OXIDATIVE STRESS-BASED HEPATOTOXICITY OF DULOXETINE IN WISTAR RATS
Keywords:Duloxetine, CYP1A2 enzyme, Hepatotoxicity, Oxidative stress
Objective: Duloxetine, a selective serotonin and noradrenaline reuptake inhibitor used in major depressive disorders, urinary incontinence and diabetic peripheral neuropathic pain. It is reported to be associated with several types of liver injuries, including hepatocellular, cholestatic and mixed hepatocellular-cholestatic patterns. The objective of this study was to assess the effect of duloxetine or its metabolites on oxidative stress-induced liver damages.
Methods: In this study, animals were divided into five groups. In the first group, the only vehicle was given orally for 21 d. The second group has been considered as hepatotoxic control group where Erythromycin was given orally for 14 d and remaining three groups have been considered as test groups where duloxetine, fluvoxamine and duloxetine along with fluvoxamine were administered orally for 21 d. Liver GSH, oxidised lipid (malonaldehyde MDA), superoxide dismutase (SOD), catalase (CAT), protein carbonyl (PC) and plasma alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) levels were measured to determine the level of hepatotoxicity. Scanning electron microscopy (SEM) study of liver tissues was also performed to examine the liver injuries.
Results: GSH and SOD levels were found to be decreased in duloxetine-treated groups with respect to the hepatotoxic control group, whereas increased level of MDA, CAT and PC signify the damages of liver cells. Increased level of plasma ALT, AST and ALP at the same time indicated liver tissue damage. Opposite effects were observed in the case of duloxetine and fluvoxamine-treated groups. SEM of liver tissues revealed that the tissue injury occurred in Duloxetin treated groups, whereas the restoration of normal tissue architecture took place due to the administration of duloxetine and fluvoxamine-treated groups.
Conclusion: Our results collectively indicated that hydroxylated and epoxide metabolites of duloxetine might have hepatotoxic potential due to oxidative stress produced by the release of free radicals or reactive oxygen species.
Patel DS, Deshpande SS, Patel CG, Singh S. Duloxetine: a dual-action antidepressant. Indo Global J Pharm Sci 2011;1:63-76.
Chan CY, New LS, Ho HK, Chan ECY. Reversible time-dependent inhibition of cytochrome P450 enzymes by duloxetine and inertness of its thiophene ring towards bioactivation. Toxicol Lett 2011;206:314-24.
Wernicke J, Pangallo B, Wang F. Hepatic effects of duloxetine-I: non-clinical and clinical trial data. Curr Drug Saf 2008;3:132-42.
Wernicke J, Acharya N, Strombom I. Hepatic effects of duloxetine-II: spontaneous reports and epidemiology of hepatic events. Curr Drug Saf 2008;3:143-53.
McIntyre RS, Panjwani ZD, Nguyen HT, Woldeyohannes HO, Alsuwaidan M, Soczynska JK. The hepatic safety profile of duloxetine: a review. Expert Opin Drug Metab Toxicol 2008;4:281-5.
Vuppalanchi R, Hayashi PH, Chalasani N, Fontana RJ, Bonkovsky H, Saxena R, et al. Duloxetine hepatotoxicity: a case-series from the drug-induced liver injury network. Aliment Pharmacol Ther 2010;32:1174-83.
Hanje AJ, Pell LJ, Votolato NA, Frankel WL, Kirkpatrick RB. Case report: fulminant hepatic failure involving duloxetine hydrochloride. Clin Gastroenterol Hepatol 2006:4;912-7.
Nassr AH, Hameid A. Protective role of dimethyl diphenyl bicarboxylate (DDB) against erythromycin-induced hepatotoxicity in male rats. Toxicol In Vitro 2007;21:618-25.
Yamauchi M, Tatebayashi T, Nagase K, Kojima M, Imanishi T. Chronic treatment with Fluvoxamine desensitizes 5-HT2C receptor-mediated hypolocomotion in rats. Pharmacol Biochem Behav 2004:78;683-9.
Calabrese F, Molteni R, Cattaneo A, Macchi F, Racagni G, Gennarelli M, et al. Long-term duloxetine treatment normalises altered brain-derived neurotrophic factor expression in serotonin transporter knockout rats through the modulation of specific neurotrophin isoforms. Mole Pharmacol 2010;77;846-53.
Reitman S, Frankel S. A colorimetric method for the determination of SGOT and SGPT. Am J Clin Pathol 1957:28;53-6.
Tietz NW. Fundamentals of clinical chemistry. 2nd Ed. WB Saunders Company: Philadelphia; 1976. p. 602-4.
Rehman I, Kode A, Biswas SK. Assay for quantitative determination of glutathione and glutathione disulphide levels using enzymatic recycling methods. Nat Protoc 2007:1;3159-65.
Claiborne A. Catalase activity. CRS Hand Book of Methods for Oxygen Radical Research. Greenwald RA. CRC Press: Boca Raton, USA; 1985. p. 283-4.
Lodhi RL, Maity S, Kumar P, Saraf SA, Keith was G, Saha S. Evaluation of the mechanism of hepatotoxicity of leflunomide using albino Wistar rats. Afr J Pharm Pharmacol 2013;7:1625-31.
Reznick AZ, Packer L. Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Method Enzymol 1994;233:357-63.
Russmann S, Kullak-Ublick GA, Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem 2009;16:3041-53.
Boverhof DR, Burgoon LD, Tashiro C, Chittim B, Harkema JR, Jump DB, et al. Temporal and dose-dependent hepatic gene expression patterns in mice provide new insights into TCDD-mediated hepatotoxicity. Toxicol Sci 2005;85:1048-63.
Troudi A, Samet AM, Zeghal N. Hepatotoxicity induced by gibberellic acid in adult rats and their progeny. Exp Toxicol Pathol 2010;62:637-42.
Reid AB, Kurten RC, McCullough SS, Brock RW, Hinson JA. Mechanisms of acetaminophen-induced hepatotoxicity: role of oxidative stress and mitochondrial permeability transition in freshly isolated mouse hepatocytes. J Pharmacol Exp Ther 2005;312:509-16.
Vetriselvan S, Victor R, Muthappan M, Gnanasekaran D, Chellappann DS. Hepatoprotective effects of aqueous extract of Andrographis paniculata against ccl4 induced hepatotoxicity in albino Wistar rats. Asian J Pharm Clin Res 2011;4:93-4.
Saha S. Hepatotoxicity of thiazolidinedione antidiabetic drugs: a structural toxicity relationship studies. National University of Singapore, Ph. D. thesis; 2010. p. 1-137.
Suzuki YJ, Carini M, Butterfield DA. Protein carbonylation. Antioxid Redox Signal 2010:12;325-7.
Baudrimont I, Ahouandjivo R, Creppy EE. Prevention of lipid peroxidation induced by ochratoxin an in vero cells in culture by several agents. Chem Biol Interact 1997:104;29-40.
Reiter RJ, Tan D, Osuna C, Gitto E. Actions of melatonin in the reduction of oxidative stress. J Biomed Sci 2000:7;444-58.