Troxerutin alleviates hepatorenal toxicity induced by carbon tetrachloride in male mice

Document Type : Original Article

Authors

1 Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

2 Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

3 Research Center of Tropical and Infectious Diseases, Kerman University of Medical Sciences, Kerman, Iran

10.22038/ijbms.2025.84752.18337

Abstract

Objective(s): Troxerutin (TRX) is a natural bioflavonoid with several medicinal properties. We assessed its protective effect on carbon tetrachloride-related hepatorenal damage in male mice.
Materials and Methods: Male mice were assigned to five groups: Control, TRX, CCL4, CCL4 + TRX 75 mg/kg, CCL4 + TRX 150 mg/kg. Animals received oral TRX (75 and 150 mg/kg) daily for four weeks. After treatments, serum liver enzymes aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Serum blood urine nitrogen (BUN), and creatinine (Cr) levels were assessed. Malondialdehyde (MDA, the primary lipid peroxidation product), activity of anti-oxidant enzymes glutathione peroxidase (GPX), superoxide dismutase (SOD), and total anti-oxidant capacity (TAC) were determined. Using the immunoblotting method, Bax, Bcl-2, cleaved caspase-3, and cytochrome-c protein concentrations were evaluated in the kidney and liver tissues. The Hematoxylin and Eosin (H&E) staining were used to assess the kidney and liver histopathological changes.
Results: CCl4 caused a significant increase in the concentrations of liver and kidney indices such as ALT (P<0.05), Cr (P<0.01), AST (P<0.001), and BUN (P<0.001). Furthermore, CCl4 significantly increased the MDA level in the liver (P<0.01) and kidney (P<0.001) tissues while decreasing anti-oxidant status. TRX could significantly decrease ALT, AST, Cr, BUN, and MDA concentrations and increase SOD, GPx, and TAC activities in comparison to the CCl4-damaged control group. In addition, TRX caused an attenuation in the pro and anti-apoptotic markers in the kidney and liver tissues. 
Conclusion: TRX displayed liver and kidney protection, possibly by its free radical scavenging and anti-oxidant effects.

Keywords

Main Subjects


1. Das P, Holt S. Liver disease and renal dysfunction. Medicine 2011; 39:492-496.
2. Balahoroğlu R, Dülger H, Özbek H, Bayram İ, Şekeroğlu MR. Protective effects of anti-oxidants on the experimental liver and kidney toxicity in mice. Eur J Gen Med 2008; 5:157-164.
3. Kim YC, Yim HK, Jung YS, Park JH, Kim SY. Hepatic injury induces contrasting response in liver and kidney to chemicals that are metabolically activated: role of male sex hormone. Toxicol Appl Pharmacol 2007; 223:56-65.
4. Adewole S, Salako A, Doherty O, Naicker T. Effect of melatonin on carbon tetrachloride-induced kidney injury in Wistar rats. Afr J Biomed Res 2007; 10:153-164.
5. Soliman A, Fahmy S. Protective and curative effects of the 15 KD isolated protein from the Peganum harmala L. seeds against carbon tetrachloride induced oxidative stress in brain, tests and erythrocytes of rats. Eur Rev Med Pharmacol Sci 2011; 15:888-899.
6. Anand KV, Anandhi R, Pakkiyaraj M, Geraldine P. Protective effect of chrysin on carbon tetrachloride (CCl4)—induced tissue injury in male Wistar rats. Toxicol Ind Health 2011; 27:923-933.
7. Mizuguchi S, Takemura S, Minamiyama Y, Kodai S, Tsukioka T, Inoue K, et al. S‐allyl cysteine attenuated CCl4‐induced oxidative stress and pulmonary fibrosis in rats. Biofactors 2006; 26:81-92.
8. Khan MR, Rizvi W, Khan GN, Khan RA, Shaheen S. Carbon tetrachloride-induced nephrotoxicity in rats: Protective role of Digera muricata. J Ethnopharmacol 2009; 122:91-99.
9. Hismiogullari AA, Hismiogullari SE, Karaca O, Sunay FB, Paksoy S, Can M, et al. The protective effect of curcumin administration on carbon tetrachloride (CCl 4)-induced nephrotoxicity in rats. Pharmacol Rep 2015; 67:410-416.
10. Qiu DK, Hua J, Li JQ, Li EL. CD14 expression on Kupffer cells during the course of carbon tetrachloride‐mediated liver injury. Chin J Dig Dis 2005; 6:137-141.
11. Al-Fartosi KG, Majid A, Auda MA, Hussein MH. The role of Camel’s milk against some oxidant-anti-oxidant markers of male rats treated with CCl4. Int J Res Pharmaceut Biomed Sci 2012; 3:385-389.
12. Erdemli Z, Erdemli ME, Gul M, Altinoz E, Gul S, Kocaman G, et al. Ameliorative effects of crocin on the inflammation and oxidative stress-induced kidney damages by experimental periodontitis in rat. Iran J Basic Med Sci 2021; 24:825-832.
13. Erdemli Z, Gul M, Gokturk N, Kayhan E, Demircigil N, Ozsoy EN, et al. Ameliorative effects of thymoquinone on the caspase 3, kidney function and oxidative stress tartrazine-induced nephrotoxicity. Toxicon 2024; 241:107660.
14. Panat NA, Maurya DK, Ghaskadbi SS, Sandur SK. Troxerutin, a plant flavonoid, protects cells against oxidative stress-induced cell death through radical scavenging mechanism. Food Chem 2016; 194:32-45.
15. Sampath S, Karundevi B. Effect of troxerutin on insulin signaling molecules in the gastrocnemius muscle of high fat and sucrose-induced type-2 diabetic adult male rat. Mol Cell Biochem 2014; 395:11-27.
16. Subastri A, Ramamurthy C, Suyavaran A, Mareeswaran R, Rao PL, Harikrishna M, et al. Spectroscopic and molecular docking studies on the interaction of troxerutin with DNA. Int J Biol Macromol 2015; 78:122-129.
17. Geetha R, Yogalakshmi B, Sreeja S, Bhavani K, Anuradha CV. Troxerutin suppresses lipid abnormalities in the heart of high-fat–high-fructose diet-fed mice. Mol Cell Biochem 2014; 387:123-134.
18. Shan Q, Zhuang J, Zheng G, Zhang Z, Zhang Y, Lu J, et al. Troxerutin reduces kidney damage against BDE-47-induced apoptosis via inhibiting NOX2 activity and increasing Nrf2 activity. Oxid Med Cell Longev 2017; 2017: :6034692.
19. Hermenean A, Ardelean A, Stan M, Herman H, Mihali C-V, Costache M, et al. Protective effects of naringenin on carbon tetrachloride-induced acute nephrotoxicity in mouse kidney. Chem Biol Interact 2013; 205:138-147.
20. Fu Y, Zheng S, Lin J, Ryerse J, Chen A. Curcumin protects the rat liver from CCl4-caused injury and fibrogenesis by attenuating oxidative stress and suppressing inflammation. Mol Pharmacol 2008; 73:399-409.
21. Unal Y, Tuncal S, Kosmaz K, Kucuk B, Kismet K, Cavusoglu T, et al. The effect of calcium dobesilate on liver damage in experimental obstructive jaundice. J Invest Surg 2019; 32:238-244.
22. Hakimizadeh E, Kaeidi A, Rahmani M, Allahtavakoli M, Hassanshahi J. Calcium dobesilate ameliorates hepatorenal injury induced by carbon tetrachloride in mice. Iran J Basic Med Sci 2022; 25:148-154.
23. Hakimizadeh E, Kaeidi A, Hassanshahi J, Mehrbani M, Rahmani M. Ameliorating effect of pistachio hydroalcoholic extract on cisplatin-induced nephrotoxicity in mice. RJP 2021; 8:73-79.
24. Hakimizadeh E, Kaeidi A, Taghipour Z, Mehrzadi S, Allahtavakoli M, Shamsizadeh A, et al. Ceftriaxone improves senile neurocognition damages induced by D-galactose in mice. Iran J Basic Med Sci 2020; 23:368-375.
25. Najafizadeh A, Kaeidi A, Rahmani M, Hakimizadeh E, Hassanshahi J. The protective effect of carvacrol on acetaminophen-induced renal damage in male rats. Mol Biol Rep 2022; 49:1763-1771.
26. Kaeidi A, Sahamsizadeh A, Allahtavakoli M, Fatemi I, Rahmani M, Hakimizadeh E, et al. The effect of oleuropein on unilateral ureteral obstruction induced-kidney injury in rats: The role of oxidative stress, inflammation and apoptosis. Mol Biol Rep 2020; 47:1371-1379.
27. Kaeidi A, Taghipour Z, Allahtavakoli M, Fatemi I, Hakimizadeh E, Hassanshahi J. Ameliorating effect of troxerutin in unilateral ureteral obstruction induced renal oxidative stress, inflammation, and apoptosis in male rats. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:879-888.
28. Zamanian M, Bazmandegan G, Sureda A, Sobarzo-Sanchez E, Yousefi-Manesh H, Shirooie S. The protective roles and molecular mechanisms of troxerutin (vitamin P4) for the treatment of chronic diseases: A mechanistic review. Curr Neuropharmacol 2021; 19:97-110.
29. Fan S-h, Zhang Z-f, Zheng Y-l, Lu J, Wu D-m, Shan Q, et al. Troxerutin protects the mouse kidney from d-galactose-caused injury through anti-inflammation and anti-oxidation. Int Immunopharmacol 2009; 9:91-96.
30. Adam B, Pentz R, Siegers C, Strubelt O, Tegtmeier M. Troxerutin protects the isolated perfused rat liver from a possible lipid peroxidation by coumarin. Phytomedicine 2005; 12:52-61.
31. Shan Q, Zhuang J, Zheng G, Zhang Z, Zhang Y, Lu J, et al. Troxerutin reduces kidney damage against BDE-47-induced apoptosis via inhibiting NOX2 activity and increasing Nrf2 activity. Oxid Med Cell Longev 2017; 2017:6034692.
32. Badalzadeh R, Layeghzadeh N, Alihemmati A, Mohammadi M. Beneficial effect of troxerutin on diabetes-induced vascular damages in rat aorta: Histopathological alterations and anti-oxidation mechanism. Int J Endocrinol Metab 2015; 13 :e25969.
33. Mokhtari B, Badalzadeh R, Alihemmati A, Mohammadi M. Phosphorylation of GSK-3β and reduction of apoptosis as targets of troxerutin effect on reperfusion injury of diabetic myocardium. Eur J Pharmacol 2015; 765:316-321.
34. Hagen TM. Oxidative stress, redox imbalance, and the aging process. Antioxid Redox Signal 2003; 5:503-506.
35. Okolo K, Siminialayi I, Orisakwe O. Carbon tetrachloride induced hepatorenal toxicity in rats: Possible protective effects of wild Pleurotus tuber-regium, Clin Phytosci 3 2017; 3: 1-7.