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In vitro and in vivo evaluation of the mechanisms of citalopram-induced hepatotoxicity

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Abstract

Even though citalopram is commonly used in psychiatry, there are several reports on its toxic effects. So, the current study was designed to elucidate the mechanisms of cytotoxic effects of in vitro and in vivo citalopram treatment on liver and the following cytolethal events. For in vitro experiments, freshly isolated rat hepatocytes were exposed to citalopram along with/without various agents. To do in vivo studies liver function enzyme assays and histological examination were performed. In the in vitro experiments, citalopram (500 µM) exposure demonstrated cell death, a marked elevation in ROS formation, mitochondrial potential collapse, lysosomal membrane leakiness, glutathione (GSH) depletion and lipid peroxidation. In vivo biochemistry panel assays for liver enzymes function (AST, ALT and GGTP) and histological examination confirmed citalopram (20 mg/kg)-induced damage. citalopram-induced oxidative stress cytotoxicity markers were significantly prevented by antioxidants, ROS scavengers, MPT pore sealing agents, endocytosis inhibitors, ATP generators and CYP inhibitors. Either enzyme induction or GSH depletion were concomitant with augmented citalopram-induced damage both in vivo and in vitro which were considerably ameliorated with antioxidants and CYP inhibitors. In conclusion, it is suggested that citalopram hepatotoxicity might be a result of oxidative hazard leading to mitochondrial/lysosomal toxic connection and disorders in biochemical markers which were supported by histomorphological studies.

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References

  • Abdelmajeed NA (2009) Oxidative tissue damage induced by citalopram in rat different organs. RES J Med Med Sci 4:580–586

    CAS  Google Scholar 

  • Abdel-Razaq W, Kendall D, Bates T (2011) The effects of antidepressants on mitochondrial function in a model cell system and isolated mitochondria. Neurochem Res 36:327–338

    Article  CAS  PubMed  Google Scholar 

  • Addabbo Montagnani M, Goligorsky MS (2009) Mitochondria and reactive oxygen species. Hypertension 53:885–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ahmadian E, Jafari S, Khosroushahi AY (2015) Role of angiotensin II in stem cell therapy of cardiac disease. J Renin Angiotensin Aldosterone Syst 16:702–711

    Article  CAS  PubMed  Google Scholar 

  • Attia SM, Bakheet SA (2013) Citalopram at the recommended human doses after long-term treatment is genotoxic for male germ cell. Food Chem Toxicol 53:281–285

    Article  CAS  PubMed  Google Scholar 

  • Bayir H, Kagan VE (2008) Bench-to-bedside review: mitochondrial injury, oxidative stress and apoptosis–there is nothing more practical than a good theory. Crit Care 12:206

    Article  PubMed  PubMed Central  Google Scholar 

  • Boya P, Kroemer G (2008) Lysosomal membrane permeabilization in cell death. Oncogene 27:6434–6451

    Article  CAS  PubMed  Google Scholar 

  • Chatuphonprasert W, Sangkawat T, Nemoto N, Jarukamjorn K (2011) Suppression of beta-naphthoflavone induced CYP1A expression and lipid-peroxidation by berberine. Fitoterapia 82:889–895

    Article  CAS  PubMed  Google Scholar 

  • Drew R, Miners JO (1984) The effects of buthionine sulphoximine (BSO) on glutathione depletion and xenobiotic biotransformation. Biochem Pharmacol 33:2989–2994

    Article  CAS  PubMed  Google Scholar 

  • Dykens JA, Jamieson JD, Marroquin LD, Nadanaciva S, Xu JJ, Dunn MC, Smith AR, Will Y (2008) In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone. Toxicol Sci 103:335–345

    Article  CAS  PubMed  Google Scholar 

  • Eftekhari A, Azarmi Y, Parvizpur A, Eghbal MA (2015) Involvement of oxidative stress and mitochondrial/lysosomal cross-talk in olanzapine cytotoxicity in freshly isolated rat hepatocytes. Xenobiotica 46:369–378

    Article  PubMed  Google Scholar 

  • Eghbal MA, Tafazoli S, Pennefather P, O’Brien PJ (2004) Peroxidase catalysed formation of cytotoxic prooxidant phenothiazine free radicals at physiological pH. Chem Biol Interact 151:43–51

    Article  CAS  PubMed  Google Scholar 

  • Eghbal MA, Taziki S, Sattari MR (2014) Mechanisms of phenytoin-induced toxicity in freshly isolated rat hepatocytes and the protective effects of taurine and/or melatonin. J Biochem Mol Toxicol 28:111–118

    Article  CAS  PubMed  Google Scholar 

  • Guerra LN, Escudero A, Sáinz M, Venegoni M, Montastruc JL, Carvajal A (2014) Hepatotoxicity related to agomelatine and other new antidepressants. J Clin Psychopharmacol 34:327–330

    Article  PubMed  Google Scholar 

  • Haj-Mirzaian A, Rahimi-Balaei M, Naserzadeh P, Dehpour A, Mehr SE, Hosseini M-J (2015) Tropisetron attenuated the anxiogenic effects of social isolation by modulating nitrergic system and mitochondrial function. Biochim Biophys Acta 1850:2464–2475

    Article  PubMed  Google Scholar 

  • Heidari R, Babaei H, Eghbal MA (2013) Cytoprotective effects of taurine against toxicity induced by isoniazid and hydrazine in isolated rat hepatocytes. Arh Hig Rada Toksikol 64:15–24

    Article  PubMed  Google Scholar 

  • Heidari R, Babaei H, Eghbal M (2014a) Amodiaquine-induced toxicity in isolated rat hepatocytes and the cytoprotective effects of taurine and/or N-acetyl cysteine. Res Pharm Sci 9:97–105

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heidari R, Babaei H, Roshangar L, Eghbal MA (2014b) Effects of enzyme induction and/or glutathione depletion on methimazole-induced hepatotoxicity in mice and the protective role of N-acetylcysteine. Adv Pharm Bull 4:21–28

    CAS  PubMed  Google Scholar 

  • Hroudova J, Fisar Z (2010) Activities of respiratory chain complexes and citrate synthase influenced by pharmacologically different antidepressants and mood stabilizers. Neuroendocrinol Lett 31:336–342

    CAS  PubMed  Google Scholar 

  • Hwang J, Zheng LT, Ock J, Lee MG, Kim S-H, Lee H-W, Lee W-H, Park H-C, Suk K (2008) Inhibition of glial inflammatory activation and neurotoxicity by tricyclic antidepressants. Neuropharmacol 55:826–834

    Article  CAS  Google Scholar 

  • Jaeschke H, McGill MR, Ramachandran A (2012) Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. Drug Metab Rev 44:88–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jamshidzadeh A, Niknahad H, Kashafi H (2007) Cytotoxicity of chloroquine in isolated rat hepatocytes. J Appl Toxicol 27:322–326

    Article  CAS  PubMed  Google Scholar 

  • Kalgutkar AS, Gardner I, Obach RS, Shaffer CL, Callegari E, Henne KR, Mutlib AE, Dalvie DK, Lee JS, Nakai Y (2005) A comprehensive listing of bioactivation pathways of organic functional groups. Curr Drug Metab 6:161–225

    Article  CAS  PubMed  Google Scholar 

  • Khan S, O’Brien PJ (1991) 1-bromoalkanes as new potent nontoxic glutathione depletors in isolated rat hepatocytes. Biochem Biophys Res Commun 179:436–441

    Article  CAS  PubMed  Google Scholar 

  • Lim S, Lee S-J, Nam K-W, Kim KH, Mar W (2013) Hepatoprotective effects of reynosin against thioacetamide-induced apoptosis in primary hepatocytes and mouse liver. Arch Pharm Res 36:485–494

    Article  CAS  PubMed  Google Scholar 

  • López-Torres E, Lucena MI, Seoane J, Verge C, Andrade RJ (2004) Hepatotoxicity related to citalopram. Am J Psychiatry 161:923–924

    Article  PubMed  Google Scholar 

  • Luzio JP, Pryor PR, Bright NA (2007) Lysosomes: fusion and function. Nat Rev Mol Cell Biol 8:622–632

    Article  CAS  PubMed  Google Scholar 

  • Milkiewicz P, Chilton A, Hubscher S, Elias E (2003) Antidepressant induced cholestasis: hepatocellular redistribution of multidrug resistant protein (MRP2). Gut 52:300–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minguez L, Farcy E, Ballandonne C, Lepailleur A, Serpentini A, Lebel J-M, Bureau R, Halm-Lemeille M-P (2014) Acute toxicity of eight antidepressants: what are their modes of action? Chemosphere 108:314–319

    Article  CAS  PubMed  Google Scholar 

  • Mohammadi Z, Azarnia M, Mirabolghasemi G, Shiravi A, Mohammadi Z (2013) Histological changes in the liver of fetuses of pregnant rats following citalopram administration. Indian J Pharmacol 45:517–521

    Article  PubMed  PubMed Central  Google Scholar 

  • O’Brien P, Siraki A (2005) Accelerated cytotoxicity mechanism screening using drug metabolising enzyme modulators. Curr Drug Metab 6:101–109

    Article  PubMed  Google Scholar 

  • Overø KF, Svendsen O (1978) Toxicological aspects of food safety. In: Leonard BJ (ed) Hepatotoxicity of citalopram in rats and first-pass metabolism. Springer, Berlin Heidelberg, pp 177–180

    Google Scholar 

  • Pelkonen O, Maenpaa J, Taavitsainen P, Rautio A, Raunio H (1998) Inhibition and induction of human cytochrome P450 (CYP) enzymes. Xenobiotica 28:1203–1253

    Article  CAS  PubMed  Google Scholar 

  • Pourahmad J, Hosseini M-J, Eskandari MR, Shekarabi SM, Daraei B (2010) Mitochondrial/lysosomal toxic cross-talk plays a key role in cisplatin nephrotoxicity. Xenobiotica 40:763–771

    Article  CAS  PubMed  Google Scholar 

  • Pourahmad J, Eskandari MR, Kaghazi A, Shaki F, Shahraki J, Fard JK (2012) A new approach on valproic acid induced hepatotoxicity: involvement of lysosomal membrane leakiness and cellular proteolysis. Toxicol In Vitro 26:545–551

    Article  CAS  PubMed  Google Scholar 

  • Reed DJ, Babson JR, Beatty PW, Brodie AE, Ellis WW, Potter DW (1980) High-performance liquid chromatography analysis of nanomole levels of glutathione, glutathione disulfide, and related thiols and disulfides. Anal Biochem 106:55–62

    Article  CAS  PubMed  Google Scholar 

  • Santos N, Medina W, Martins N, Mingatto FE, Curti C, Santos A (2008) Aromatic antiepileptic drugs and mitochondrial toxicity: effects on mitochondria isolated from rat liver. Toxicol In Vitro 22:1143–1152

    Article  CAS  PubMed  Google Scholar 

  • Shaki F, Hosseini M-J, Ghazi-Khansari M, Pourahmad J (2012) Toxicity of depleted uranium on isolated rat kidney mitochondria. Biochim Biophys Acta 1820:1940–1950

    Article  CAS  PubMed  Google Scholar 

  • Siegmund SV, Brenner DA (2005) Molecular pathogenesis of alcohol-induced hepatic fibrosis. Alcohol Clin Exp Res 29:102S–109S

    Article  CAS  PubMed  Google Scholar 

  • Solomons K, Gooch S, Wong A (2005) Toxicity with selective serotonin reuptake inhibitors. Am J Psychiatry 162:1225

    Article  PubMed  Google Scholar 

  • Taziki S, Sattari MR, Eghbal MA (2013) Mechanisms of trazodone-induced cytotoxicity and the protective effects of melatonin and/or taurine toward freshly isolated rat hepatocytes. J Biochem Mol Toxicol 27:457–462

    CAS  PubMed  Google Scholar 

  • Uchiyama M, Mihara M (1978) Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 86:271–278

    Article  CAS  PubMed  Google Scholar 

  • Voican CS, Corruble E, Naveau S, Perlemuter G (2014) Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry 171:404–415

    Article  PubMed  Google Scholar 

  • von Moltke LL, Greenblatt DJ, Grassi JM, Granda BW, Venkatakrishnan K, Duan SX, Fogelman SM, Harmatz JS, Shader RI (1999) Citalopram and desmethylcitalopram in vitro: human cytochromes mediating transformation, and cytochrome inhibitory effects. Biol Psychiatry 46:839–849

    Article  Google Scholar 

  • Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM, Heydorn WE (2014) A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. Am J Psychiatry 161:1079–1083

    Article  Google Scholar 

  • Xia Z, Bergstrand A, DePierre JW, Nässberger L (1999a) The antidepressants imipramine, clomipramine, and citalopram induce apoptosis in human acute myeloid leukemia HL-60 cells via caspase-3 activation. J Biochem Mol Toxicol 13:338–347

    Article  CAS  PubMed  Google Scholar 

  • Xia Z, Lundgren B, Bergstrand A, DePierre JW, Nässberger L (1999b) Changes in the generation of reactive oxygen species and in mitochondrial membrane potential during apoptosis induced by the antidepressants imipramine, clomipramine, and citalopram and the effects on these changes by Bcl-2 and Bcl-X L. Biochem Pharmacol 57:1199–1208

    Article  CAS  PubMed  Google Scholar 

  • Yilmaz O, Keser S, Tuzcu M, Guvenc M, Cetintas B, Irtegun S, Tastan H, Sahin K (2009) A practical HPLC method to measure reduced (GSH) and oxidized (GSSG) glutathione concentrations in animal tissues. J Anim Vet Adv 8:343–347

    CAS  Google Scholar 

  • Yoshida T (1996) Determination of reduced and oxidized glutathione in erythrocytes by high-performance liquid chromatography with ultraviolet absorbance detection. J Chromatogr B Biomed Sci Appl 678:157–164

    Article  CAS  Google Scholar 

  • Yun J, Lee Y, Yun K, Oh S (2015) Bergenin decreases the morphine-induced physical dependence via antioxidative activity in mice. Arch Pharmacal Res 38:1248–1254

    Article  CAS  Google Scholar 

  • Zitka O, Skalickova S, Gumulec J, Masarik M, Adam V, Hubalek J, Trnkova L, Kruseova J, Eckschlager T, Kizek R (2012) Redox status expressed as GSH: GSSG ratio as a marker for oxidative stress in paediatric tumour patients. Oncol Lett 4:1247–1253

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors would like to thank Drug Applied Research Center of Tabriz University of Medical Sciences, Tabriz, Iran, for providing technical facilities. This is a report of a database from thesis entitled “Evaluation of the mechanisms of hepatic injuries induced by antidepressant drugs” registered and funded by a grant (Grant number: 77/93) from the Drug Applied Research Center of Tabriz University of Medical Sciences, Tabriz, Iran. The authors are also thankful to the University’s “Students’ Research Committee” for providing technical supports to the study.

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Authors and Affiliations

  1. Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Elham Ahmadian

  2. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Elham Ahmadian, Hossein Babaei, Daryoush Mohammadnejad & Mohammad Ali Eghbal

  3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Postal Code 51664-14766, Tabriz, Iran

    Elham Ahmadian, Aziz Eftekhari, Javad Khalili Fard, Hossein Babaei, Alireza Mohajjel Nayebi & Mohammad Ali Eghbal

  4. Students’ Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    Elham Ahmadian, Aziz Eftekhari & Javad Khalili Fard

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  1. Elham Ahmadian
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Correspondence to Mohammad Ali Eghbal.

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Drug applied research center (Grant number: 77/93).

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Ahmadian, E., Eftekhari, A., Fard, J.K. et al. In vitro and in vivo evaluation of the mechanisms of citalopram-induced hepatotoxicity. Arch. Pharm. Res. 40, 1296–1313 (2017). https://doi.org/10.1007/s12272-016-0766-0

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  • DOI: https://doi.org/10.1007/s12272-016-0766-0

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