title: Evaluating the Role of Drug Metabolism and Reactive Intermediates in Trazodone-Induced Cytotoxicity toward Freshly-Isolated Rat Hepatocytes.
abstract: Background:Trazodone is an antidepressant agent widely administered for the treatment of depressive disorders. On the other hand, several cases of hepatic injury have been reported after Trazodone administration. Although the precise mechanism(s) of trazodone-induced liver injury is not known, some investigations proposed the role of reactive intermediates in this complication. This study was designed to investigate the role of reactive metabolites in hepatocytes injury induced by trazodone.Methods:Isolated rat hepatocytes were prepared by the method of collagenase enzyme perfusion via the portal vein. Cells were treated with trazodone, its cytotoxic metabolite, and different enzyme inhibitors and cytoprotective agents.Results:It was found that trazodone was toxic towards hepatocytes and caused 50% cell death after 2 h of incubation at a dose of 450 µM. The trazodone postulated reactive metabolite;m-chlorophenyl piperazine (m-CPP) was less toxic and caused 50% cell death at a dose of 750 µM at a similar time period. Cellular glutathione (GSH) depletion and lipid peroxidation were detected when hepatocytes were treated with trazodone and/or m-CPP. Depleting hepatocytes GSH beforehand, increased cytotoxicity of both trazodone and m-CPP. Troleandomycin as the CYP3A4 inhibitor prevented cytotoxicity of trazodone but slightly affected m-CPP-induced cell injury. Inhibition of CYP2D6 by quinidine and cimetidine increased the cytotoxicity of both trazodone and m-CPP. Antioxidants and ATP suppliers slightly prevented cytotoxicity of trazodone and m-CPP.Conclusion:As inhibitors of CYP3A4 and 2D6 affected trazodone cytotoxicity, it is suggested that trazodone -induced cytotoxicity, at least in part, is mediated by its reactive metabolites.
authors.affiliation: Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: A
authors.initials: A
authors.lastname: Najibi
authors.affiliation: Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: R
authors.initials: R
authors.lastname: Heidari
authors.affiliation: Pharmacology and Toxicology Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: J
authors.initials: J
authors.lastname: Zarifi
authors.affiliation: Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: A
authors.initials: A
authors.lastname: Jamshidzadeh
authors.affiliation: Pharmacology and Toxicology Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: N
authors.initials: N
authors.lastname: Firoozabadi
authors.affiliation: Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: H
authors.initials: H
authors.lastname: Niknahad
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008658:Inactivation, Metabolic / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014196:Trazodone / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D005978:Glutathione; D014196:Trazodone