Hepato-protective effects of Silymarin against methotrexate-induced hepatotoxicity in rat model
Main Article Content
Keywords
Methotrexate, Silymarin (silly), Hepatotoxicity, rats
Abstract
Aim: Assessment of the possible Hepatoprotective effects of Silymarin against hepatotoxicity induced by MTX in rats.
Materials and methods: An 24 Albino Wister rats were included in this study, they were randomly divided into 4 groups each of 6. Group 1: control group (administered 0.9% N/S 1ml/kg/d ip) for 5 days. Group 2: MTX group (received MTX in a dose of 20mg/kg/day ip) as a single dose at day 1 and observed till day 5 of the experiment. Group 3: Silymarin group (received MTX in a dose of 20mg/kg/d
ip as a single dose then Silymarin 300 mg /kg/ d ip for 5days). Group 4: vehicle group received 1ml/kg ip for each rat (10%DMSO + 40% PEG300 + 5% Tween400 + 45% Normalsalin) vehicle solution for 5 days. At day 5 all animals were sacrificed, serum was aspirated for the assessment of ALT, AST, ALP, TSB levels by colorimetric assay. Liver was removed and divided into 2 parts for histopathological examination and for assessment of tissue TNF-alpha, caspase-3, MDA, total antioxidant capacity, and TLR4 levels by ELISA method.
Results: Mean serum levels of ALT, AST, ALP and TSB as well as tissue MDA, TNFα, TlLR4, Caspse3 were significantly increased in MTX group compared with the control and vehicle groups together with significant reduction in total antioxidant capacity and obvious histological damage, whereas meanwhile treatment of rats with Silymarin together with MTX resulted in significant reduction in mean serum levels of ALT, AST, ALP and TSB as well as tissue MDA, TNFα,TlLR4,Caspse3 together with significant increment in total antioxidant capacity and near normal restoration of hepatic tissue architecture.
Conclusions: Silymarin has Hepatoprotective effect against MTX induced hepatotoxicity by its antioxidant, anti-inflammatory, and anti- apoptotic properties
References
1. Tukukino C, Wallerstedt SM. Drug information centre queries and responses about drug interactions over 10 years-A descriptive analysis. Basic & clinical pharmacology & toxicology. 2019; 126(1): 65-74.
2. van de Meeberg MM, Seinen ML, Fidder HH, Lin M, Oldenburg B, de Boer NK, et al. Subcutaneous administration, higher age and lower renal function are associated with erythrocyte methotrexate accumulation in Crohn’s disease: a cross-sectional study. BMC gastroenterology. 2022; 22(1): 365.
3. Lee TH, Oh JY, Hong SP, Lee JM, Roh SM, Kim SH, Park HB. ZIF-8 particle size effects on reverse osmosis performance of polyamide thinfilm Nano composite membranes: Importance of particle deposition. Journal of membrane science. 2019; 570, 23-33.
4. Slama HB, Chenari Bouket A, Pourhassan Z, Alenezi FN, Silini A, Cherif-Silini H, et al. Diversity of synthetic dyes from textile
industries, discharge impacts and treatment methods. Applied Sciences. 2021; 11(14): 6255
5. Abo-Haded HM, Elkablawy MA, Al-Johani Z, Al-Ahmadi O, El-Agamy DS. Hepatoprotective effect of Sitagliptin against methotrexate induced liver toxicity. PLoS one. 2017; 12(3): e0174295.
6. El-Baz AM, Shata A, Hassan HM, El-Sokkary MM, Khodir AE. The therapeutic role of Lactobacillus and Montelukast in combination with metformin in diabetes mellitus complications through modulation of gut microbiota and suppression of oxidative stress. International Immunopharmacology. 2021; 96: 107757
7. Qiu M, Liu L, Ling Q, Cai Y, Yu S, Wang S, et al. Biochar for the removal of contaminants from soil and water: a review. Biochar. 2022; 4(1): 19
8. Di Martino JS, Nobre AR, Mondal C, Taha I, Farias EF, Fertig EJ, A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy. Nature cancer. 2022; 3(1): 90-107.
9. Cheema HI, Haselow D, Dranoff JA. Review of existing evidence demonstrates that methotrexate does not cause liver fibrosis. Journal of Investigative Medicine. 2022; 70(7): 1452-1460.
10. Liu L, Hu, X. Study on the Mechanism of Soothing Liver Mixture against Liver Injury induced by Antituberculosis Drugs through Lipopolysaccharide/Toll-Like Receptor 4/Nuclear Factor Kappa B Signal Pathway. Indian Journal of Pharmaceutical Sciences. 2022; 84(2): 311-318.
11. El-Naggar A, Lee SS, Rinklebe J, Farooq M, Song H, Sarmah AK, et al. Biochar application to low fertility soils: A review of current status, and future prospects. Geoderma. 2019; 337: 536-554.
12. El-Baz AM, Shata A, Hassan HM, El-Sokkary MM, Khodir AE. The therapeutic role of Lactobacillus and Montelukast in combination with metformin in diabetes mellitus complications through modulation of gut microbiota and suppression of oxidative stress. International Immunopharmacology. 2021; 96: 107757
13. Botros SR, Matouk AI, Anter A, Khalifa MM, Heeba GH. Protective effect of empagliflozin on gentamicin-induced acute renal injury via regulation of SIRT1/NF-κB signaling pathway. Environmental Toxicology and Pharmacology. 2022; 94: 103907.
14. Haddadi R, Nayebi AM, Brooshghalan SE. Silymarin prevents apoptosis through inhibiting the Bax/caspase-3 expression and suppresses toll like receptor-4 pathway in the SNc of 6-OHDA intoxicated rats. Biomedicine & Pharmacotherapy. 2018; 104: 127-136.
15. Gomes VJ, Nunes PR, Matias ML, Ribeiro VR, Devides AC, Bannwart-Castro CF, et al. Silibinin induces in vitro M2-like phenotype polarization in monocytes from preeclamptic women. International Immunopharmacology. 2020; 89: 107062.
16. Jafaripour L, Naserzadeh R, Alizamani E, Mashhadi SMJ, Moghadam ER, Nouryazdan N, Ahmadvand H. Effects of rosmarinic acid on methotrexate-induced nephrotoxicity and hepatotoxicity in Wistar rats. Indian journal of nephrology. 2021; 31(3): 218.
17. Oliveira PJ, Seiça R, Coxito PM, Rolo AP, Palmira CM, Santos MS, Moreno AJ. Enhanced permeability transition explains the reduced calcium uptake in cardiac mitochondria from streptozotocin-induced diabetic rats. FEBS letters. 2003; 554(3): 511-514 .
18. Mazali FC, Johnson RJ, Mazzali M. Use of uric acid-lowering agents limits experimental cyclosporine nephropathy. Nephron Experimental nephrology. 2012; 120(1): e12-e19.
19. Peng J, Chen F, Liu Y, Zhang F, Cao L, You Q, Yang D, Chang Z, et al. A light-driven dual-Nano transformer with deep tumor penetration for
efficient chemo-immunotherapy. Theranostics. 2022 Jan 24; 12(4):1756-1768, doi: 10.7150/thno.68756.
20. Sahindokuyucu-Kocasari F, Akyol Y, Ozmen O, Erdemli-Kose SB, Garli S. Apigenin alleviates methotrexate-induced liver and kidney injury in
mice. Human & Experimental Toxicology. 2021; 40(10): 1721-1731.
21. Emara M, ElSawy H, Bauch G. A spatiotemporal model for peak AoI in uplink IoT networks: Timeversus event-triggered traffic. IEEE internet of things journal. 2020; 7(8): 6762-6777.
22. Abdelaziz RM, Abdelazem AZ, Hashem KS, Attia YA. Protective effects of hesperidin against MTX-induced hepatotoxicity in male albino rats. Naunyn-Schmiedebergs Archives of Pharmacology. 2020; 393: 1405-1417.
23. Dogan G, Taskin B. Hydrolytic enzymes producing bacterial endophytes of some poaceae plants. Polish journal of microbiology. 2021; 70(3): 297-304.
24. Emmanuel R, Karuppiah C, Chen SM, Palanisamy S, Padmavathy S, Prakash P. Green synthesis of gold nanoparticles for trace level detection of a hazardous pollutant (nitrobenzene) causing Methemoglobinaemia. Journal of hazardous materials. 2014; 279: 117-124.
25. Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, et al. Balanced crystalloids versus saline in critically ill adults.
New England Journal of Medicine. 2018; 378(9): 829-839.
26. Negre-Salvayre A, Auge N, Ayala V, Basaga H, Boada J, Brenke R, et al. Pathological aspects of lipid peroxidation. Free radical research. 2010; 44(10): 1125-1171
27. Du K, Ramachandran A, McGill MR, Mansouri A, Asselah T, Farhood A, et al. Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity. Food and Chemical Toxicology. 2017; 108: 339-350 .
28. Khodir AE, Ghoneim HA, Rahim MA, Suddek GM. Montelukast attenuates lipopolysaccharideinduced cardiac injury in rats. Human & experimental toxicology. 2016; 35(4): 388-397
29. Kishawy HA, Hegab H, Umer U, Mohany A. Application of acoustic emissions in machining processes: analysis and critical review. The International Journal of Advanced Manufacturing Technology. 2018; 98: 1391-1407.
30. Kuzmich AS, Khomenko TM, Fedorov SN, Makarieva TN, Shubina LK, et al. Cytotoxic and cancer preventive activity of benzotrithioles and benzotrithioles oxides, synthetic analogues of varacins. Medicinal Chemistry Research. 2017; 26: 397-404 .
31. Kim OS, Cho YJ, Lee K, Yoon SH, Kim M, Na H, et al. Introducing EzTaxon-e: a prokaryotic 16S rRNA gene sequence database with phylotypes that represent uncultured species. International journal of systematic and evolutionary microbiology. 2012; 62(Pt_3): 716-721
32. Roghani M, Kalantari H, Khodayar MJ, Khorsandi L, Kalantar M, Goudarzi M, et al. Alleviation of liver dysfunction, oxidative stress
and inflammation underlies the protective effect of ferulic acid in methotrexate-induced hepatotoxicity. Drug design, development and therapy. 2020; 1933-1941.
33. Oliveira PJ, Gonçalves L, Monteiro P, Providencia LA, Moreno AJ. Are the antioxidant properties of carvedilol important for the protection of cardiac mitochondria? Current vascular pharmacology. 2005; 3(2): 147-158.
34. Özkan E, Yardimci S, Dulundu E, Topaloğlu Ü, Şehirli Ö, Ercan F, et al. Protective potential of Montelukast against hepatic ischemia/reperfusioninjury in rats. Journal of Surgical Research. 2010; 159(1): 588-594.
35. El-Baz AM, Shata A, Hassan HM, El-Sokkary MM, Khodir AE. The therapeutic role of Lactobacillus and Montelukast in combination
with metformin in diabetes mellitus complications through modulation of gut microbiota and suppression of oxidative stress. International Immunopharmacology. 2021; 96: 107757
2. van de Meeberg MM, Seinen ML, Fidder HH, Lin M, Oldenburg B, de Boer NK, et al. Subcutaneous administration, higher age and lower renal function are associated with erythrocyte methotrexate accumulation in Crohn’s disease: a cross-sectional study. BMC gastroenterology. 2022; 22(1): 365.
3. Lee TH, Oh JY, Hong SP, Lee JM, Roh SM, Kim SH, Park HB. ZIF-8 particle size effects on reverse osmosis performance of polyamide thinfilm Nano composite membranes: Importance of particle deposition. Journal of membrane science. 2019; 570, 23-33.
4. Slama HB, Chenari Bouket A, Pourhassan Z, Alenezi FN, Silini A, Cherif-Silini H, et al. Diversity of synthetic dyes from textile
industries, discharge impacts and treatment methods. Applied Sciences. 2021; 11(14): 6255
5. Abo-Haded HM, Elkablawy MA, Al-Johani Z, Al-Ahmadi O, El-Agamy DS. Hepatoprotective effect of Sitagliptin against methotrexate induced liver toxicity. PLoS one. 2017; 12(3): e0174295.
6. El-Baz AM, Shata A, Hassan HM, El-Sokkary MM, Khodir AE. The therapeutic role of Lactobacillus and Montelukast in combination with metformin in diabetes mellitus complications through modulation of gut microbiota and suppression of oxidative stress. International Immunopharmacology. 2021; 96: 107757
7. Qiu M, Liu L, Ling Q, Cai Y, Yu S, Wang S, et al. Biochar for the removal of contaminants from soil and water: a review. Biochar. 2022; 4(1): 19
8. Di Martino JS, Nobre AR, Mondal C, Taha I, Farias EF, Fertig EJ, A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy. Nature cancer. 2022; 3(1): 90-107.
9. Cheema HI, Haselow D, Dranoff JA. Review of existing evidence demonstrates that methotrexate does not cause liver fibrosis. Journal of Investigative Medicine. 2022; 70(7): 1452-1460.
10. Liu L, Hu, X. Study on the Mechanism of Soothing Liver Mixture against Liver Injury induced by Antituberculosis Drugs through Lipopolysaccharide/Toll-Like Receptor 4/Nuclear Factor Kappa B Signal Pathway. Indian Journal of Pharmaceutical Sciences. 2022; 84(2): 311-318.
11. El-Naggar A, Lee SS, Rinklebe J, Farooq M, Song H, Sarmah AK, et al. Biochar application to low fertility soils: A review of current status, and future prospects. Geoderma. 2019; 337: 536-554.
12. El-Baz AM, Shata A, Hassan HM, El-Sokkary MM, Khodir AE. The therapeutic role of Lactobacillus and Montelukast in combination with metformin in diabetes mellitus complications through modulation of gut microbiota and suppression of oxidative stress. International Immunopharmacology. 2021; 96: 107757
13. Botros SR, Matouk AI, Anter A, Khalifa MM, Heeba GH. Protective effect of empagliflozin on gentamicin-induced acute renal injury via regulation of SIRT1/NF-κB signaling pathway. Environmental Toxicology and Pharmacology. 2022; 94: 103907.
14. Haddadi R, Nayebi AM, Brooshghalan SE. Silymarin prevents apoptosis through inhibiting the Bax/caspase-3 expression and suppresses toll like receptor-4 pathway in the SNc of 6-OHDA intoxicated rats. Biomedicine & Pharmacotherapy. 2018; 104: 127-136.
15. Gomes VJ, Nunes PR, Matias ML, Ribeiro VR, Devides AC, Bannwart-Castro CF, et al. Silibinin induces in vitro M2-like phenotype polarization in monocytes from preeclamptic women. International Immunopharmacology. 2020; 89: 107062.
16. Jafaripour L, Naserzadeh R, Alizamani E, Mashhadi SMJ, Moghadam ER, Nouryazdan N, Ahmadvand H. Effects of rosmarinic acid on methotrexate-induced nephrotoxicity and hepatotoxicity in Wistar rats. Indian journal of nephrology. 2021; 31(3): 218.
17. Oliveira PJ, Seiça R, Coxito PM, Rolo AP, Palmira CM, Santos MS, Moreno AJ. Enhanced permeability transition explains the reduced calcium uptake in cardiac mitochondria from streptozotocin-induced diabetic rats. FEBS letters. 2003; 554(3): 511-514 .
18. Mazali FC, Johnson RJ, Mazzali M. Use of uric acid-lowering agents limits experimental cyclosporine nephropathy. Nephron Experimental nephrology. 2012; 120(1): e12-e19.
19. Peng J, Chen F, Liu Y, Zhang F, Cao L, You Q, Yang D, Chang Z, et al. A light-driven dual-Nano transformer with deep tumor penetration for
efficient chemo-immunotherapy. Theranostics. 2022 Jan 24; 12(4):1756-1768, doi: 10.7150/thno.68756.
20. Sahindokuyucu-Kocasari F, Akyol Y, Ozmen O, Erdemli-Kose SB, Garli S. Apigenin alleviates methotrexate-induced liver and kidney injury in
mice. Human & Experimental Toxicology. 2021; 40(10): 1721-1731.
21. Emara M, ElSawy H, Bauch G. A spatiotemporal model for peak AoI in uplink IoT networks: Timeversus event-triggered traffic. IEEE internet of things journal. 2020; 7(8): 6762-6777.
22. Abdelaziz RM, Abdelazem AZ, Hashem KS, Attia YA. Protective effects of hesperidin against MTX-induced hepatotoxicity in male albino rats. Naunyn-Schmiedebergs Archives of Pharmacology. 2020; 393: 1405-1417.
23. Dogan G, Taskin B. Hydrolytic enzymes producing bacterial endophytes of some poaceae plants. Polish journal of microbiology. 2021; 70(3): 297-304.
24. Emmanuel R, Karuppiah C, Chen SM, Palanisamy S, Padmavathy S, Prakash P. Green synthesis of gold nanoparticles for trace level detection of a hazardous pollutant (nitrobenzene) causing Methemoglobinaemia. Journal of hazardous materials. 2014; 279: 117-124.
25. Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, et al. Balanced crystalloids versus saline in critically ill adults.
New England Journal of Medicine. 2018; 378(9): 829-839.
26. Negre-Salvayre A, Auge N, Ayala V, Basaga H, Boada J, Brenke R, et al. Pathological aspects of lipid peroxidation. Free radical research. 2010; 44(10): 1125-1171
27. Du K, Ramachandran A, McGill MR, Mansouri A, Asselah T, Farhood A, et al. Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity. Food and Chemical Toxicology. 2017; 108: 339-350 .
28. Khodir AE, Ghoneim HA, Rahim MA, Suddek GM. Montelukast attenuates lipopolysaccharideinduced cardiac injury in rats. Human & experimental toxicology. 2016; 35(4): 388-397
29. Kishawy HA, Hegab H, Umer U, Mohany A. Application of acoustic emissions in machining processes: analysis and critical review. The International Journal of Advanced Manufacturing Technology. 2018; 98: 1391-1407.
30. Kuzmich AS, Khomenko TM, Fedorov SN, Makarieva TN, Shubina LK, et al. Cytotoxic and cancer preventive activity of benzotrithioles and benzotrithioles oxides, synthetic analogues of varacins. Medicinal Chemistry Research. 2017; 26: 397-404 .
31. Kim OS, Cho YJ, Lee K, Yoon SH, Kim M, Na H, et al. Introducing EzTaxon-e: a prokaryotic 16S rRNA gene sequence database with phylotypes that represent uncultured species. International journal of systematic and evolutionary microbiology. 2012; 62(Pt_3): 716-721
32. Roghani M, Kalantari H, Khodayar MJ, Khorsandi L, Kalantar M, Goudarzi M, et al. Alleviation of liver dysfunction, oxidative stress
and inflammation underlies the protective effect of ferulic acid in methotrexate-induced hepatotoxicity. Drug design, development and therapy. 2020; 1933-1941.
33. Oliveira PJ, Gonçalves L, Monteiro P, Providencia LA, Moreno AJ. Are the antioxidant properties of carvedilol important for the protection of cardiac mitochondria? Current vascular pharmacology. 2005; 3(2): 147-158.
34. Özkan E, Yardimci S, Dulundu E, Topaloğlu Ü, Şehirli Ö, Ercan F, et al. Protective potential of Montelukast against hepatic ischemia/reperfusioninjury in rats. Journal of Surgical Research. 2010; 159(1): 588-594.
35. El-Baz AM, Shata A, Hassan HM, El-Sokkary MM, Khodir AE. The therapeutic role of Lactobacillus and Montelukast in combination
with metformin in diabetes mellitus complications through modulation of gut microbiota and suppression of oxidative stress. International Immunopharmacology. 2021; 96: 107757
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Mar 1, 2023
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Bayader Abdulhadi Abdul Kadhim, Fadhaa Abdulameer Ghafil, Sahar A. Majeed, Heider Qassam, & Najah R. Hadi. (2023). Hepato-protective effects of Silymarin against methotrexate-induced hepatotoxicity in rat model. Journal of Population Therapeutics and Clinical Pharmacology, 30(1), 373-382. https://doi.org/10.47750/jptcp.2023.1096
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All articles published in JPTCP are licensed under Copyright Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Bayader Abdulhadi Abdul Kadhim, Fadhaa Abdulameer Ghafil, Sahar A. Majeed, Heider Qassam, & Najah R. Hadi. (2023). Hepato-protective effects of Silymarin against methotrexate-induced hepatotoxicity in rat model. Journal of Population Therapeutics and Clinical Pharmacology, 30(1), 373-382. https://doi.org/10.47750/jptcp.2023.1096