mourad D, Hojaiban K, Mousallem P, Khabbaz LR. Lethal hepatotoxicity following 5-fluorouracil/cisplatin chemotherapy: a relevant case report. Per Med. 2017 May;14(3):197-201. doi: 10.2217/pme-2016-0085. Epub 2017 May 5. PMID: 29767581.
5. Fukuno S, Nagai K, Yoshida S, Suzuki H, Konishi H. Taurine as a protective agent for 5-fluorouracil-induced hepatic damage related to oxidative stress. Pharmazie. 2016 Sep 1;71(9):530-532. doi: 10.1691/ph.2016.6611. PMID: 29441849.
6. Ray S, Roy K, Sengupta C. In vitro evaluation of protective effects of ascorbic acid and water extract of Spirulina plantesis (blue green algae) on 5-fluorouracil-induced lipid peroxidation. Acta Pol Pharm. 2007 Jul-Aug;64(4):335-44. PMID: 18536159.
7. Gerszon J, Rodacka A, Puchała M. Antioxidant properties of resveratrol and its protective effects in neurodegenerative diseases. Med J Cell Biol. 2014;4:97-117.
8. Beauloye C, Bertrand L, Horman S, Hue L. AMPK activation, a preventive therapeutic target in the transition from cardiac injury to heart failure. Cardiovasc Res. 2011 May 1;90(2):224-33. doi: 10.1093/cvr/cvr034. Epub 2011 Feb 1. PMID: 21285292.
9. Liu FC, Tsai YF, Tsai HI, Yu HP. Anti-Inflammatory and Organ-Protective Effects of Resveratrol in Trauma-Hemorrhagic Injury. Mediators Inflamm. 2015;2015:643763. doi: 10.1155/2015/643763. Epub 2015 Jul 26. PMID: 26273141; PMCID: PMC4529946.
10. Švajger U, Jeras M. Anti-inflammatory effects of resveratrol and its potential use in therapy of immune-mediated diseases. Int Rev Immunol. 2012 Jun;31(3):202-22. doi: 10.3109/08830185.2012.665108. PMID: 22587021.
11. Xia N, Daiber A, Förstermann U, Li H. Antioxidant effects of resveratrol in the cardiovascular system. Br J Pharmacol. 2017;174(12):1633-1646. doi:10.1111/bph.13492
12. Singh D, Cho WC, Upadhyay G. Drug-Induced Liver Toxicity and Prevention by Herbal Antioxidants: An Overview. Front Physiol. 2016 Jan 26;6:363. doi: 10.3389/fphys.2015.00363. PMID: 26858648; PMCID: PMC4726750.
13. Radwan OK, Ahmed RF. Amendment effect of resveratrol on diclofenac idiosyncratic toxicity: Augmentation of the anti-inflammatory effect by assessment of Arachidonic acid and IL-1β levels. J App Pharm Sci. 2016;6(12):170-7.
14. Gelen V, Şengül E, Yıldırım S, Atila G. The protective effects of naringin against 5-fluorouracil-induced hepatotoxicity and nephrotoxicity in rats. Iran J Basic Med Sci. 2018 Apr;21(4):404-410. doi: 10.22038/IJBMS.2018.27510.6714. PMID: 29796225; PMCID: PMC5960758.
15. Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol. 1978;52:302-10. doi: 10.1016/s0076-6879(78)52032-6. PMID: 672633.
16. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem. 1968 Oct 24;25(1):192-205. doi: 10.1016/0003-2697(68)90092-4. PMID: 4973948.
17. Sun M, Zigman S. An improved spectrophotometric assay for superoxide dismutase based on epinephrine autoxidation. Anal Biochem. 1978 Oct 1;90(1):81-9. doi: 10.1016/0003-2697(78)90010-6. PMID: 727489.
18. Aebi H. Catalase in vitro. Methods Enzymol. 1984;105:121-6. doi: 10.1016/s0076-6879(84)05016-3. PMID: 6727660.
19. Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: biochemical role as a component of glutathione peroxidase. Science. 1973 Feb 9;179(4073):588-90. doi: 10.1126/science.179.4073.588. PMID: 4686466.
20. El-Hoseany NMA. Protective effect of captopril against 5-fluorouracil-induced hepato and nephrotoxicity in male albino rats. J Am Sci. 2013;8:680-685
21. Thriveni V, Manjunatha H, Santhosh KH. Hepatoprotective Effect of Curcumin and Capsaicin against Lipopolysaccharide Induced Liver Damage in Mice. Pharmacog J. 2017;9(6):947-51.
22. Adikwu E, Nelson EC, Fiyebo P. Selenium as a therapeutic adjuvant for isoniazid/rifampicin‑induced hepatotoxicity. BLDE Univ J Health Sci. 2020;5:60-7.
23. Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology. 2014 Sep;147(3):577-594.e1. doi: 10.1053/j.gastro.2014.06.043. Epub 2014 Jul 25. PMID: 25066692.
24. Dimitriu D, Lupusoru C, Cojocaru I, Gafitanu C, Palade L, Lupusoru R. Assessing biochemical andoxidative stress parameters after vaginal and oral administration of 5-fluorouracil in laboratory animals. Farmacia. 2015;63:230-3.
25. Adikwu E, Braimbaifa N, Obianime AW. Melatonin and Alpha Lipoic Acid: Possible Mitigants for Lopinavir/Ritonavir- Induced Renal Toxicity in Male Albino Rats. Physiol Pharmacol. 2016;19:232-40.
26. Behling EB, Sendão MC, Francescato HD, Antunes LM, Costa RS, Bianchi Mde L. Comparative study of multiple dosage of quercetin against cisplatin-induced nephrotoxicity and oxidative stress in rat kidneys. Pharmacol Rep. 2006 Jul-Aug;58(4):526-32. PMID: 16963799.
27. Grotto D, Maria SL, Valentini J, Paniz C, Schmitt G, Garcia SC. Importance of the lipid peroxidation biomarkers and methodological aspects FOR malondialdehyde quantification. Quím. Nova. 2009;32(1):169-174.
28. El-Sayyad HI, Ismail MF, Shalaby FM, et al. Histopathological effects of cisplatin, doxorubicin and 5-flurouracil (5-FU) on the liver of male albino rats. Int J Biol Sci. 2009;5(5):466-473. Published 2009 Jun 28. doi:10.7150/ijbs.5.466
29. Gelen V, Şengül E, Gedikli S, Atila G, Uslu H, Makav M. The protective effect of rutin and quercetin on 5-FU-induced hepatotoxicity in rats. Asian Pac J Trop Biomed. 2017;7:647–653.
30. Al-Asmari AK, Khan AQ, Al-Masri N. Mitigation of 5-fluorouracil-induced liver damage in rats by vitamin C via targeting redox-sensitive transcription factors. Hum Exp Toxicol. 2016 Nov;35(11):1203-1213. doi: 10.1177/0960327115626583. Epub 2016 Jul 11. PMID: 26921358.
31. Almroth BC, Sturve J, Berglund A, Förlin L. Oxidative damage in eelpout (Zoarces viviparus), measured as protein carbonyls and TBARS, as biomarkers. Aquat Toxicol. 2005 Jun 15;73(2):171-80. doi: 10.1016/j.aquatox.2005.03.007. Epub 2005 Apr 13. PMID: 15917092.
32. Afolabi OK, Adeleke GE, Ugbaja RN. Crocin Alleviates 5-Fluorouracil-induced Hepatotoxicity through the abrogation of Oxidative Stress in Male Wistar rats. Asian Pac J Health Sci. 2016;3(2):58-68
33. Cordova-Gomez M, Galano A, Raul J, Alvarez-Idaboy JR. Piceatannol, a better peroxyl radical scavenger than resveratrol. RSC Adv. 2013;3:20209-20218
34. Kavas GO, Ayral PA, Elhan AH. The effects of resveratrol on oxidant/antioxidant systems and their cofactors in rats. Adv Clin Exp Med. 2013 Mar-Apr;22(2):151-5. PMID: 23709370.
35. KKincaid B, Bossy-Wetzel E. Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration. Front Aging Neurosci. 2013;5:48. Published 2013 Sep 6. doi:10.3389/fnagi.2013.00048
36. Robb EL, Page MM, Wiens BE, Stuart JA. Molecular mechanisms of oxidative stress resistance induced by resveratrol: Specific and progressive induction of MnSOD. Biochem Biophys Res Commun. 2008 Mar 7;367(2):406-12. doi: 10.1016/j.bbrc.2007.12.138. Epub 2007 Dec 31. PMID: 18167310.
37. Tadolini B, Juliano C, Piu L, Franconi F, Cabrini L. Resveratrol inhibition of lipid peroxidation. Free Radic Res. 2000 Jul;33(1):105-14. doi: 10.1080/10715760000300661. PMID: 10826926.