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Research ArticleTOXICOLOGY

Toxicity of Alpidem, a Peripheral Benzodiazepine Receptor Ligand, but Not Zolpidem, in Rat Hepatocytes: Role of Mitochondrial Permeability Transition and Metabolic Activation

Alain Berson, Véronique Descatoire, Angela Sutton, Daniel Fau, Béatrice Maulny, Nathalie Vadrot, Gérard Feldmann, Brigitte Berthon, Thierry Tordjmann and Dominique Pessayre
Journal of Pharmacology and Experimental Therapeutics November 2001, 299 (2) 793-800;
Alain Berson
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Véronique Descatoire
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Angela Sutton
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Daniel Fau
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Béatrice Maulny
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Nathalie Vadrot
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Gérard Feldmann
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Brigitte Berthon
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Thierry Tordjmann
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Dominique Pessayre
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Abstract

Whereas alpidem is hepatotoxic, zolpidem is not. Despite closely related chemical structures, alpidem, but not zolpidem, is a peripheral benzodiazepine receptor (PBR) ligand, and is also more lipophilic than zolpidem. We compared their effects in isolated rat liver mitochondria and rat hepatocytes. Zolpidem did not affect calcium-induced mitochondrial permeability transition (MPT) in mitochondria, caused little glutathione depletion in hepatocytes, and was not toxic, even at 500 μM. At 250 to 500 μM, alpidem prevented calcium-induced MPT in isolated mitochondria, but caused severe glutathione depletion in hepatocytes that was increased by 3-methylcholanthrene, a cytochrome P4501A inducer, and decreased by cystine, a glutathione precursor. Although cell calcium increased, mitochondrial cytochromec did not translocate to the cytosol and cells died of necrosis. Cell death was prevented by cystine, but not cyclosporin A, an MPT inhibitor. At low concentrations (25–50 μM), in contrast, alpidem accelerated calcium-induced MPT in mitochondria. It did not deplete glutathione in hepatocytes, but nevertheless caused some cell death that was prevented by cyclosporin A, but not by cystine. Alpidem (10 μM) also increased the toxicity of tumor necrosis factor-α (1 ng/ml) in hepatocytes. In conclusion, low concentrations of alpidem increase both calcium-induced MPT in mitochondria, and TNF-α toxicity in cells, like other PBR ligands. Like other lipophilic protonatable amines, however, alpidem inhibits calcium-induced MPT at high concentrations. At these high concentrations, toxicity involves cytochrome P4501A-mediated metabolic activation, glutathione depletion, and increased cell calcium, without MPT involvement. In contrast, zolpidem has no mitochondrial effects, causes little glutathione depletion, and is not toxic.

Footnotes

  • This work was supported in part by Contract 96173 between INSERM and Synthelabo Groupe.

  • Abbreviations:
    PBR
    peripheral benzodiazepine receptor
    MPT
    mitochondrial permeability transition
    TNF-α
    tumor necrosis factor-α
    DMSO
    dimethyl sulfoxide
    • Received March 26, 2001.
    • Accepted July 31, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 2
1 Nov 2001
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Research ArticleTOXICOLOGY

Toxicity of Alpidem, a Peripheral Benzodiazepine Receptor Ligand, but Not Zolpidem, in Rat Hepatocytes: Role of Mitochondrial Permeability Transition and Metabolic Activation

Alain Berson, Véronique Descatoire, Angela Sutton, Daniel Fau, Béatrice Maulny, Nathalie Vadrot, Gérard Feldmann, Brigitte Berthon, Thierry Tordjmann and Dominique Pessayre
Journal of Pharmacology and Experimental Therapeutics November 1, 2001, 299 (2) 793-800;

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Research ArticleTOXICOLOGY

Toxicity of Alpidem, a Peripheral Benzodiazepine Receptor Ligand, but Not Zolpidem, in Rat Hepatocytes: Role of Mitochondrial Permeability Transition and Metabolic Activation

Alain Berson, Véronique Descatoire, Angela Sutton, Daniel Fau, Béatrice Maulny, Nathalie Vadrot, Gérard Feldmann, Brigitte Berthon, Thierry Tordjmann and Dominique Pessayre
Journal of Pharmacology and Experimental Therapeutics November 1, 2001, 299 (2) 793-800;
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