title: A new approach on methamphetamine-induced hepatotoxicity: involvement of mitochondrial dysfunction.
abstract: 1.  Methamphetamine (METH) is a highly addictive stimulant that is among the most widely abused illicit drugs. Clinical evidence has shown that the liver is a target of METH toxicity. The exact cellular and molecular mechanisms involved in METH-induced hepatotoxicity have not yet been completely understood. 2.  In this study, the cellular pathways involved in METH liver toxicity were investigated in freshly isolated rat hepatocytes. METH cytotoxicity was associated with reactive oxygen species (ROS) formation, lipid peroxidation and rapid glutathione (GSH) depletion which is a third marker of cellular oxidative stress. Our results showed that the hepatocyte mitochondrial membrane potential (ΔΨm) was rapidly decreased by METH, which was prevented by antioxidants and ROS scavenger, suggesting that mitochondrial membrane damage was a consequence of ROS formation. Incubation of hepatocytes with METH also caused release of cytochrome c from mitochondria into the cytosol before cell lysis ensued. 3.  Our findings showed that cytotoxic action of METH is mediated by oxidative stress and subsequent changes in mitochondrial membrane conformation and cytochrome c release into the cytosol which causes mitochondrial collapse of ΔΨm.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, Zanjan University of Medical Sciences , Zanjan , Iran .
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Eskandari
authors.forename: Mokhtar
authors.initials: M
authors.lastname: Rahmati
authors.forename: Ali Reza
authors.initials: AR
authors.lastname: Khajeamiri
authors.forename: Farzad
authors.initials: F
authors.lastname: Kobarfard
authors.forename: Maryam
authors.initials: M
authors.lastname: Noubarani
authors.forename: Himan
authors.initials: H
authors.lastname: Heidari
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014343:Trypan Blue
chemical_list: D017382:Reactive Oxygen Species; D008694:Methamphetamine; D005978:Glutathione; D014343:Trypan Blue