Role of the Mitochondrial Permeability Transition in Salicylate Toxicity to Cultured Rat Hepatocytes: Implications for the Pathogenesis of Reye's Syndrome

Role of the Mitochondrial Permeability Transition in Salicylate Toxicity to Cultured Rat... 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 Ca 2+ enhanced salicylate lethality. Salicylate-dependent cell killing was blocked by 0.5–5 μM 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 of the fluorophore calcein from the cytosol into mitochondria prior to cell killing, an event blocked by cyclosporin A. Salicylate toxicity was enhanced at high extracellular Ca 2+ . In the range of 10–100 μM, several chemically diverse calcium antagonists blocked or reduced salicylate toxicity including verapamil, diltiazem, chlorpromazine, nifedipine, and nisoldipine. Calcium antagonists also blocked the increase of mitochondrial free Ca 2+ in high Ca 2+ buffer, as determined by confocal imaging of the fluorophore Rhod-2. These data with salicylate suggest that onset of the MPT may be the common pathophysiologic mechanism causing mitochondrial injury in Reye's syndrome and Reye's-related drug toxicities. Further, elevated intramitochondrial Ca 2+ may be a predisposing condition promoting onset of the MPT by Reye's-related chemicals. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Toxicology and Applied Pharmacology Elsevier

Role of the Mitochondrial Permeability Transition in Salicylate Toxicity to Cultured Rat Hepatocytes: Implications for the Pathogenesis of Reye's Syndrome

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Publisher
Elsevier
Copyright
Copyright © 1997 Academic Press
ISSN
0041-008x
D.O.I.
10.1006/taap.1997.8313
Publisher site
See Article on Publisher Site

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 Ca 2+ enhanced salicylate lethality. Salicylate-dependent cell killing was blocked by 0.5–5 μM 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 of the fluorophore calcein from the cytosol into mitochondria prior to cell killing, an event blocked by cyclosporin A. Salicylate toxicity was enhanced at high extracellular Ca 2+ . In the range of 10–100 μM, several chemically diverse calcium antagonists blocked or reduced salicylate toxicity including verapamil, diltiazem, chlorpromazine, nifedipine, and nisoldipine. Calcium antagonists also blocked the increase of mitochondrial free Ca 2+ in high Ca 2+ buffer, as determined by confocal imaging of the fluorophore Rhod-2. These data with salicylate suggest that onset of the MPT may be the common pathophysiologic mechanism causing mitochondrial injury in Reye's syndrome and Reye's-related drug toxicities. Further, elevated intramitochondrial Ca 2+ may be a predisposing condition promoting onset of the MPT by Reye's-related chemicals.

Journal

Toxicology and Applied PharmacologyElsevier

Published: Dec 1, 1997

References

  • Mechanisms by which mitochondria transport calcium
    Gunter, T.E.; Pfeiffer, D.R.
  • Reye's syndrome: Current concepts
    Heubi, J.E.; Partin, J.C.; Partin, J.S.; Schubert, W.K.
  • Mitochondrial Ca 2+
    Jiang, T.; Acosta, D.
  • Enhanced induction of the mitochondrial permeability transition following acute menadione administration
    Saxena, K.; Henry, T.R.; Solem, L.E.; Wallace, K.B.

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