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The role of resveratrol in hepatotoxicity caused by methotrexate

Year 2021, Volume: 6 Issue: 2, 57 - 63, 31.08.2021
https://doi.org/10.24880/maeuvfd.922106

Abstract

Methotrexate is an immunosuppressive and antineoplastic drug that may induce hepatotoxicity. Resveratrol is a compound that has a protective effect thanks to its antioxidant role. In present study was aimed to investigate posibble protective effects of resveratrol in methotrexate induced hepatotoxicity. Eighteen Wistar Albino rats were equally divided into three groups: Control, Methotrexate, Methotrexate + Resveratrol. After a single dose of methotrexate (15 mg/kg, i.p.), resveratrol (10 mg/kg, orally) was applied for 7 days. Fallowing 7 days, rats were sacrificed. Histopathological (H-E staining), immunohistochemical (Tumor Necrosis Factor Alpha, inducible Nitric Oxide Synthases, Nuclear Factor Kappa) and biochemical (Total Oxidant Status, Total antioxidants Status and Oxidative Stress Index) analyses were assayed in liver tissue samples. Additionally, Aspartate Aminotransferase, Alanine Aminotransferase, Gamma Glutamyl Transferase and Total Biluribin activities were assayed in serum samples for biochemical analyses. Normal liver tissues were observed in control groups. Histopatholocigal changes, high staining of Tumor Necrosis Factor Alpha, inducible Nitric Oxide Synthases, Nuclear Factor Kappa, increasing levels of tissue Total Oxidant Status, Oxidative Stress Index and decreasing levels of tissue Total antioxidants Status were observed in methotrexate groups. Moreover, Aspartate Aminotransferase, Alanine Aminotransferase, Gamma Glutamyl Transferase and Total Biluribin levels increased in methotrexate groups too (p<0.05). However, these findings were lower in the Methotrexate + Resveratrol groups (p<0.05). In this study were observed that oxidant levels could increase after methotrexate applied in the liver, whereas resveratrol alleviated effects of hepatotoxicity by histopathological, immunohistochemical and biochemical analyses. However, molecular studies are needed to clearly understand mechanism of resveratrol.

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References

  • Referans1 Tunali-Akbay T, Sehirli O, Ercan F, Sener G. Resveratrol protects against methotrexate-induced hepatic injury in rats. Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques. 2010;13(2):303-10.
  • Referans2 harma S, Baboota S, Amin S, Mir SR. Ameliorative effect of a standardized polyherbal combination in methotrexate-induced nephrotoxicity in the rat. Pharmaceutical biology. 2020;58(1):184-99. Referans3 Ebrahimi R, Sepand MR, Seyednejad SA, Omidi A, Akbariani M, Gholami M, et al. Ellagic acid reduces methotrexate-induced apoptosis and mitochondrial dysfunction via up-regulating Nrf2 expression and inhibiting the IĸBα/NFĸB in rats. Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences. 2019;27(2):721-33.
  • Referans4 Hasan H, Ismail H, El-Orfali Y, Khawaja G. Therapeutic benefits of Indole-3-Carbinol in adjuvant-induced arthritis and its protective effect against methotrexate induced-hepatic toxicity. BMC Complement Altern Med. 2018;18(1):337.
  • Referans5 Taskin B, Erdoğan MA, Yiğittürk G, Günenç D, Erbaş O. Antifibrotic Effect of Lactulose on a Methotrexate-Induced Liver Injury Model. Gastroenterology research and practice. 2017;2017:7942531.
  • Referans6 Genestier L, Paillot R, Quemeneur L, Izeradjene K, Revillard J-P. Mechanisms of action of methotrexate. Immunopharmacology. 2000;47(2-3):247-57.
  • Referans7 Samdanci ET, Huz M, Ozhan O, Tanbek K, Pamukcu E, Akatli AN, et al. Cytoprotective effects of molsidomine against methotrexate-induced hepatotoxicity: an experimental rat study. Drug design, development and therapy. 2019;13:13-21.
  • Referans8 Vardi N, Parlakpinar H, Cetin A, Erdogan A, Cetin Ozturk I. Protective effect of β-carotene on methotrexate–induced oxidative liver damage. Toxicologic pathology. 2010;38(4):592-7.
  • Referans9 Cao Y, Shi H, Sun Z, Wu J, Xia Y, Wang Y, et al. Protective Effects of Magnesium Glycyrrhizinate on Methotrexate-Induced Hepatotoxicity and Intestinal Toxicity May Be by Reducing COX-2. Frontiers in pharmacology. 2019;10:119.
  • Referans10 Amirfakhrian H, Abedi SM, Sadeghi H, Azizi S, Hosseinimehr SJ. The use of 99mTc-phytate for assessment the protective effect of vitamin E against hepatotoxicity induced by methotrexat in rat. Nuclear medicine review Central & Eastern Europe. 2018;21(1):8-13.
  • Referans11 Vittori Gouveia LdA, Cardoso CA, de Oliveira GMM, Rosa G, Moreira ASB. Effects of the intake of sesame seeds (Sesamum indicum L.) and derivatives on oxidative stress: A systematic review. Journal of medicinal food. 2016;19(4):337-45.
  • Referans12 Moghadam AR, Tutunchi S, Namvaran-Abbas-Abad A, Yazdi M, Bonyadi F, Mohajeri D, et al. Pre-administration of turmeric prevents methotrexate-induced liver toxicity and oxidative stress. BMC complementary and alternative medicine. 2015;15(1):1-13.
  • Referans13 Neradil J, Pavlasova G, Veselska R. New mechanisms for an old drug; DHFR-and non-DHFR-mediated effects of methotrexate in cancer cells. Klin Onkol. 2012;25(Suppl 2):2S87-2S92.
  • Referans14 Al Kury LT, Dayyan F, Ali Shah F, Malik Z, Khalil AAK, Alattar A, et al. Ginkgo biloba Extract Protects against Methotrexate-Induced Hepatotoxicity: A Computational and Pharmacological Approach. Molecules. 2020;25(11).
  • Referans15 Burns J, Yokota T, Ashihara H, Lean ME, Crozier A. Plant foods and herbal sources of resveratrol. Journal of agricultural and food chemistry. 2002;50(11):3337-40.
  • Referans16 Li S, Zheng X, Zhang X, Yu H, Han B, Lv Y, et al. Exploring the liver fibrosis induced by deltamethrin exposure in quails and elucidating the protective mechanism of resveratrol. Ecotoxicol Environ Saf. 2021;207:111501.
  • Referans17 Kulkarni SS, Cantó C. The molecular targets of resveratrol. Biochimica et biophysica acta. 2015;1852(6):1114-23.
  • Referans18 Mattison JA, Wang M, Bernier M, Zhang J, Park S-S, Maudsley S, et al. Resveratrol prevents high fat/sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. Cell metabolism. 2014;20(1):183-90.
  • Referans19 Fremont L. Biological effects of resveratrol. Life sciences. 2000;66(8):663-73.
  • Referans20 Eki Nci-Akdemi RF, Yildirim S, Kandemi RF, Gülçi Nİ, Küçükler S, Sağlam YS, et al. The effects of casticin and myricetin on liver damage induced by methotrexate in rats. Iranian journal of basic medical sciences. 2018;21(12):1281-8.
  • Referans21 KOCAMAN N, ÇOLAKOĞLU N. Tekrarlayan Dozlarda Metotreksat Uygulamasının Sıçan Böbrek Dokusu Üzerine Etkileri. Fırat Tıp Dergisi. 2013;18(4):198-202.
  • Referans22 Yuluğ E, Türedi S, Alver A, Türedi S, Kahraman C. Effects of resveratrol on methotrexate-induced testicular damage in rats. The scientific world journal. 2013;2013.
  • Referans23 Refaiy A, Muhammad E, ElGanainy E. Semiquantitative smoothelin expression in detection of muscle invasion in transurethral resection and cystectomy specimens in cases of urinary bladder carcinoma. African Journal of Urology. 2011;17(1).
  • Referans24 Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clinical biochemistry. 2004;37(4):277-85.
  • Referans25 Erel O. A new automated colorimetric method for measuring total oxidant status. Clinical biochemistry. 2005;38(12):1103-11.
  • Referans26 Kosecik M, Erel O, Sevinc E, Selek S. Increased oxidative stress in children exposed to passive smoking. International journal of cardiology. 2005;100(1):61-4.
  • Referans27 Mahmoud AM, Hussein OE, Hozayen WG, Abd el-Twab SM. Methotrexate hepatotoxicity is associated with oxidative stress, and down-regulation of PPARγ and Nrf2: Protective effect of 18β-Glycyrrhetinic acid. Chemico-biological interactions. 2017;270:59-72.
  • Referans28 Liedtke C, Trautwein C. The role of TNF and Fas dependent signaling in animal models of inflammatory liver injury and liver cancer. European journal of cell biology. 2012;91(6-7):582-9.
  • Referans29 Iyer VV, Ovacik MA, Androulakis IP, Roth CM, Ierapetritou MG. Transcriptional and metabolic flux profiling of triadimefon effects on cultured hepatocytes. Toxicology and applied pharmacology. 2010;248(3):165-77.
  • Referans30 Elsawy H, Algefare AI, Alfwuaires M, Khalil M, Elmenshawy OM, Sedky A, et al. Naringin alleviates methotrexate-induced liver injury in male albino rats and enhances its antitumor efficacy in HepG2 cells. Bioscience reports. 2020;40(6).
  • Referans31. Meng X, Zhou J, Zhao CN, Gan RY, Li HB. Health Benefits and Molecular Mechanisms of Resveratrol: A Narrative Review. Foods (Basel, Switzerland). 2020;9(3).
  • Referans32 Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-κB, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. The Journal of Immunology. 2000;164(12):6509-19.
  • Referans33 Tsai SH, Lin‐Shiau SY, Lin JK. Suppression of nitric oxide synthase and the down‐regulation of the activation of NFκB in macrophages by resveratrol. British journal of pharmacology. 1999;126(3):673-80.
  • Referans34 Mammadov R, Suleyman B, Akturan S, Cimen FK, Kurt N, Suleyman Z, et al. Effect of lutein on methotrexate-induced oxidative lung damage in rats: a biochemical and histopathological assessment. The Korean journal of internal medicine. 2019;34(6):1279.
  • Referans35 Kawada N, Seki S, Inoue M, Kuroki T. Effect of antioxidants, resveratrol, quercetin, and N‐acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells. Hepatology. 1998;27(5):1265-74.
  • Referans36 Ahmad A, Ahmad R. Resveratrol mitigate structural changes and hepatic stellate cell activation in N′-nitrosodimethylamine-induced liver fibrosis via restraining oxidative damage. Chemico-biological interactions. 2014;221:1-12.
  • Referans37 Zhou X, Yang J, Zhou M, Zhang Y, Liu Y, Hou P, et al. Resveratrol attenuates endothelial oxidative injury by inducing autophagy via the activation of transcription factor EB. Nutrition & metabolism. 2019;16(1):1-12.
Year 2021, Volume: 6 Issue: 2, 57 - 63, 31.08.2021
https://doi.org/10.24880/maeuvfd.922106

Abstract

Project Number

-

References

  • Referans1 Tunali-Akbay T, Sehirli O, Ercan F, Sener G. Resveratrol protects against methotrexate-induced hepatic injury in rats. Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques. 2010;13(2):303-10.
  • Referans2 harma S, Baboota S, Amin S, Mir SR. Ameliorative effect of a standardized polyherbal combination in methotrexate-induced nephrotoxicity in the rat. Pharmaceutical biology. 2020;58(1):184-99. Referans3 Ebrahimi R, Sepand MR, Seyednejad SA, Omidi A, Akbariani M, Gholami M, et al. Ellagic acid reduces methotrexate-induced apoptosis and mitochondrial dysfunction via up-regulating Nrf2 expression and inhibiting the IĸBα/NFĸB in rats. Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences. 2019;27(2):721-33.
  • Referans4 Hasan H, Ismail H, El-Orfali Y, Khawaja G. Therapeutic benefits of Indole-3-Carbinol in adjuvant-induced arthritis and its protective effect against methotrexate induced-hepatic toxicity. BMC Complement Altern Med. 2018;18(1):337.
  • Referans5 Taskin B, Erdoğan MA, Yiğittürk G, Günenç D, Erbaş O. Antifibrotic Effect of Lactulose on a Methotrexate-Induced Liver Injury Model. Gastroenterology research and practice. 2017;2017:7942531.
  • Referans6 Genestier L, Paillot R, Quemeneur L, Izeradjene K, Revillard J-P. Mechanisms of action of methotrexate. Immunopharmacology. 2000;47(2-3):247-57.
  • Referans7 Samdanci ET, Huz M, Ozhan O, Tanbek K, Pamukcu E, Akatli AN, et al. Cytoprotective effects of molsidomine against methotrexate-induced hepatotoxicity: an experimental rat study. Drug design, development and therapy. 2019;13:13-21.
  • Referans8 Vardi N, Parlakpinar H, Cetin A, Erdogan A, Cetin Ozturk I. Protective effect of β-carotene on methotrexate–induced oxidative liver damage. Toxicologic pathology. 2010;38(4):592-7.
  • Referans9 Cao Y, Shi H, Sun Z, Wu J, Xia Y, Wang Y, et al. Protective Effects of Magnesium Glycyrrhizinate on Methotrexate-Induced Hepatotoxicity and Intestinal Toxicity May Be by Reducing COX-2. Frontiers in pharmacology. 2019;10:119.
  • Referans10 Amirfakhrian H, Abedi SM, Sadeghi H, Azizi S, Hosseinimehr SJ. The use of 99mTc-phytate for assessment the protective effect of vitamin E against hepatotoxicity induced by methotrexat in rat. Nuclear medicine review Central & Eastern Europe. 2018;21(1):8-13.
  • Referans11 Vittori Gouveia LdA, Cardoso CA, de Oliveira GMM, Rosa G, Moreira ASB. Effects of the intake of sesame seeds (Sesamum indicum L.) and derivatives on oxidative stress: A systematic review. Journal of medicinal food. 2016;19(4):337-45.
  • Referans12 Moghadam AR, Tutunchi S, Namvaran-Abbas-Abad A, Yazdi M, Bonyadi F, Mohajeri D, et al. Pre-administration of turmeric prevents methotrexate-induced liver toxicity and oxidative stress. BMC complementary and alternative medicine. 2015;15(1):1-13.
  • Referans13 Neradil J, Pavlasova G, Veselska R. New mechanisms for an old drug; DHFR-and non-DHFR-mediated effects of methotrexate in cancer cells. Klin Onkol. 2012;25(Suppl 2):2S87-2S92.
  • Referans14 Al Kury LT, Dayyan F, Ali Shah F, Malik Z, Khalil AAK, Alattar A, et al. Ginkgo biloba Extract Protects against Methotrexate-Induced Hepatotoxicity: A Computational and Pharmacological Approach. Molecules. 2020;25(11).
  • Referans15 Burns J, Yokota T, Ashihara H, Lean ME, Crozier A. Plant foods and herbal sources of resveratrol. Journal of agricultural and food chemistry. 2002;50(11):3337-40.
  • Referans16 Li S, Zheng X, Zhang X, Yu H, Han B, Lv Y, et al. Exploring the liver fibrosis induced by deltamethrin exposure in quails and elucidating the protective mechanism of resveratrol. Ecotoxicol Environ Saf. 2021;207:111501.
  • Referans17 Kulkarni SS, Cantó C. The molecular targets of resveratrol. Biochimica et biophysica acta. 2015;1852(6):1114-23.
  • Referans18 Mattison JA, Wang M, Bernier M, Zhang J, Park S-S, Maudsley S, et al. Resveratrol prevents high fat/sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. Cell metabolism. 2014;20(1):183-90.
  • Referans19 Fremont L. Biological effects of resveratrol. Life sciences. 2000;66(8):663-73.
  • Referans20 Eki Nci-Akdemi RF, Yildirim S, Kandemi RF, Gülçi Nİ, Küçükler S, Sağlam YS, et al. The effects of casticin and myricetin on liver damage induced by methotrexate in rats. Iranian journal of basic medical sciences. 2018;21(12):1281-8.
  • Referans21 KOCAMAN N, ÇOLAKOĞLU N. Tekrarlayan Dozlarda Metotreksat Uygulamasının Sıçan Böbrek Dokusu Üzerine Etkileri. Fırat Tıp Dergisi. 2013;18(4):198-202.
  • Referans22 Yuluğ E, Türedi S, Alver A, Türedi S, Kahraman C. Effects of resveratrol on methotrexate-induced testicular damage in rats. The scientific world journal. 2013;2013.
  • Referans23 Refaiy A, Muhammad E, ElGanainy E. Semiquantitative smoothelin expression in detection of muscle invasion in transurethral resection and cystectomy specimens in cases of urinary bladder carcinoma. African Journal of Urology. 2011;17(1).
  • Referans24 Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clinical biochemistry. 2004;37(4):277-85.
  • Referans25 Erel O. A new automated colorimetric method for measuring total oxidant status. Clinical biochemistry. 2005;38(12):1103-11.
  • Referans26 Kosecik M, Erel O, Sevinc E, Selek S. Increased oxidative stress in children exposed to passive smoking. International journal of cardiology. 2005;100(1):61-4.
  • Referans27 Mahmoud AM, Hussein OE, Hozayen WG, Abd el-Twab SM. Methotrexate hepatotoxicity is associated with oxidative stress, and down-regulation of PPARγ and Nrf2: Protective effect of 18β-Glycyrrhetinic acid. Chemico-biological interactions. 2017;270:59-72.
  • Referans28 Liedtke C, Trautwein C. The role of TNF and Fas dependent signaling in animal models of inflammatory liver injury and liver cancer. European journal of cell biology. 2012;91(6-7):582-9.
  • Referans29 Iyer VV, Ovacik MA, Androulakis IP, Roth CM, Ierapetritou MG. Transcriptional and metabolic flux profiling of triadimefon effects on cultured hepatocytes. Toxicology and applied pharmacology. 2010;248(3):165-77.
  • Referans30 Elsawy H, Algefare AI, Alfwuaires M, Khalil M, Elmenshawy OM, Sedky A, et al. Naringin alleviates methotrexate-induced liver injury in male albino rats and enhances its antitumor efficacy in HepG2 cells. Bioscience reports. 2020;40(6).
  • Referans31. Meng X, Zhou J, Zhao CN, Gan RY, Li HB. Health Benefits and Molecular Mechanisms of Resveratrol: A Narrative Review. Foods (Basel, Switzerland). 2020;9(3).
  • Referans32 Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-κB, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. The Journal of Immunology. 2000;164(12):6509-19.
  • Referans33 Tsai SH, Lin‐Shiau SY, Lin JK. Suppression of nitric oxide synthase and the down‐regulation of the activation of NFκB in macrophages by resveratrol. British journal of pharmacology. 1999;126(3):673-80.
  • Referans34 Mammadov R, Suleyman B, Akturan S, Cimen FK, Kurt N, Suleyman Z, et al. Effect of lutein on methotrexate-induced oxidative lung damage in rats: a biochemical and histopathological assessment. The Korean journal of internal medicine. 2019;34(6):1279.
  • Referans35 Kawada N, Seki S, Inoue M, Kuroki T. Effect of antioxidants, resveratrol, quercetin, and N‐acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells. Hepatology. 1998;27(5):1265-74.
  • Referans36 Ahmad A, Ahmad R. Resveratrol mitigate structural changes and hepatic stellate cell activation in N′-nitrosodimethylamine-induced liver fibrosis via restraining oxidative damage. Chemico-biological interactions. 2014;221:1-12.
  • Referans37 Zhou X, Yang J, Zhou M, Zhang Y, Liu Y, Hou P, et al. Resveratrol attenuates endothelial oxidative injury by inducing autophagy via the activation of transcription factor EB. Nutrition & metabolism. 2019;16(1):1-12.
There are 36 citations in total.

Details

Primary Language English
Subjects Health Care Administration
Journal Section Research Articles
Authors

Meltem Özgöçmen 0000-0003-3190-4486

Şükriye Yeşilot 0000-0003-3354-8489

Project Number -
Publication Date August 31, 2021
Submission Date April 19, 2021
Published in Issue Year 2021 Volume: 6 Issue: 2

Cite

APA Özgöçmen, M., & Yeşilot, Ş. (2021). The role of resveratrol in hepatotoxicity caused by methotrexate. Veterinary Journal of Mehmet Akif Ersoy University, 6(2), 57-63. https://doi.org/10.24880/maeuvfd.922106