The mitochondrial permeability transition: a new pathophysiological mechanism for Reye's syndrome and toxic liver injury.
Aspirin, Neem oil, valproic, adipic, benzoic, isovaleric, 3-mercaptopropionic and 4-pentenoic acids are implicated in the pathogenesis of Reye's syndrome, Jamaican vomiting sickness, and related chemical toxicities. These disorders are characterized by hyperammonemia, hypoglycemia, microvesicular steatosis and encephalopathy. The goal of this study was to determine whether chemicals implicated in Reye's-related disorders induce the mitochondrial permeability translation (MPT). The MPT is induced by opening of a high-conductance, cyclosporin-sensitive pore in the mitochondrial inner membrane, causing swelling, depolarization and uncoupling of oxidative phosphorylation. In freshly isolated rat liver mitochondria, unhydrolyzed aspirin (300 microM) did not induce the MPT in the presence of 50 microM CaCl2. Salicylate, the hydrolysis product of aspirin and its active metabolite, was much more potent causing dose-dependent onset of the MPT in a therapeutic range of concentrations (37.5-300 microM). Similarly, Neem oil and valproic, adipic, benzoic, isovaleric, 3-mercaptopropionic and 4-pentenoic acids induced onset of the MPT. In all cases, cyclosporin A (200 nM), a specific inhibitor of the permeability transition pore, blocked the MPT caused by these inducers. Induction of the MPT by these agents was not caused by mitochondrial depolarization because concentrations of valproic acid and salicylate inducing the MPT had little effect on mitochondrial delta psi. Moreover, equivalent uncoupling caused by 5 nM carbonyl cyanide p-trifluoromethoxyphenylhydrazone did not induce an MPT. These data suggest that induction of the MPT is a common pathophysiological mechanism causing mitochondrial injury in Reye's syndrome and Reye's-related drug toxicities.
Trost
L C
LC
Department of Cell Biology & Anatomy, School of Medicine, University of North Carolina at Chapel Hill, USA.
Lemasters
J J
JJ
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D002264:Carboxylic Acids / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D016572:Cyclosporine / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects*; D008933:Mitochondrial Swelling / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012202:Reye Syndrome / Q000139:chemically induced*; D012430:Ruthenium Red / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014635:Valproic Acid / Q000494:pharmacology
D002264:Carboxylic Acids; D012430:Ruthenium Red; D014635:Valproic Acid; D016572:Cyclosporine; D001241:Aspirin