HEPATOPROTECTIVE POTENTIAL OF MALABAR TAMARIND (Garcinia gummi-gutta) FRUIT-RIND EXTRACT IN ACETAMINOPHEN-INDUCED TOXICITY THROUGH MODULATION OF CYP2E1 GENE EXPRESSION IN HEPATIC CELLS OF WISTAR RATS
DOI:
https://doi.org/10.48165/Keywords:
Acetaminophen, CYP2E1, Garcinia gummi-gutta, liver, Wistar ratsAbstract
The present study was aimed to assess the hepatoprotective effect of ethanolic extract of Garcinia gummi-gutta (GGE) fruit rind on acetaminophen-induced toxicity in a rat model and to explore the possible mechanism of action by assessing hepatic histopathology, serum biochemical parameters and expression of CYP2E1 gene in hepatic cells. The group I and 11 animals served as normal control and hepatotoxic control group, respectively; while group III, IV and V were administrated with GGE fruit-rind extract @ 50, 100 & 200 mg kg-1 orally, respectively, for 10 days. The group VI (positive control) received drug silymarin @ 100 mg kg-1 day-1 orally for 10 days. Hepatotoxicity was induced by single oral administration of acetaminophen (2 g kg-1) on 8th day. The results revealed that the extract produced dose-dependent hepatoprotective effect against acetaminophen-induced hepatic damage by improving the serum bio chemical profile towards the normal range. Histopathology of liver showed that pretreatment with fruit-rind extract attenuated the toxicant-induced hepatocellular necrosis and enhanced the regeneration of hepatic cells. The hepatic expression level of CYP2E1 gene was found down-regulated in a dose dependent manner in extract-treated group as compared to the normal control group. The study revealed remarkable hepatoprotective effect of GGE in acetaminophen-induced toxicity in rats through regeneration of hepatic cells and by decreasing the formation of reactive metabolite, NAPQ1 by modulation of CYP2E1 gene expression in liver.
Downloads
References
Abushouk, A.I., Reggi, R., Yarla, N.S., Palmery, M. and Peluso, I. 2018. Association of antioxidant nutraceuticals and acetaminophen (paracetamol): Friend or foe? Journal of Food and Drug Analysis, 26(2): S78–S87.
Abirami, A., Nagarani, G. and Siddhuraju, P. 2015. Hepatoprotective effect of leaf extracts from Citrus hystrix and C. maxima against paracetamol induced liver injury in rats. Food Science Human Wellness, 4(1): 35-41.
Babu, P.S., Krishna, V., Maruthi, K., Shankarmurthy, K. and Babu, R. 2011. Evaluation of acute toxicity and hepatoprotective activity of the methanolic extract of Dichrostachys cinerea (Wight and Arn.) leaves. Pharmacognosy Research, 3(1): 40. [doi:10.4103/0974-8490.79114].
Barathane, D., Manimekalai, K. and Salwe, K.J. 2020. Hypolipidemic and antioxidant effect of Garcinia gummi-gutta Barkson atherogenic diet-induced hyperlipidemic rats. Biomedical and Pharmacology Journal, 13(4): 1903-1912.
Brennan, P.N., Cartlidge, P., Manship, T. and Dillon, J.F. 2021. EASL clinical practice guidelines: Drug-induced liver injury (DILI). Frontline Gastroenterology, 13(4): 332-336. Chen, W., Yang, C. and Yin, M. 2014. Protective effects from Houttuynia cordata aqueous extract against acetaminophen-induced liver injury. Biomedicine (Taipei). 4(1): 5. [10.7603/s40681- 014-0005-2].
Das, J., Ghosh, J., Manna, P. and Sil, P.C. 2010. Acetaminophen induced acute liver failure via oxidative stress and JNK activation: Protective role of taurine by the suppression of cytochrome P450 2E1. Free Radical Research, 44(3): 340-355.
Deore, A.B., Sapakal, V.D. and Naikwade, N.S. 2011. Antioxidant and hepatoprotective activity of Garcinia indica Linn fruit rind. Pharmacie Globale, 6: 1-5.
Dhanya, P. and Benny, P.J. 2014. Larvicidal action of Garcinia gummi-gutta. Robs. var. gummi gutta on dengue victim Aedes aegypti. Indian Journal of Applied Research, 4(1): 21-22. Engwa, G.A. 2018. Free radicals and the role of plant phytochemicals as antioxidants against oxidative stress related diseases. Phytochemicals – Source of Antioxidants and Role in Disease Prevention. [doi:5572/intechopen.76719].
Kokhdan, E.P., Ahmadi, K., Sadeghi, H., Sadeghi, H., Dadgary, F., Danaei, N. and Aghamaali, M.R. 2017. Hepatoprotective effect of Stachys pilifera ethanol extract in carbon tetrachloride induce hepatotoxicity in rats. Pharmaceutical Biology, 55(1): 1389-1393.
Gill, P., Bhattacharyya, S., McCullough, S., Letzig, L., Mishra, P.J., Luo, C., Dweep, H., Omirinde, J.O., Bejide, R., Isola, T.O., Usende, L.I. and Basiru, A. 2014. Comparative hepatoprotective activity of ethanolic extracts of Cuscuta australis against acetaminophen intoxication in Wistar rats. International Scholarly Research Notices, 2014, pp.1–6. [doi:10.1155/2014/730516].
James, L. 2017. MicroRNA regulation of CYP 1A2, CYP3A4 and CYP2E1 expression in acetaminophen toxicity. Scientific Reports, 7(1): 12331 [doi:10.1038/s41598-017-11811-y]. Guillén-Enríquez, C., López-Teros, V., Martín-Orozco, U., López-Díaz, J., del Hierro-Ochoa, J., Ramos-Jiménez, A., Astiazarán-García, H., Martínez-Ruiz, N. and Wall-Medrano, A. 2018. Selected physiological effects of a Garcinia gummi-gutta extract in rats fed with different hypercaloric diets. Nutrients, 10(5): 565. [doi:10.3390/nu10050565].
Ganesan, K., Jayachandran, M. and Xu, B. 2017. A critical review on hepatoprotective effects of bioactive food components. Critical Reviews in Food Science and Nutrition, 58(7): 1165-1229. García, N.P., Lores, O.F., Fuentes, D.P, Martínez, D.T. and Hernandez, J.B. 2014. Reduction of hepatotoxicity induced by acetaminophen overdoses in a mouse model of inflammation induced by Freund´s adjuvants. Journal of Allergy & Therapy, 5: 183. [doi:10.4172/2155- 6121.1000183].
Nili-Ahmadabadi, A., Ghobadi, S., Dastan, D. and Soleimani, M. 2018. Hepatoprotective potential and antioxidant activity of Allium tripedale in acetaminophen-induced oxidative damage. Research in Pharmaceutical Sciences, 14(6): 488. [doi:10.4103/1735-5362.272535].
Ghosh, M.N. 1984. Fundamentals of Experimental Pharmacology (2nd edn.). Scientific Book Agency; Kolkata, India.
Ha, K.T., Yoon, S.J., Choi, D.Y., Kim, D.W., Kim, J.K. and Kim, C.H. 2005. Protective effect of Lycium chinense fruit on carbon tetrachloride-induced hepatotoxicity. Journal of Ethno pharmacology, 96(3): 529-535.
Hinson, J.A., Roberts, D.W. and James, L.P. 2010. Mechanisms of acetaminophen-induced liver necrosis. Handbook of Experimental Pharmacology, 196: 369-405. [doi:10.1007/978-3-642- 00663-0_12].
Iorga, A., Dara, L. and Kaplowitz, N. 2017. Drug-induced liver injury: Cascade of events leading to cell death, apoptosis or necrosis. International Journal of Molecular Sciences, 18(5): 1018. [doi:10.3390/ijms18051018].
Islam, M.T., Quispe, C., Islam, Md.A., Ali, E.S., Saha, S., Asha, U.H., Mondal, M., Razis, A.F.A., Sunusi, U., Kamal, R.M., Kumar, M. and Sharifi-Rad, J. 2021. Effects of nerol on paracetamol-induced liver damage in Wistar albino rats. Biomedicine & Pharmacotherapy, 140: 111732. [doi:10.1016/j.biopha.2021.111732].
Janghel, V., Patel, P. and Chandel, S.S. 2019. Plants used for the treatment of icterus (jaundice) in Central India: A review. Annals of Hepatology, 18(5): 658-672.
Jing, Y., Wu, K., Liu, J., Ai, Q., Ge, P., Dai, J., Jiang, R., Zhou, D., Che, Q., Wan, J. and Zhang, L. 2015. Aminotriazole alleviates acetaminophen poisoning via downregulating P450 2E1 and
A.V. Rehna et al.
suppressing inflammation. PLOS ONE, 10(4): 0122781. [doi:10.1371/journal.pone.0122781]. Katarey, D. and Verma, S. 2016. Drug-induced liver injury. Clinical Medicine, 16(6): S104-S109. Keshari, P., Pradeep, P. and Bhat, S. 2019. Evaluation of hepatoprotective potential of
Rhododendron arboreum Sm. stem bark as Abhava pratinidhi Dravya (Substitute) of Rohitaka (Tecomella undulata (Sm.) Seem.) against paracetamol induced hepatotoxicity in experimental rats. Pharmacognosy Journal, 11(5): 1148-1154.
Khatib, N.A., Digaswala, P., Gupta, C.D. and Varghese, A. 2010. Hepato-protective potential of Garcinia indica fruit rind extract against acetaminophen induced hepatic damage in Wistar rats. Pharmacology [online], 1: 561-566.
Kullak-Ublick, G.A., Andrade, R.J., Merz, M., End, P., Benesic, A., Gerbes, A.L. and Aithal, G.P. 2017. Drug-induced liver injury: Recent advances in diagnosis and risk assessment. Gut, 66: 1154-1164. [doi:10.1136/gutjnl-2016-313369].
Lim, S.H., Lee, H.S., Lee, C.H. and Choi, C.-I. 2021. Pharmacological activity of Garcinia indica (Kokum): An updated review. Pharmaceuticals, 14(12): 1338. [doi:10.3390/ph14121338]. Livak, K.J. and Schmittgen, T.D.2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCt method. Methods. 25: 402-408.
Mahendran, P. and Devi, C.S. 2001. Effect of Garcinia cambogia extract on lipids and lipoprotein composition in dexamethasone administered rats. Indian Journal of Physiology & Pharmacology, 45(3): 345-350.
Manyike, P., Kharasch, E., Kalhorn, T. and Slattery, J. 2000. Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clinical Pharmacology & Therapeutics, 67(3): 275-282.
Mathew, G.E., Mathew, B., Shaneeb, M.M. and Nyanthara, B. 2011. Diuretic activity of leaves of Garcinia cambogia in rats. Indian Journal of Pharmaceutical Sciences, 73: 228-230. Mazzio, E.A. and Soliman, K.F.A. 2008. In vitro screening for the tumoricidal properties of international medicinal herbs. Phytotherapy Research, 23(3): 385-398.
McGill, M.R., Sharpe, M.R., Williams, C.D., Taha, M., Curry, S.C. and Jaeschke, H. 2012. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. Journal of Clinical Investigation, 122(4): 1574-1583.
Mundugaru, R., Varadharajan, M.C. and Basavaiah R. 2014. Hepatoprotective activity of fruit extract of Garcinia pedunculata. Bangladesh Journal of Pharmacology, 9: 483-487. Nili-Ahmadabadi, A., Alibolandi, P., Ranjbar, A., Mousavi, L., Nili-Ahmadabadi, H., Larki Harchegani, A., Ahmadimoghaddam, D. and Omidifar, N. 2018. Thymoquinone attenuates hepatotoxicity and oxidative damage caused by diazinon: An in vivo study. Research in Pharmaceutical Sciences, 13(6): 500. [doi:10.4103/1735-5362.245962].
Noureddin, N. and Kaplowitz, N. 2018. Overview of mechanisms of drug-induced liver injury (DILI) and key challengesin DILIresearch. pp. 3-18. In: Drug-induced Liver Toxicity. Methods in Pharmacology and Toxicology (eds. Y. Will and M. Chen). Humana Press, New Jersey, USA.
Okokon, J., Simeon, J. and Umoh, E. 2016. Nephroprotective activity of Homalium Letestui stem extract against paracetamol induced kidney injury. Journal of Experimental and Integrative Medicine, 6(1): 38. [doi:10.5455/jeim.250216.or.147].
Prasanth, N.V., Rasheed, S.P, Thomas, T., Joseph, S. and Varghese, C. 2013. Evaluation of in vitro and in vivo anti-inflammatory activity of Garcinia cambogia. L. International Journal Pharmacy and Pharmaceutical Sciences, 5: 263-264.
Raghavendra, M., Yatish, K.V. and Lalithamba, H.S. 2017. Plant-mediated green synthesis of ZnO nanoparticles using Garcinia gummi-gutta seed extract: Photoluminescence, screening of their catalytic activity in antioxidant, formylation and biodiesel production. The European Physical Journal Plus, 132(8): 358. [doi:10.1140/epjp/i2017-11627-1].
Raskovic, A., Milanovic, I., Pavlovic, N., Cebovic, T., Vukmirovic, S. and Mikov, M. 2014. Antioxidant activity of rosemary (Rosmarinus officinalis L.) essential oil and its
Hepatoprotective potential of Malabar tamarind fruit-rind extract 387
hepatoprotective potential. BMC Complementary and Alternative Medicine, 14: 225. [doi: 10.1186/1472-6882-14-225].
Reddy, M.K., Reddy, A.G., Kumar, B.K., Madhuri, D., Boobalan, G. and Reddy, M.A. 2017. Protective effect of rutin in comparison to silymarin against induced hepatotoxicity in rats. Veterinary World. 10(1): 74-80.
Rehna, A., Neethu, K.P. and Deepa, A.K. 2021. Phytochemical analysis and antimicrobial activity of ethanolic extract of dried fruit rind of Garcinia gummi-gutta. Journal Ayurveda and Herbal Medicine, 7(2): 81-85.
Sallie, R., Tredger, J. and William, R.1991. Drugs and the liver. Biopharmaceutics & Drug Disposition, 12: 251-259.
Samarajeewa, U. and Shanmugapirabu, N. 1983. A cheap method for preservation of fish. pp. 80- 81. In: Proceedings of the 6th International Congress of Food Science and Technology, Vol. 1, Boole Press, Dublin, Ireland.
Sarvankumar, G., Lalitha, V., Sengottuvelu, S., Sharif, S.H. and Sivakumar, T. 2011. Hepatoprotective activity of Vitex negundo Linn bark against chemical induced toxicity in experimental rats. International Journal of Advanced Pharmaceutical Sciences, 2: 534-540.
Semwal, R.B., Semwal, D.K., Vermaak, I. and Viljoen, A. 2015. A comprehensive scientific overview of Garcinia cambogia. Fitoterapia, 102: 134-148.
Singh, H., Prakash, A., Kalia, A.N. and Majeed, A.B.A. 2016. Synergistic hepatoprotective potential of ethanolic extract of Solanum xanthocarpum and Juniperus communis against paracetamol and azithromycin induced liver injury in rats. Journal of Traditional and Complementary Medicine, 6(4): 370-376.
Smith, Y.R.A. and Adanlawo, I.G. 2015. Protective effect of saponin extract from the root of Garcinia kola (Bitter kola) against paracetamol-induced hepatotoxicity in Albino rats. International Journal of Biological, Food, Veterinary and Agricultural Engineering, 9(2): 130-134.
Stanger, B.Z. 2015. Cellular homeostasis and repair in the mammalian liver. Annual Review of Physiology, 77(1): 179-200.
Subramanya, S.B., Venkataraman, B., Meeran, M.F.N., Goyal, S.N., Patil, C.R. and Ojha, S. 2018. Therapeutic potential of plants and plant derived phytochemicals against acetaminophen induced liver injury. International Journal of Molecular Sciences, 19(12): 3776. [doi:10.3390/ijms19123776].
Sumayya, P.A., Murugan, M., Gopukumar, S.T. and Praseetha, P.K. 2016. Estimation of phytochemical, antimicrobial and molecular comparison of fruit extracts of Garcinia cambogia and Tamarindus indica. Research Journal of Pharmacological, Biological and Chemical Sciences, 7(1): 1256-1263.
Sarkar, J., Kumar, N. and Gupta, P. 2020. Evaluation of hepatoprotective action of Solanum melongena L. peel extract against paracetamol induced liver damage in albino rats. Medical Science, 24(104): 2013-2024.
Tungmunnithum, D., Thongboonyou, A., Pholboon, A. and Yangsabai, A. 2018. Flavonoids and other phenolic compounds from medicinal plants for pharmaceutical and medical aspects: An overview. Medicines, 5(3):93. [doi:10.3390/medicines5030093].
Wang, X., Wu, Q., Liu, A., Anadón, A., Rodríguez, J.L., Martínez-Larrañaga, M.R., Yuan, Z. and Martínez, M.A. 2017. Paracetamol: Overdose-induced oxidative stress toxicity, metabolism, and protective effects of various compounds in vivo and in vitro. Drug Metabolism Reviews, 49(4): 395-437. [doi:10.1080/03602532.2017.1354014].
Yamaura, K., Nakayama, N., Shimada, M. and Ueno, K. 2011. Protective effects of goldenseal (Hydrastis canadensis L.) on acetaminophen-induced hepatotoxicity through inhibition of CYP2E1 in rats. Pharmacognosy Research, 3(4): 250. [doi:10.4103/09748490.89745].
Yuan, L. and Kaplowitz, N. 2013. Mechanisms of drug-induced liver injury. Clinics in Liver Disease, 17(4): 507-518.