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Curcumin protects against ketoconazole-induced hepatotoxicity in Wistar rats

Year 2025, Volume: 42 Issue: 2, 133 - 138, 30.06.2025

Abstract

Ketoconazole (KZ) is a broad-spectrum antifungal drug that can cause hepatotoxicity. Curcumin (CM), an isolate of Curcuma longa L. is used in folk medicine to treat various ailments. This study assessed whether CM can protect against a rat model of KZ-induced hepatotoxicity. Thirty healthy adult Wistar rats (220-240g) were randomly grouped (n=5/group) and supplemented orally with CM (50, 100 and 200 mg/kg/day) prior to the oral administration of KZ (200 mg/kg/day) for 14 days. On day 15, the rats were weighed and anesthetized. Blood samples were collected, and sera were extracted for biochemical analyses. Liver samples were excised, weighed and processed for oxidative stress markers and histology. KZ significantly (p < 0.01) decreased body weight and significantly (p< 0.001) decreased liver glutathione, superoxide dismutase, catalase, and glutathione peroxidase levels when compared to control. KZ significantly (p < 0.01) increased liver weight and significantly (p < 0.001) increased serum gamma-glutamyl transferase, alkaline phosphatase, amino transferases, lactate dehydrogenase, total bilirubin and liver malondialdehyde levels when compared to control. KZ caused hepatocyte necrosis. However, CM supplementation significantly restored body and liver weights at 50 mg/kg (p < 0.05), 100 mg/kg (p < 0.01) and 200 mg/kg (p < 0.01) when compared to KZ. CM supplementation restored serum biochemical and liver oxidative stress markers at 50 mg/kg (p < 0.05), 100 mg/kg (p < 0.01) and 200 mg/kg (p < 0.001) when compared to KZ. CM restored liver histology. CM was effective against KZ-induced hepatotoxicity in a dose-related fashion.

Ethical Statement

The European Communities Council Directive of 24 November 1986 (86/609/EEC) was carefully and vividly followed during the course of this study as stated in the methodology section.

Thanks

Thanks for the privilege give to us to submit our research work.

References

  • Zhou ZX, Yin XD, Zhang Y, Shao QH, Mao XY, Hu WJ, S.et al. Antifungal Drugs and Drug-Induced Liver Injury: A Real-World Study Leveraging the FDA Adverse Event Reporting System Database. Front. Pharmacol. 2022; 13:891336.
  • Khoza S, Moyo I, Ncube D. Comparative Hepatotoxicity of Fluconazole, Ketoconazole, Itraconazole, Terbinafine, and Griseofulvin in Rats. J Toxicol. 2017;2017:6746989.
  • Ying YJ, Xiao Lu N, Mei TQ, Yan ZS, Yan De Z. Ketoconazole Associated Hepatotoxicity: A Systematic Review and Meta-analysis. Biomed Environ Sci, 2013; 26(7): 605-610
  • Greenblatt HK, Greenblatt DJ. Liver Injury Associated with Ketoconazole: Review of the Published Evidence. The J Clin Pharmacol 2014; 54(12) 1321–1329
  • Mahmoud Bothina L, Ahmad El-roghy, Eman S, Kefafy, Maisa A et al. Light and electron microscopic study on the effect of ketoconazole on the liver of adult male albino rats. Menoufia Med J, 2016; 29 (4), 21. 929-35.
  • Farzaei MH, Zobeiri M, Parvizi F, El-Senduny FF, Marmouzi L, Coy-Barrera E et al. Curcumin in Liver Diseases: A Systematic Review of the Cellular Mechanisms of Oxidative Stress and Clinical Perspective. Nutrients. 2018; 10(7): 855. 1-28
  • Liu S, Liu J, He L, Liu L, Cheng B, Zhou F, Cao D, He Y. A Comprehensive Review on the Benefits and Problems of Curcumin with Respect to Human Health. Mole. 2022; 27(14):4400.
  • Monfared AL, Yousefizadeh Y. Curcumin ameliorates sertraline-mediated testicular toxicity in rats via inhibition of oxidative stress Iranian J Toxiciol, 2023; 17 (1)25-34.
  • Damiano S, Longobardi C,Andretta E, Prisco F, Piegari G, Squillacioti C et al. Antioxidative Effects of Curcumin on the Hepatotoxicity Induced by Ochratoxin A in Rats , Antioxidants (Basel). 2021;10(1): 125; 1-6
  • Farashbandi AL, Shariati M, Mokhtari M. Comparing the Protective Effects of Curcumin and Ursodeoxycholic Acid after Ethanol-Induced Hepatotoxicity in Rat Liver. Ethiop J Health Sci. 2021; 31 (3) 673-682
  • Ahmad MM, Rezk NA, Fawzy A, Sabry M. Protective effects of curcumin and silymarin against paracetamol induced hepatotoxicity in adult male albino rats. Gene. 2019; 5;712:143966.
  • 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 (2) 399-409
  • European Communities Council Directive of 24 November 1986 (86/609/EEC),
  • Hamza AA, Gamel M, Abdalla A, Abdalla Y, Amin A. Gentiana lutea attenuates hepatotoxicity induced by ketoconazole in rats by fortifying the cellular antioxidant defense system. The J Basic and Appl Zool 2023;84;1,1-12
  • Adikwu E, Kemelayefa J. Acyclovir-Induced Nephrotoxicity: The Protective Benefit of Curcumin. Eur J Biol 2021;80 (1):22-28.
  • Rotruck JT, Rope AL, Ganther HF, Swason AB. Selenium: biochemical role as a component of glutathione peroxidase. Sci. 1973; 179: 588–590.
  • Sedlak, J, Lindsay RH. Estimation of total, protein-bound and non-protein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem. 1968; 25: 192-205.
  • Sun M, Zigman S. AnImproved Spectrophotometer Assay of Superoxide Dismutase Based On Epinephrine, Antioxidation. Analy Biochem 1978; 90: 81-89
  • Aebi H. Catalase in vitro. In Method in Enzymology, Colowick SP and Kaplane NO, Eds.,New York, NY, USA: Academic Press, 1984
  • Buege JA, Aust SD. Microsomal lipid peroxidation. Meth Enzymol. 1978; 52: 302-310.
  • Gulati K, Reshi MR, Rai N, Ray A. Hepatotoxicity: Its Mechanisms, Experimental Evaluation and Protective Strategies. Am J Pharmacol. 2018; 1(1): 1004
  • Noureddin, N., Kaplowitz, N. (2018). Overview of Mechanisms of Drug-Induced Liver Injury (DILI) and Key Challenges in DILI Research. In: Chen, M., Will, Y. (eds) Drug-Induced Liver Toxicity. Methods in Pharmacology and Toxicology. Humana, New York, NY.
  • Rodriguez, R. J, Buckholz, C. J. Hepatotoxicity of ketoconazole in Sprague-Dawley rats:Glutathione depletion, flavin- contanung monooxygenases-mediated bioactivation and hepatic covalent binding. Xenobiotica, 2003; 33, 429– 441
  • Mahdavi H, Hadadi Z, Ahmadi M. A Review of the Anti-oxidation, Anti-inflammatory and Anti-tumor Properties of Curcumin. Trad Integr Med 2017; 2(4): 188-195.
  • Amacher DE, Schomaker SJ, Boldt SE, Mirsky M. The relationship among microsomal enzyme induction, liver weight and histological change in cynomolgus monkey toxicology studies. Food Chem Toxicol 2006;44 4 528-37
  • Adikwu E, Ebong NO, Ezeude CF. Preclinical benefit of silymarin in ketoconazole-induced hepatotoxicity Eurasian J Tox. 2024;6(2): 22-27
  • Adikwu E, Liverpool E. Valproic acid induced hepatotoxicity in rats: Protective effect of selenium. J Nat Sci Med 2021;4:118-23
  • Fu S, Wu D, Jiang W, Li J, Long J, Jia C, Zhou T. Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives. Front. Pharmacol. 2020; 10:1667
  • Giannini E G, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ 2005; 172 (3), 367–379.
  • Padda, M. S., Sanchez, M., Akhtar, A. J, Boyer, J. L. Drug-induced cholestasis. Hepatol 2011; 53 (4), 1377–1387.
  • Thakur S, Kumar V, Das R, Sharma V, Sharma V, Mehta DK. Biomarkers of Hepatic Toxicity: An Overview, Current Ther Res, 2024; 100, 100737,
  • Plaa G, Zimmerson H. Evaluation of hepatotoxicity: Physiological and biochemical measures of hepatic function. Comp Toxicol, 1997; 9, 97–109.
  • Allameh A, Niayesh-Mehr R, Aliarab A, Sebastiani G, Pantopoulos K. Oxidative Stress in Liver Pathophysiology and Disease. Antioxidants (Basel). 2023; 12(9):1653; 1-23.
  • Valko M, Rhodes C, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress- induced cancer. ChemicoBiol Inter, 2006; 160, 1–40.
  • Halliwell B. Antioxidant defence mechanisms: From the beginning to the end (of the beginning) Free Radic. Res. 1999; 31:261–272.
  • Stricker BH Ch, Blok APR, Bronkhorst FB. Ketoconazole-associated hepatic injury: A clinicopathological study of 55 cases, J of Hepatol. 1986; 3 ;3, 399-406
  • Banerjee P, Gaddam N, Chandler V, Chakraborty S. Oxidative Stress–Induced Liver Damage and Remodeling of the Liver Vasculature, The American J Pathol, 2023; 193 (10)1400-1414.
  • Marchiani A, Rozzo C, Fadda A, Delogu G, Ruzza P. Curcumin and curcumin-like molecules: From spice to drugs. Curr Med Chem 2014; 21: 204-22.
  • Lin YG, Kunnumakkara AB, Nair A, Merritt WM, Han LY, Armaiz-Pena GN. et al. Curcumin inhibits tumor growth and angiogenesis in ovarian carcinoma by targeting the nuclear factor-κB pathway. Clin Cancer Res 2007; 13: 3423- 30.
  • Kohli K, Ali J, Ansari MJ, Raheman Z. Curcumin: A natural anti-inflammatory agent. Indian J Pharmacol 2005; 37: 141-7
There are 40 citations in total.

Details

Primary Language English
Subjects Gastroenterology and Hepatology
Journal Section Research Article
Authors

Bamiwuye Similoluwa 0000-0003-4349-8227

Nwakaego Ebong 0000-0002-8629-4390

Bamiwuye Similoluwa 0009-0005-5717-1649

Submission Date August 28, 2024
Acceptance Date April 16, 2025
Publication Date June 30, 2025
Published in Issue Year 2025 Volume: 42 Issue: 2

Cite

APA Similoluwa, B., Ebong, N., & Similoluwa, B. (2025). Curcumin protects against ketoconazole-induced hepatotoxicity in Wistar rats. Deneysel Ve Klinik Tıp Dergisi, 42(2), 133-138.
AMA Similoluwa B, Ebong N, Similoluwa B. Curcumin protects against ketoconazole-induced hepatotoxicity in Wistar rats. J. Exp. Clin. Med. June 2025;42(2):133-138.
Chicago Similoluwa, Bamiwuye, Nwakaego Ebong, and Bamiwuye Similoluwa. “Curcumin Protects Against Ketoconazole-Induced Hepatotoxicity in Wistar Rats”. Deneysel Ve Klinik Tıp Dergisi 42, no. 2 (June 2025): 133-38.
EndNote Similoluwa B, Ebong N, Similoluwa B (June 1, 2025) Curcumin protects against ketoconazole-induced hepatotoxicity in Wistar rats. Deneysel ve Klinik Tıp Dergisi 42 2 133–138.
IEEE B. Similoluwa, N. Ebong, and B. Similoluwa, “Curcumin protects against ketoconazole-induced hepatotoxicity in Wistar rats”, J. Exp. Clin. Med., vol. 42, no. 2, pp. 133–138, 2025.
ISNAD Similoluwa, Bamiwuye et al. “Curcumin Protects Against Ketoconazole-Induced Hepatotoxicity in Wistar Rats”. Deneysel ve Klinik Tıp Dergisi 42/2 (June2025), 133-138.
JAMA Similoluwa B, Ebong N, Similoluwa B. Curcumin protects against ketoconazole-induced hepatotoxicity in Wistar rats. J. Exp. Clin. Med. 2025;42:133–138.
MLA Similoluwa, Bamiwuye et al. “Curcumin Protects Against Ketoconazole-Induced Hepatotoxicity in Wistar Rats”. Deneysel Ve Klinik Tıp Dergisi, vol. 42, no. 2, 2025, pp. 133-8.
Vancouver Similoluwa B, Ebong N, Similoluwa B. Curcumin protects against ketoconazole-induced hepatotoxicity in Wistar rats. J. Exp. Clin. Med. 2025;42(2):133-8.