title: Involvement of oxidative stress and mitochondrial/lysosomal cross-talk in olanzapine cytotoxicity in freshly isolated rat hepatocytes.
abstract: 1. Olanzapine (OLZ) is a widely used atypical antipsychotic agent for the treatment of schizophrenia and other disorders. Serious hepatotoxicity and elevated liver enzymes have been reported in patients receiving OLZ. However, the cellular and molecular mechanisms of the OLZ hepatotoxicity are unknown. 2. In this study, the cytotoxic effect of OLZ on freshly isolated rat hepatocytes was assessed. Our results showed that the cytotoxicity of OLZ in hepatocytes is mediated by overproduction of reactive oxygen species (ROS), mitochondrial potential collapse, lysosomal membrane leakiness, GSH depletion and lipid peroxidation preceding cell lysis. All the aforementioned OLZ-induced cellular events were significantly (p < 0.05) prevented by ROS scavengers, antioxidants, endocytosis inhibitors and adenosine triphosphate generators. Also, the present results demonstrated that CYP450 is involved in OLZ-induced oxidative stress and cytotoxicity mechanism. 3. It is concluded that OLZ hepatotoxicity is associated with both mitochondrial/lysosomal involvement following the initiation of oxidative stress in hepatocytes.
authors.affiliation: a Biotechnology Research Center, Tabriz University of Medical Sciences , Tabriz , Iran .|b Drug Applied Research Center, Tabriz University of Medical Sciences , Tabriz , Iran .|c Pharmacology and Toxicology Department, School of Pharmacy, Tabriz University of Medical Sciences , Tabriz , Iran , and.|d Students' Research Committee, Tabriz University of Medical Sciences , Tabriz , Iran.
authors.forename: Aziz
authors.initials: A
authors.lastname: Eftekhari
authors.affiliation: b Drug Applied Research Center, Tabriz University of Medical Sciences , Tabriz , Iran .|c Pharmacology and Toxicology Department, School of Pharmacy, Tabriz University of Medical Sciences , Tabriz , Iran , and.
authors.forename: Yadollah
authors.initials: Y
authors.lastname: Azarmi
authors.affiliation: b Drug Applied Research Center, Tabriz University of Medical Sciences , Tabriz , Iran .|c Pharmacology and Toxicology Department, School of Pharmacy, Tabriz University of Medical Sciences , Tabriz , Iran , and.
authors.forename: Alireza
authors.initials: A
authors.lastname: Parvizpur
authors.affiliation: b Drug Applied Research Center, Tabriz University of Medical Sciences , Tabriz , Iran .|c Pharmacology and Toxicology Department, School of Pharmacy, Tabriz University of Medical Sciences , Tabriz , Iran , and.
authors.forename: Mohammad Ali
authors.initials: MA
authors.lastname: Eghbal
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001569:Benzodiazepines / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002469:Cell Separation; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D019803:Glutathione Disulfide / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D000077152:Olanzapine; D018384:Oxidative Stress / Q000187:drug effects*; D010634:Phenobarbital; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D065607:Cytochrome P-450 Enzyme Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D001569:Benzodiazepines; D000255:Adenosine Triphosphate; D000077152:Olanzapine; D019803:Glutathione Disulfide; D010634:Phenobarbital
keywords: Hepatotoxicity; ROS formation; liver damage; mitochondrial/lysosomal dysfunction; olanzapine