In vitro and in vivo evaluation of the mechanisms of citalopram-induced hepatotoxicity.
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.
Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.|Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.|Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Postal Code 51664-14766, Tabriz, Iran.|Students' Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
Elham
E
Ahmadian
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Postal Code 51664-14766, Tabriz, Iran.|Students' Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
Aziz
A
Eftekhari
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Postal Code 51664-14766, Tabriz, Iran.|Students' Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
Javad Khalili
JK
Fard
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.|Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Postal Code 51664-14766, Tabriz, Iran.
Hossein
H
Babaei
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Postal Code 51664-14766, Tabriz, Iran.
Alireza Mohajjel
AM
Nayebi
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Daryoush
D
Mohammadnejad
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. m.a.eghbal@hotmail.com.|Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Postal Code 51664-14766, Tabriz, Iran. m.a.eghbal@hotmail.com.
Mohammad Ali
MA
Eghbal
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000503:physiopathology; D015283:Citalopram / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008111:Liver Function Tests; D008928:Mitochondria / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000633:toxicity*
D000975:Antioxidants; D015283:Citalopram; D005978:Glutathione; D017382:Reactive Oxygen Species; D017367:Selective Serotonin Reuptake Inhibitors
Antioxidants; Citalopram; Cytotoxicity; Mitochondrial/lysosomal dysfunction; Oxidative stress