title: Mitochondrial dysfunction induced by sertraline, an antidepressant agent.
abstract: Sertraline, a selective serotonin reuptake inhibitor, has been used for the treatment of depression. Although it is generally considered safe, cases of sertraline-associated liver injury have been documented; however, the possible mechanism of sertraline-associated hepatotoxicity is entirely unknown. Here, we report that mitochondrial impairment may play an important role in liver injury induced by sertraline. In mitochondria isolated from rat liver, sertraline uncoupled mitochondrial oxidative phosphorylation and inhibited the activities of oxidative phosphorylation complexes I and V. Additionally, sertraline induced Ca(2+)-mediated mitochondrial permeability transition (MPT), and the induction was prevented by bongkrekic acid (BA), a specific MPT inhibitor targeting adenine nucleotide translocator (ANT), implying that the MPT induction is mediated by ANT. In freshly isolated rat primary hepatocytes, sertraline rapidly depleted cellular adenosine triphosphate (ATP) and subsequently induced lactate dehydrogenase leakage; both were attenuated by BA. Our results, including ATP depletion, induction of MPT, inhibition of mitochondrial respiration complexes, and uncoupling oxidative phosphorylation, indicate that sertraline-associated liver toxicity is possibly via mitochondrial dysfunction.
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research/U.S. FDA, Jefferson, Arkansas 72079, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Letha
authors.initials: L
authors.lastname: Couch
authors.forename: Masahiro
authors.initials: M
authors.lastname: Higuchi
authors.forename: Jia-Long
authors.initials: JL
authors.lastname: Fang
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000633:toxicity*; D001865:Bongkrekic Acid / Q000494:pharmacology; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000226:Mitochondrial ADP, ATP Translocases / Q000187:drug effects / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D010085:Oxidative Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D017367:Selective Serotonin Reuptake Inhibitors / Q000633:toxicity*; D020280:Sertraline / Q000633:toxicity*; D013997:Time Factors
chemical_list: D000255:Adenosine Triphosphate; D000928:Antidepressive Agents; D001865:Bongkrekic Acid; D016572:Cyclosporine; D045222:Electron Transport Chain Complex Proteins; D007770:L-Lactate Dehydrogenase; D000226:Mitochondrial ADP, ATP Translocases; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline