HEPATOPROTECTIVE EFFECT OF PRAZOSIN IS COMPARABLE TO N-ACETYLCYSTEINE IN ACETAMINOPHEN INDUCED HEPATOTOXICITY IN MICE
AbstractBackground: Autonomic nervous system modulates acetaminophen induced hepatotoxicity. The purpose of the study was to determine the hepatoprotective effect of α1 antagonist (prazosin) and β2 agonist (salbutamol) on acetaminophen induced hepatotoxicity in mice. Methods: This experimental study was conducted at Post Graduate Medical Institute, Lahore in which 50 adult mice were divided in to five groups. With the exception of normal control, hepatotoxicity was induced in all other study groups by giving single intraperitoneal injection of acetaminophen 300 mg/ kg. First and second groups served as normal and toxic control were given distilled water 6 ml/ kg while third, fourth and fifth experimental groups were given N-acetylcysteine (300 mg/ kg), prazosin (0.18 mg/ kg) and salbutamol (0.35 mg/ kg) intraperitoneally at 2,4 and 8 hours after acetaminophen injection. Serum liver enzymes were analysed at 0 and 72 hours while histopathological finding were assessed at the end of study by using SPSS-20. Results: All the groups treated with toxic dose of acetaminophen showed significant increase in serum ALT, i.e., B (Toxic control 3372%), C (NAC treated 282%), D (Prazosin treated 582%), E(Salbutamol treated 3297%) and AST levels, i.e., B (Toxic control 2750% ), C (NAC treated 230% ), D (Prazosin treated 280%), E(Salbutamol treated 828%) with p-value ˂0.001 . When this increase was compared between groups, the lowest increase in serum ALT and AST levels was observed in N-acetylcysteine and prazosin group with no significant difference. Similarly, experimental animals receiving prazosin and N-acetylcysteine had the lowest inflammation, degeneration and necrosis scores than the toxic control group in histopathological analysis of the liver with p-value˂0.001. Conclusion: The hepatoprotective effect of prazosin is comparable to N- acetylcysteine against acetaminophen induced hepatotoxicity in mice.Keywords: Hepatotoxicity; Acetaminophen; Prazosin; Salbutamol
Lee WM. Acetaminophen (APAP) hepatotoxicity-isn’t it time for APAP to go away? J Hepatolo 2017;67(6):1324–31.
Yoon E, Babar A, Choudhary M, Kutner M, Pyrsopoulos N. Acetaminophen-induced hepatotoxicity: a comprehensive update. J Clin Transl Hepatol 2016;28;4(2):131–42.
Athersuch TJ, Antoine DJ, Boobis AR, Coen M, Daly AK, Possamai L, et al. Paracetamol metabolism, hepatotoxicity, biomarkers and therapeutic interventions: a perspective. Toxicol Res (Camb) 2018;7(3):347–57.
Walker V, Mills GA, Anderson ME, Ingle BL, Jackson JM, Moss CL, et al. The acetaminophen metabolite N-acetyl-p- benzoquinone imine (NAPQI) inhibits glutathione synthetase in vitro; a clue to the mechanism of 5-oxoprolinuric acidosis? Xenobiotica 2017;47(2):164–75.
Marks DJ, Dargan PI, Archer JR, Davies CL, Dines AM, Wood DM, et al. Outcomes from massive paracetamol overdose: a retrospective observational study. Br J Clin Pharmacol 2017;83(6):1263–72.
Mizuno K, Ueno Y. Autonomic Nervous System and the Liver. Hepatol Res 2017;47(2):160–5.
Randle LE, Sathish JG, Kitteringham NR, Macdonald I, Williams DP, Park BK. α1-adrenoceptor antagonists prevent paracetamol-induced hepatotoxicity in mice. Br J Pharmacol 2008;153(4):820–30.
Soeda J, Mouralidarane A, Ray S, Novelli M, Thomas S, Roskams T. The beta‐adrenoceptor agonist isoproterenol rescues acetaminophen‐injured livers through increasing progenitor numbers by Wnt in mice. Hepatology 2014;60(3):1023–34.
Kiba T. The role of autonomic nervous system in liver regeneration and apoptosis-recent developments. Int J Gastroeterol 2002;66(2):79–88.
National Research Council. Guide for the care and use of laboratory animals. National Academies Press; 2010.
Tai M, Zhang J, Song S, Miao R, Liu S, Pang Q, et al. Protective effects of luteolin against acetaminophen-induced acute liver failure in mouse. Int Immunopharmacol 2015;27(1):164–70.
Zwingmann G, Bilodeau M. Metabolic insights into the hepatoprotective role of N-acteylcysteine in mouse liver. Hepatology 2006;43(3):454–63.
Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 2016;7(2):27–31.
Yin P, Lehmann R, Xu G. Effects of pre-analytical processes on blood samples used in metabolomics studies. Anal Bioanal Chem 2015;407(17):4879–92.
Shahid M, Subhan F. Comparative histopathology of acetaminophen induced hepatotoxicity in animal models of mice and rats. Pharmacol Online 2014;3(33):32–43.
Saito C, Zwingmann C, Jaeschke H. Novel mechanism of protection against acetaminophen hepatotoxicity in mice by glutathione and N-acetylcysteine. Hepatology 2010;51(1):246–54.
Clement YN, Williams AF. Protection against paracetamol-induced hepatic injury by prazosin pre-treatment in CD-1 mice. Mutat Res 2005;579:182–8.
Zubairi MB, Ahmed JH, Al-Haroon SS. Effect of adrenergic blockers, carvedilol, prazosin, metoprolol and combination of prazosin and metoprolol on paracetamol-induced hepatotoxicity in rabbits. Indian J Pharmacol 2014;46(6):644–8.
Acharya M, Lau-Cam CA. Comparison of the protective action of N-acetylcysteine, hypotaurine and taurine against acetaminophen-induced hepatotoxicity in the rat. J Biomed Sci 2010;17(1):1–11.
Wang GS, Monte A, Bagdure D, Heard K. Hepatic failure despite early acetylcysteine following large acetaminophen-diphenhydramine overdose. Pediatrics 2011;127(4):1077–80.
Kazemifar AM, Hajaghamohammadi AA, Samimi R, Alavi Z, Abbasi E, Asl MN. Hepatoprotective property of oral silymarin is comparable to N-acetylcysteine in acetaminophen poisoning. Gastroenterol Res 2012;5(5):190–4.
Rofaeil RR, Kamel MY, Abdelzaher WY. Different effects of selective β1‐adrenoceptor antagonists, nebivolol or atenolol in acetaminophen‐induced hepatotoxicity of rats. Fundam Clin Pharmacol 2017;31(2):165–73.
Andre C, Couton D, Gaston J, Erraji L, Renia L, Varlet P, et al. Βeta-2 adrenergic receptor-selective agonist clenbuterol prevents Fas-induced apoptosis and death in mice. Am J Physiol 1999;276(3):647–54.
Wen X, Huan H, Wang X, Chen X, Wu L, Zhang Y, et al. Sympathetic neurotransmitters promote the process of recellularization in decellularized liver matrix via activating the IL-6/Stat3 pathway. Biomed Mater 2016;11(6):065007.