Role of the mitochondrial permeability transition in salicylate toxicity to cultured rat hepatocytes: implications for the pathogenesis of Reye's syndrome

Toxicology and Applied Pharmacology
L C Trost, John J Lemasters

Abstract

Aspirin is strongly implicated in the pathogenesis of Reye's syndrome, a childhood disorder characterized by hyperammonemia, microvesicular steatosis, and encephalopathy. Previously, we showed that salicylate, the active metabolite of aspirin, induces the mitochondrial permeability transition (MPT) in isolated mitochondria, as do several other chemicals implicated in Reye's-related disorders. Opening of a high conductance, cyclosporin A-sensitive pore in the mitochondrial inner membrane causes the MPT, leading to swelling, depolarization, and uncoupling of oxidative phosphorylation. The goal of this study was to characterize the role of the MPT in salicylate toxicity to cultured rat hepatocytes. Salicylate (0.3-5 mM) caused concentration-dependent cell killing. In Krebs-Ringer buffer, half-maximal cell killing occurred 150 min after 3 mM salicylate. Increasing Ca2+ enhanced salicylate lethality. Salicylate-dependent cell killing was blocked by 0.5-5 microM cyclosporin A and its nonimmunosuppresive analog, 4-methylvaline cyclosporin, implicating the MPT in the pathogenesis of cell killing. The contribution of the MPT to lethal cell injury was confirmed by laser scanning confocal microscopy, which demonstrated the redistribution ...Continue Reading

Citations

Oct 23, 2001·Archives of Disease in Childhood·J F Glasgow, B Middleton
May 20, 1999·Annual Review of Pharmacology and Toxicology·T P DaltonA Puga
Mar 5, 2011·Journal of Clinical Biochemistry and Nutrition·Toshio WatanabeTetsuo Arakawa
Nov 1, 2006·The Journal of Experimental Medicine·Edward K ChowGenhong Cheng
Jul 5, 2005·Expert Opinion on Investigational Drugs·J WuM A Zern
Apr 24, 2014·Drug Metabolism Reviews·Christoffel Petrus Stephanus BadenhorstAlberdina Aike van Dijk
Feb 26, 2004·The Journal of Emergency Medicine·Kenneth D KatzRichard D Gerkin
Dec 18, 2001·Journal of Neuroscience Research·G BaiM D Norenberg
Dec 4, 2003·Journal of Neuroscience Research·K V Rama RaoM D Norenberg
May 25, 2002·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Defeng Wu, Arthur I Cederbaum
Aug 14, 2012·Journal of Applied Toxicology : JAT·Sairam BellumLouise C Abbott
Sep 8, 2000·Bulletin of Experimental Biology and Medicine·A S SaratikovI V Sukhodolo
Jun 15, 2007·Molecular and Cellular Biochemistry·Poonam Kakkar, B K Singh
Apr 29, 2005·Toxicological Sciences : an Official Journal of the Society of Toxicology·Vincent TongFrank S Abbott
Aug 16, 2005·The Journal of Biological Chemistry·Valentina BattagliaAntonio Toninello
Feb 23, 2007·Journal of Leukocyte Biology·Edward Kai-Hua ChowGenhong Cheng
Feb 26, 2015·Clinical Journal of Gastroenterology·Tomoki ShirotaShinichi Miyagawa
Jun 19, 2003·The Journal of Biological Chemistry·Andres A Caro, Arthur I Cederbaum
Oct 31, 2002·The Journal of Biological Chemistry·Defeng Wu, Arthur I Cederbaum
Jul 9, 2020·International Journal of Molecular Sciences·Itsuho FujikawaYoshihiro Suzuki-Karasaki
Jan 10, 2002·Toxicology and Applied Pharmacology·Tobi L Limke, William D Atchison
Feb 3, 2009·Clinics in Chest Medicine·Michael L SchilskySukru Emre
Aug 26, 2009·The International Journal of Biochemistry & Cell Biology·Valeriy LukyanenkoW J Lederer
Jul 7, 2009·Biochimica Et Biophysica Acta·John J LemastersAnna-Liisa Nieminen
Oct 8, 2009·Archives of Biochemistry and Biophysics·Nirupama LalJohn M Yanni
Dec 2, 2009·Chemico-biological Interactions·Hirokazu Doi, Toshiharu Horie
Nov 12, 2021·Frontiers in Physiology·Himanshi PanditaShanmugasundaram Ganapathy-Kanniappan

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antipsychotic Drugs

Antipsychotic drugs are a class of medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia and bipolar disorder. Discover the latest research on antipsychotic drugs here