The use of tamoxifen (TAM) for breast cancer treatment may cause hepatotoxicity. Ursodeoxycholic acid (UDCA) is a potential liver protective chemical compound. The protective effect of UDCA on TAM-induced hepatotoxicity in rats was analyzed in this study. Thirty five adult female Wistar rats grouped into 7 of n=5/group were used. The rats were treated for 10 days as follows: Group 1: (Placebo control) Water (10 mL/kg/day/oral), group 2: (Vehicle control) Ethanol 1% (1mL/kg/day) intraperitoneally (i.p), group 3: UDCA (40 mg/kg/day/oral) and group 4: TAM (45 mg/kg/day) i.p. Groups 5-7 were pretreated with UDCA (10, 20 and 40 mg/kg/day/oral) before treatment with TAM (45 mg/kg/day) i.p, respectively. On day 11, blood samples were collected and evaluated for biochemical markers. Liver tissues were analyzed for oxidative stress markers and histology. Results: TAM decreased body weight and increased liver weight significantly (p<0.01) when compared to the placebo control. Serum bilirubin, alkaline phosphatase, gamma-glutamyl transferase, lactate dehydrogenase, aminotransferases, high density lipoprotein cholesterol and liver malondialdehyde levels were significantly (p<0.001) elevated by TAM when compared to control. TAM significantly (p<0.001) decreased serum triglyceride, very low density lipoprotein cholesterol, total cholesterol, liver glutathione, catalase, superoxide dismutase and glutathione peroxidase levels when compared to the control. TAM caused liver steatosis and necrosis in rats. However, UDCA pretreatment significantly prevented the aforementioned changes caused by TAM in a dose-related fashion. UDCA may be a therapeutic option for TAM associated hepatotoxicity.
Published in | American Journal of Internal Medicine (Volume 12, Issue 6) |
DOI | 10.11648/j.ajim.20241206.12 |
Page(s) | 110-119 |
Creative Commons |
This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited. |
Copyright |
Copyright © The Author(s), 2024. Published by Science Publishing Group |
Tamoxifen, Ursodeoxycholic Acid, Liver, Toxicity, Rat, Protection
[1] | Mudd TW, Guddati AK. Management of hepatotoxicity of chemotherapy and targeted agents. Am J Cancer Res. 2021, 11(7): 3461-3474. PMID: 34354855; PMCID: PMC8332851. |
[2] | Björnsson ES. Hepatotoxicity by drugs: the most common implicated agents. Int J Mol Sci. 2016; 17: 224; 1-7. |
[3] | Hoofnagle JH, Björnsson ES. Drug-induced liver injury-types and phenotypes. New N Engl J Med. 2019; 381: 264–273. |
[4] | Mourad HH, Abd-El Razikb AN, Hosnya EN, El-Gizawy MM. Effect of sage oil on tamoxifen-induced hepatotoxicity and nephrotoxicity in female rats Egypt Pharmaceut J 2021; 19: 350–360. |
[5] | Jena SK, Suresh S, Sangamwar AT. Modulation of tamoxifen-induced hepatotoxicity by tamoxifen-phospholipid complex. J Pharm Pharmacol 2015; 67: 1198–1206. |
[6] | Zhou W, Zhang X, Cai Y, Sun W, Hao L. Osthole prevents tamoxifen-induced liver injury in mice. Acta Pharmacol Sinica 2019; 40: 608–619. |
[7] | El-Sherbiny GA, Taye A, Abdel-Raheem IT. Role of ursodeoxycholic acid in prevention of hepatotoxicity caused by amoxicillin-clavulanic acid in rats Ann Hepatol 2009; 8(2): 134-140. PMID: 19502657. |
[8] | Guicciardi ME, Gores GJ. Is ursodeoxycholate an antiapoptotic drug. Hepatol 1998; 28(6): 1721-1723. |
[9] | Lukivskaya O, Patsenker E, Buko V. Protective effect of ursodeoxycholic acid on liver mitochondrial function in rats with alloxan-induced diabetes: link with oxidative stress. J. Life Sci 2007; 80: 2397–402. |
[10] | Chen X, Xu J, Zhang C, Yu T, Wang H, Zhao M, Xu D, et al. The protective effects of ursodeoxycholic acid on isoniazid plus rifampicin induced liver injury in mice. Eur J Clin Pharmacol 2011; 659: 53–60. |
[11] | Alhumaidha KA, El-Awdan SA, El-Iraky WI, El-Denshary ES. Protective effects of ursodeoxycholic acid on ceftriaxone-induced hepatic injury in rats Bull Fac Pharm Cairo Univer. 2014 (52) 45-50. |
[12] | Ljubuncic P, Abu-Salach O, Bomzon A. Ursodeoxycholic acid and superoxide anion. World J Gastroenterol. 2005; 21; 11(31): 4875-8. |
[13] | Uraz S, Tahan V, Aygun C, Eren F, Unluguzel G, Yuksel M et al. Role of ursodeoxycholic acid in prevention of methotrexate-induced liver toxicity. Dig Dis Sci 2008; 53(4): 1071-1077. |
[14] | Mitsuyoshi H, Nakashima T, Sumida Y, Yoh T, Nakajima Y, Ishikawa H et al. Ursodeoxycholic acid protects hepatocytes against oxidative injury via induction of antioxidants. Biochem Biophys Res Commun 1999; 263: 537–542. |
[15] | Suddek G. M. Protective role of thymoquinone against liver damage induced by tamoxifen in female rats. Canadian J Physiol Pharmacol. 2014; 92(8): 640-644. |
[16] | Buege JA, Aust SD. 1978. Microsomal lipid peroxidation. Methods Enzymol. 52: 302-10. |
[17] | Aebi H. Catalase in vitro. Methods Enzymol 1984; 105: 121- 126. |
[18] | Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’ reagent. Anal Biochem. 1986; 25: 192-205. |
[19] | Sun M, Zigman S. An Improved spectrophotometer assay of superoxide dismutase based on epinephrine antioxidation. Anal Biochem 1978; 90: 81-89. |
[20] | Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: biochemical role as a component of glutathione peroxidase. Sci 1973; 179: 588-90. |
[21] | Ore A, Adeogun A. I, Akinloye O. A. Hydroethanolic Extract of Defatted Buchholzia coriacea seeds alleviates tamoxifen-induced hepatic triglyceride accumulation, inflammation and Oxidative Distress in Rat. Med. 2022, 9, (1) 1-17 |
[22] | Gao F, Lv J, Wang Y, Fan R, Li Q, Zhang Z, Wei L. Tamoxifen induces hepatotoxicity and changes to hepatocyte morphology at the early stage of endocrinotherapy in mice. Biomed Rep. 2016; 4(1): 102–106. |
[23] | Adikwu E, Ebinyo NC,, Benalayefa, O. Protective effect of lycopene against Tamoxifen-induced hepatotoxicity in albino rats, Biomed and Biotech Res J 2020; 4(2) 69-75. |
[24] | Owumi SE, Olusola JK, Arunsi UO, Oyelere AK. Chlorogenic acid abates oxido-inflammatory and apoptotic responses in the liver and kidney of Tamoxifen-treated rats, Toxicol Res, 2021; 10(2) 345–353. |
[25] | Liu L, Zou P, Zheng L, Linarelli L. E, Amarell S, Passaro, A. et al.. Tamoxifen reduces fat mass by boosting reactive oxygen species. Cell Death Dis 2015: 6 e1586; 1-7. |
[26] | Adikwu E, Ebinyo NC, Ejovwoke CA. Resveratrol abrogates 5-flourouracil-induced hepatotoxicity: A preclinical study Trend Pharm Sci 2020: 6(4): 263-270. |
[27] | Rahate KP, Rajasekaran A. Hepatoprotection by active fractions from Desmostachya bipinnata stapf (L.) against tamoxifen-induced hepatotoxicity. Ind J Pharmacol 2015; 47: 311–315. |
[28] | Horn, K. D., Wax, P., Schneider, S. M., Martin, T. G., Nine, J. S., Moraca, M. A et al. Biomarkers of liver regeneration allow early prediction of hepatic recovery after acute necrosis. Am J Clin Path, 1999; 112(3) 351-357. |
[29] | Gowda, S., Desai, P. B., Hull, V. V., Avinash, A. K., Vernekar, S. N., Kulkarni, S. S. A Review on laboratory liver function tests. Pan Afr Med J 2009; 3; 17-1-11 PMID: 21532726; PMCID: PMC2984286. |
[30] | Gudbrandsen, O. A., Rost T. H, Berge R. K. Causes and prevention of tamoxifen-induced accumulation of triacylglycerol in rat liver. J Lipid Res. 2006. 47: 2223–2232. |
[31] | Owoade, A. O., Adetutu, A., Ogundipe, O. O., Owoade, A. W, Kehinde, E. O. Effects of tamoxifen administration on lipid profile in female albino rats. Asian J Res Biochem, 2022; 10(3), 10-22 |
[32] | Famurewa AC, Ekeleme-Egedigwe CA, David EE, Eleazu CO, Folawiyo AM, Obasi NA. Zinc abrogates anticancer drug tamoxifen-induced hepatotoxicity by suppressing redox imbalance, NO/iNOS/NF-ĸB signaling, and caspase-3-dependent apoptosis in female rats. Toxicol Mech Meth. 2020; 30: 115–23. |
[33] | Sakr SA, Mahran HA, Quora HA. Ameliorative effect of curcumin against tamoxifen induced hepatotoxicity in female albino rats J Exp Appl Animal Sci. 2017: 2(2)223-239. |
[34] | Mahboub FA. The Effect of Green Tea (Camellia sinensis) Extract against hepato-toxicity induced by tamoxifen in rats. J Food Process Technol 2016; 7: 625; 1-5 |
[35] | Rolo A. P, Teodoro J. S, Palmeira C. M. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic. Biol. Med. 2012; 52: 59–69. |
[36] | Marek, C. B., Peralta, R. M., Itinose, A. M, Bracht, A. Influence of tamoxifen on gluconeogenesis and glycolysis in the perfused rat liver. Chem Biol Interact. 2011; 193: 22–33. |
[37] | Ribeiro MP, Santos AE, Custódio JB. Mitochondria: the gateway for tamoxifen induced liver injury. Toxicol. 2014; 323: 10–18. |
[38] | Yilmaz, S., Gönenç, I. M, Yilmaz, E. Genotoxicity of the some selective estrogen receptor modulators: a review. Cytotechnology, 2014; 66(4): 533–541. |
[39] | Sherif RN, Eltahry HM, Abubakr SE. Protective effects of black seed and vitamin C on tamoxifen induced liver changes in adult female albino rat; biochemical and microscopic study Egypt J Anat, 2017; 40(1): 155-171. |
[40] | Lapenna D, Ciofani G, Festi D, Neri M, Pierdomenico SD, Giamberardino MA et al. Antioxidant properties of ursodeoxycholic acid, Biochem Pharmacol. 2002; 64(11)1661-1667. |
[41] | Geetha A, Parameswari SA. Effect of ursodeoxycholic acid on hydrogen peroxide induced lipid peroxidation in sheep liver mitochondria. Ind J Physiol Pharm. 2002, 46; 3; 343-8. PMID: 12613399. |
[42] | Larosche I, Letteron P, Fromenty B, Vadrot N, Abbey-Toby A, Feldmann G. et al. Tamoxifen inhibits topoisomerases, depletes mitochondrial DNA, and triggers steatosis in mouse liver. J Pharmacol Exp Ther. 2007; 321(2): 526–535. |
APA Style
Adikwu, E., Nnanna, T. B., Bokolo, B. (2024). Therapeutic Benefit of Ursodeoxycholic Acid in Tamoxifen-Induced Hepatotoxicity in Rats. American Journal of Internal Medicine, 12(6), 110-119. https://doi.org/10.11648/j.ajim.20241206.12
ACS Style
Adikwu, E.; Nnanna, T. B.; Bokolo, B. Therapeutic Benefit of Ursodeoxycholic Acid in Tamoxifen-Induced Hepatotoxicity in Rats. Am. J. Intern. Med. 2024, 12(6), 110-119. doi: 10.11648/j.ajim.20241206.12
AMA Style
Adikwu E, Nnanna TB, Bokolo B. Therapeutic Benefit of Ursodeoxycholic Acid in Tamoxifen-Induced Hepatotoxicity in Rats. Am J Intern Med. 2024;12(6):110-119. doi: 10.11648/j.ajim.20241206.12
@article{10.11648/j.ajim.20241206.12, author = {Elias Adikwu and Tobechi Brendan Nnanna and Bonsome Bokolo}, title = {Therapeutic Benefit of Ursodeoxycholic Acid in Tamoxifen-Induced Hepatotoxicity in Rats }, journal = {American Journal of Internal Medicine}, volume = {12}, number = {6}, pages = {110-119}, doi = {10.11648/j.ajim.20241206.12}, url = {https://doi.org/10.11648/j.ajim.20241206.12}, eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ajim.20241206.12}, abstract = {The use of tamoxifen (TAM) for breast cancer treatment may cause hepatotoxicity. Ursodeoxycholic acid (UDCA) is a potential liver protective chemical compound. The protective effect of UDCA on TAM-induced hepatotoxicity in rats was analyzed in this study. Thirty five adult female Wistar rats grouped into 7 of n=5/group were used. The rats were treated for 10 days as follows: Group 1: (Placebo control) Water (10 mL/kg/day/oral), group 2: (Vehicle control) Ethanol 1% (1mL/kg/day) intraperitoneally (i.p), group 3: UDCA (40 mg/kg/day/oral) and group 4: TAM (45 mg/kg/day) i.p. Groups 5-7 were pretreated with UDCA (10, 20 and 40 mg/kg/day/oral) before treatment with TAM (45 mg/kg/day) i.p, respectively. On day 11, blood samples were collected and evaluated for biochemical markers. Liver tissues were analyzed for oxidative stress markers and histology. Results: TAM decreased body weight and increased liver weight significantly (p<0.01) when compared to the placebo control. Serum bilirubin, alkaline phosphatase, gamma-glutamyl transferase, lactate dehydrogenase, aminotransferases, high density lipoprotein cholesterol and liver malondialdehyde levels were significantly (p<0.001) elevated by TAM when compared to control. TAM significantly (p<0.001) decreased serum triglyceride, very low density lipoprotein cholesterol, total cholesterol, liver glutathione, catalase, superoxide dismutase and glutathione peroxidase levels when compared to the control. TAM caused liver steatosis and necrosis in rats. However, UDCA pretreatment significantly prevented the aforementioned changes caused by TAM in a dose-related fashion. UDCA may be a therapeutic option for TAM associated hepatotoxicity. }, year = {2024} }
TY - JOUR T1 - Therapeutic Benefit of Ursodeoxycholic Acid in Tamoxifen-Induced Hepatotoxicity in Rats AU - Elias Adikwu AU - Tobechi Brendan Nnanna AU - Bonsome Bokolo Y1 - 2024/11/18 PY - 2024 N1 - https://doi.org/10.11648/j.ajim.20241206.12 DO - 10.11648/j.ajim.20241206.12 T2 - American Journal of Internal Medicine JF - American Journal of Internal Medicine JO - American Journal of Internal Medicine SP - 110 EP - 119 PB - Science Publishing Group SN - 2330-4324 UR - https://doi.org/10.11648/j.ajim.20241206.12 AB - The use of tamoxifen (TAM) for breast cancer treatment may cause hepatotoxicity. Ursodeoxycholic acid (UDCA) is a potential liver protective chemical compound. The protective effect of UDCA on TAM-induced hepatotoxicity in rats was analyzed in this study. Thirty five adult female Wistar rats grouped into 7 of n=5/group were used. The rats were treated for 10 days as follows: Group 1: (Placebo control) Water (10 mL/kg/day/oral), group 2: (Vehicle control) Ethanol 1% (1mL/kg/day) intraperitoneally (i.p), group 3: UDCA (40 mg/kg/day/oral) and group 4: TAM (45 mg/kg/day) i.p. Groups 5-7 were pretreated with UDCA (10, 20 and 40 mg/kg/day/oral) before treatment with TAM (45 mg/kg/day) i.p, respectively. On day 11, blood samples were collected and evaluated for biochemical markers. Liver tissues were analyzed for oxidative stress markers and histology. Results: TAM decreased body weight and increased liver weight significantly (p<0.01) when compared to the placebo control. Serum bilirubin, alkaline phosphatase, gamma-glutamyl transferase, lactate dehydrogenase, aminotransferases, high density lipoprotein cholesterol and liver malondialdehyde levels were significantly (p<0.001) elevated by TAM when compared to control. TAM significantly (p<0.001) decreased serum triglyceride, very low density lipoprotein cholesterol, total cholesterol, liver glutathione, catalase, superoxide dismutase and glutathione peroxidase levels when compared to the control. TAM caused liver steatosis and necrosis in rats. However, UDCA pretreatment significantly prevented the aforementioned changes caused by TAM in a dose-related fashion. UDCA may be a therapeutic option for TAM associated hepatotoxicity. VL - 12 IS - 6 ER -