Document Type : Original Article

Authors

1 MSc Student in Physiology, Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran

2 Associate Professor of Physiology, Physiology Research Center, Institute of Basic and Clinical Physiology Sciences , Kerman University of Medical Sciences, Kerman, Iran

3 Professor of Physiology, Endocrinology and Metabolism Research Center, Kerman University of Medical Sciences, Kerman, Iran

4 Professor of Biochemistry, Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran

5 Medical Student, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran

6 MSc Student in Physiology, Gastroenterology and Hhepatology Research Center, Kerman University of Medical Sciences, Kerman, Iran

Abstract

Background: A majority of people widely use acetaminophen as a sedative. Overusing the drug for prolonged periods of time can lead to acute liver damage. Mumijo, as a strong antioxidant and anti-inflammatory drug, could possibly reduce some of the acetaminophen-induced side effects on the liver. Thus, the aim of this study is to evaluate the effect of Mumijo on the liver damage caused by the use of acetaminophen.
Methods: 40 male Wistar rats were randomly divided into five groups: sham, acetaminophen, low and high doses of mumijo, and vehicle. All groups except the sham group received a single dose of 500 mg/kg acetaminophen via ip injection. Then the groups that were under treatment received 150 mg/kg (low dose) and 250 mg/kg (high dose) of mumijo, and the vehicle group received distilled water as vehicle. After 24 hours, blood samples were taken for biochemical tests, and a part of the liver was extracted for histopathological examination.
Results: acetaminophen increases the activities of functional liver enzymes including alanine amino transferase (ALT), aspartate aminotransferase (AST), and gamma glutamine transferase (GGT). In groups under treatment, values of the mentioned enzymes were significantly reduced in comparison with the acetaminophen and vehicle groups (P <0.05), and on the other hand, malondialdehyde (MDA), nitric oxide (NO), and protein carbonyl (PC) increase caused by acetaminophen were reduced by mumijo. Furthermore, the amount of glutathione (GPX) was increased by mumijo (P <0.05). From a histopathological point of view, necrosis and liver damage caused by acetaminophen was decreased by mumijo.
Conclusion:The findings showed that mumijo is salient in preventing liver damage caused by consumption of high doses of acetaminophen probably through reducing oxidant activities and also through increasing anti-inflammatory and antioxidant activities.
 

Keywords

  1. Hinson JA, Roberts DW, James LP. Mechanisms of acetaminophen-induced liver necrosis. Handb Exp Pharmacol 2010; (196):369-405
  2. Dong H, Haining RL, Thummel KE, Rettie AE, Nelson SD. Involvement of human cytochrome P450 2D6 in the bioactivation of acetaminophen. Drug Metab Dispos 2000;28 (12):1397-400.
  3. Potter WZ, Thorgeirsson SS, Jollow DJ, Mitchell JR. Acetaminophen-induced hepatic necrosis. V. Correlation of hepatic necrosis, covalent binding and glutathione depletion in hamsters. Pharmacology 1974;12 (3):129-43.
  4. McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest 2012;122 (4):1574-83.
  5. Jiang J, Briede JJ, Jennen DG, Van Summeren A, Saritas-Brauers K, Schaart G, et al. Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. ToxicolLett 2015;234 (2):139-50.
  6. Dirksen K, Burgener IA, Rothuizen J, van den Ingh T, Penning LC, Spee B, et al. Sensitivity and specificity of plasma ALT, ALP, and Bile Acids for hepatitis in Labrador retrievers. J Vet Intern Med 2017;31 (4):1017-27.
  7. Sheen CL, Dillon JF, Bateman DN, Simpson KJ, Macdonald TM. Paracetamol toxicity: epidemiology, prevention and costs to the health-care system. QJM 2002;95 (9):609-19.
  8. Grace E, Herbert M, Essien G, Nsikan U, Akpan H, Ubana E, et al. The protective effect of combined leaf extracts of gongronema latifolium and nauclea latifolia on acetaminophen-induced liver toxicity in rats. British Journal of Applied Science & Technology 2014;4 (15):21-52.
  9. Golestan Jahromi M, Nabavizadeh F, Vahedian J, Nahrevanian H, Dehpour AR, Zare-Mehrjardi A. Protective effect of ghrelin on acetaminophen-induced liver injury in rat. Peptides 2010;31 (11):2114-7.
  10. Agarwal SP, Khanna R, Karmarkar R, Anwer MK, Khar RK. Shilajit: a review. Phytother Res 2007;21 (5):401-5.
  11. Goel RK, Banerjee RS, Acharya SB. Antiulcerogenic and antiinflammatory studies with shilajit. J Ethnopharmacol 1990;29 (1):95-103.
  12. Stohs SJ. Safety and efficacy of shilajit (mumie, moomiyo). Phytother Res 2014;28 (4):475-9.
  13. Malekzadeh G, Dashti-Rahmatabadi MH, Zanbagh S, Akhavi Mirab-bashii A. Mumijo attenuates chemically induced inflammatory pain in mice. Altern Ther Health Med 2015;21 (2):42-7.
  14. Bhattacharya SK, Sen AP, Ghosal S. Effects of shilajit on biogenic free radicals. Phytotherapy Research 1995;9 (1):56-9.
  15. Joukar S, Najafipour H, Dabiri S, Sheibani M, Sharokhi N. Cardioprotective effect of mumie (shilajit) on experimentally induced myocardial injury. Cardiovasc Toxicol 2014;14 (3):214-21.
  16. Ghosal S. Free radicals, oxidative stress and antioxidant defense. Phytomedica 2000;21 (1/2):1-8.
  17. Khaksari M, Mahmmodi R, Shahrokhi N, Shabani M, Joukar S, Aqapour M. The effects of shilajit on brain edema, intracranial pressure and neurologic outcomes following the traumatic brain injury in rat. Iran J Basic Med Sci 2013;16 (7):858-64.
  18. Lin CC, Hsu YF, Lin TC, Hsu HY. Antioxidant and hepatoprotective effects of punicalagin and punicalin on acetaminophen-induced liver damage in rats. Phytother Res 2001;15 (3):206-12.
  19. Kesavulu MM, Giri R, KameswaraRao B, Apparao C. Lipid peroxidation and antioxidant enzyme levels in type 2 diabetics with microvascular complications. Diabetes Metab 2000;26 (5):387-92.
  20. Titheradge MA. The Enzymatic Measurement of Nitrate and Nitrite. In: Titheradge MA, editor. Nitric Oxide Protocols. Totowa, NJ: Humana Press; 1998;P 83-91.
  21. Lee BM, Kacew S. Lu's Basic Toxicology: Fundamentals, Target Organs, and Risk Assessment. 6th ed. London (UK): Taylor & Francis; 2012.
  22. Slee EA, Adrain C, Martin SJ. Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J Biol Chem 2001;276 (10):7320-6.
  23. Grattagliano I, Bonfrate L, Diogo CV, Wang HH, Wang DQ, Portincasa P. Biochemical mechanisms in drug-induced liver injury: certainties and doubts. World J Gastroenterol 2009;15 (39):4865-76.
  24. Myagmar BE, Shinno E, Ichiba T, Aniya Y. Antioxidant activity of medicinal herb Rhodococcum vitis-idaea on galactosamine-induced liver injury in rats. Phytomedicine 2004;11 (5):416-23.
  25. Bourdi M, Masubuchi Y, Reilly TP, Amouzadeh HR, Martin JL, George JW, et al. Protection against acetaminophen-induced liver injury and lethality by interleukin 10: role of inducible nitric oxide synthase. Hepatology 2002;35 (2):289-98.
  26. Testa B, Perrissoud D. Liver Drugs: From Experimental Pharmacology to Therapeutic Application: CRC PressI Llc; Boca Raton. pp 113-143
  27. Tripathi YB, Shukla S, Chaurasia S, Chaturvedi S. Antilipid peroxidative property of shilajit. Phytotherapy Research1996;10 (3): 269-73.
  28. Schepetkin I, Khlebnikov A, Kwon BS. Medical drugs from humus matter: Focus on mumie. Drug Development Research 2002;57 (3):140-59.
  29. Kass GE, Macanas‐Pirard P, Lee PC, Hinton RH. The role of apoptosis in acetaminophen-induced injury. Annals of the New York Academy of Sciences. 2003;1010 (1):557-9.
  30. Hu J, Yan D, Gao J, Xu C, Yuan Y, Zhu R, et al. rhIL-1Ra reduces hepatocellular apoptosis in mice with acetaminophen-induced acute liver failure. Lab Invest 2010;90 (12):1737-46.
  31. Goldin RD, Ratnayaka ID, Breach CS, Brown IN, Wickramasinghe SN. Role of macrophages in acetaminophen (paracetamol)-induced hepatotoxicity. J Pathol 1996;179 (4):432-5.
  32. Laskin DL, Gardner CR, Price VF, Jollow DJ. Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen. Hepatology 1995;21 (4):1045-50.