Pomelo (Citrus maxima) Peel Ethanolic Extract Mitigates Isoniazid–Rifampicin–Induced Hepatotoxicity in a Male Wistar Rat Model
DOI:
https://doi.org/10.33755/jkk.v12i1.985Keywords:
Tuberculosis, Hepatotoxicity, Grapefruit Peel Extract, SGOT, SGPTAbstract
Background: Tuberculosis continues to pose a substantial public health challenge in Indonesia, which currently ranks second worldwide in disease burden. Although first-line antituberculosis drugs such as isoniazid and rifampicin are highly effective, their prolonged use is frequently associated with hepatotoxicity, which may disrupt treatment continuity and compromise patient safety. Identifying adjunctive strategies capable of reducing liver injury during antituberculosis therapy therefore remains an important research priority.
Objective: This study aimed to examine the concurrent hepatoprotective effect of pomelo (Citrus maxima) peel ethanolic extract in a male Wistar rat model exposed to isoniazid–rifampicin–induced liver injury.
Methods: An experimental posttest-only control group design was applied using thirty-two male Wistar rats distributed into five groups: a normal control, a negative control receiving isoniazid and rifampicin, and three treatment groups administered pomelo peel ethanolic extract at doses of 100, 200, and 400 mg/kg body weight. Hepatotoxicity was induced with isoniazid and rifampicin, followed by extract administration two hours after drug exposure from day 4 to day 10. Liver function was assessed by measuring serum alanine aminotransferase (SGPT) and aspartate aminotransferase (SGOT). Phytochemical screening was conducted to identify major secondary metabolites present in the extract.
Results: Phytochemical analysis revealed the presence of flavonoids, tannins, alkaloids, triterpenoids, and quinones in pomelo peel extract. Rats receiving isoniazid–rifampicin exhibited marked elevations in SGPT and SGOT levels compared with the normal control group. Concurrent administration of pomelo peel extract significantly reduced these enzyme levels across all treatment doses relative to the negative control. The 400 mg/kg body weight dose produced the greatest attenuation of hepatic enzyme elevation, indicating a dose-related protective response.
Conclusion: Pomelo (Citrus maxima) peel ethanolic extract demonstrates dose-dependent hepatoprotective activity during concurrent exposure to isoniazid and rifampicin in male Wistar rats. These findings suggest that pomelo peel extract may have potential as a supportive agent to mitigate antituberculosis drug–induced liver injury, although further mechanistic, pharmacokinetic, and clinical investigations are required prior to translational application
References
Basir, N., Djabir, Y. Y., & Santoso, A. (2020). Case reports on severe antituberculosis-drug induced hepatotoxicity in tuberculosis patients: The post-incidence therapy. Nusantara Medical Science Journal, 44-50.
Devarbhavi, H., Dierkhising, R., Kremers, W. K., Sandeep, M. S., Karanth, D., & Adarsh, C. K. (2013). Single-center experience with drug-induced liver injury from India: Causes, outcome, prognosis, and predictors of mortality. The American Journal of Gastroenterology, 108(9), 1526-1532.
Fayaz, M., Sharma, A., Pestell, R. G., & Lew-Tabor, A. (2025). Exploring the hepatoprotective effects of naringin. Planta Medica, 91, 466-487. https://doi.org/10.1055/a-2595-7650Guo, Y. X., Xu, X. F., Zhang, Q. Z., Li, C., Deng, Y., Jiang, P., & Zhao, L. (2015). The inhibition of hepatic bile acids transporters Ntcp and Bsep is involved in the pathogenesis of isoniazid/rifampicin-induced hepatotoxicity. Toxicology Mechanisms and Methods, 25(5), 382-387. https://doi.org/10.3109/15376516.2015.1033074
Hassan, H. M., Guo, H., Yousef, B. A., Guerram, M., Hamdi, A. M., Zhang, L., & Jiang, Z. (2016). Role of inflammatory and oxidative stress, cytochrome P450 2E1, and bile acid disturbance in rat liver injury induced by isoniazid and lipopolysaccharide cotreatment. Antimicrobial Agents and Chemotherapy, 60(9), 5285-5293. https://doi.org/10.1128/AAC.00854-16
Hernandez-Aquino, E., & Muriel, P. (2018). Beneficial effects of naringenin in liver diseases: Molecular mechanisms. World Journal of Gastroenterology, 24(16), 1679-1707. https://doi.org/10.3748/wjg.v24.i16.1679
Ibrahim, S. R. M., Mohamed, G. A., Khayat, M. T. A., Ahmed, S., & Abo-Haded, H. M. (2022). Biochemical and pharmacological prospects of Citrus sinensis peel. Saudi Pharmaceutical Journal, 30(9), 1335-1347. https://doi.org/10.1016/j.jsps.2022.07.003
Jiang, X., Zhou, Y., Zhang, Y., Tian, D., Jiang, S., & Tang, Y. (2020). Hepatoprotective effect of pyrroloquinoline quinone against alcoholic liver injury through activating Nrf2-mediated antioxidant and inhibiting TLR4-mediated inflammation responses. Process Biochemistry, 92, 303-312. https://doi.org/10.1016/j.procbio.2020.01.023
Lei, S., Gu, R., & Ma, X. (2021). Clinical perspectives of isoniazid-induced liver injury. Liver Research, 5(2), 45-52. https://doi.org/10.1016/j.livres.2021.02.001Mishra, S. (2019). A study on defaulter rates of pulmonary tuberculosis patients along with the risk of comorbidities among MDR-TB patients availing the dots facility in Hapur district. Medpulse International Journal of Community Medicine, 11(2), 32–35. https://doi.org/10.26611/10111121
Napitupulu, R. R. J., Siregar, A. Y., & Ompusunggu, H. E. S. (2023). Pengaruh pemberian ekstrak daun sirsak terhadap kadar SGPT dan SGOT tikus yang diinduksi obat anti tuberkulosis isoniazid dan rifampisin. Nommensen Journal of Medicine, 9(1), 6-9. https://doi.org/10.36655/njm.v9i1.1138Neelam, Khatkar, A., & Sharma, K. K. (2020). Phenylpropanoids and its derivatives: Biological activities and its role in food, pharmaceutical and cosmetic industries. Critical Reviews in Food Science and Nutrition, 60(16), 2655-2675.
Nurafni, S., Sari, N. K., & Mulyani, F. (2021). Comparison of drug induced hepatotoxicity incident of fixed-dose combination and separate formulations regimen for pulmonary tuberculosis treatment in Hospital Sukabumi. Journal of Physics: Conference Series, 1764(1), 012012. https://doi.org/10.1088/1742-6596/1764/1/012012
Raja Kumar, S., Mohd Ramli, E. S., Abdul Nasir, N. A., Ismail, N. H. M., & Mohd Fahami, N. A. (2019). Preventive effect of naringin on metabolic syndrome and its mechanism of action: A systematic review. Evidence-Based Complementary and Alternative Medicine, 2019(1), 9752826.Ramappa, V., & Aithal, G. P. (2013). Hepatotoxicity related to anti-tuberculosis drugs: Mechanisms and management. Journal of Clinical and Experimental Hepatology, 3(1), 37–49. https://doi.org/10.1016/j.jceh.2012.12.001
Rani, J., Dhull, S. B., Rose, P. K., & Kidwai, M. K. (2024). Drug-induced liver injury and anti-hepatotoxic effect of herbal compounds: A metabolic mechanism perspective. Phytomedicine, 122, 155142. https://doi.org/10.1016/j.phymed.2023.155142
Sobeh, M., Mahmoud, M., Abdelfattah, M., El-Beshbishy, H., El-Shazly, A., & Wink, M. (2017). Hepatoprotective and hypoglycemic effects of a tannin rich extract from Ximenia americana var. caffra root. Phytomedicine, 33, 36-42. https://doi.org/10.1016/j.phymed.2017.07.003
Sowmya, N., Haraprasad, N., & Bp, H. (2019). Exploring the total flavonoid content of peels of Citrus auriantum, Citrus maxima and Citrus sinensis using different solvents and HPLC- analysis of flavonones - Naringin and naringenin in peels of Citrus maxima. The Pharma Innovation Journal, 8(4), 12–17.
Sudto, K., Pornpakakul, S., & Wanichwecharungruang, S. (2009). An efficient method for the large scale isolation of naringin from pomelo (Citrus grandis) peel. International Journal of Food Science & Technology, 44(9), 1737-1742.
Wali, A. F., Rashid, S., Rashid, S. M., Ansari, M. A., Khan, M. R., Haq, N., Alhareth, D. Y., Ahmad, A., & Rehman, M. U. (2020). Naringenin regulates doxorubicin-induced liver dysfunction: Impact on oxidative stress and inflammation. Plants, 9(4), 550.World Health Organization. (2023). Global tuberculosis report 2023. https://www.who.int/publications/i/item/9789240083851
Zhao, C., Fan, J., Liu, Y., Guo, W., Cao, H., Xiao, J., Wang, Y., & Liu, B. (2019). Hepatoprotective activity of Ganoderma lucidum triterpenoids in alcohol-induced liver injury in mice, an iTRAQ-based proteomic analysis. Food Chemistry, 271, 148-156. https://doi.org/10.1016/j.foodchem.2018.07.115
Zhuang, X., Li, L., Liu, T., Zhang, R., Yang, P., & Wang, X. (2022). Mechanisms of isoniazid and rifampicin-induced liver injury and the effects of natural medicinal ingredients: A review. Frontiers in Pharmacology, 13, 1037814. https://doi.org/10.3389/fphar.2022.1037814.
