PT  - JOURNAL ARTICLE
AU  - Berson, Alain
AU  - Descatoire, Véronique
AU  - Sutton, Angela
AU  - Fau, Daniel
AU  - Maulny, Béatrice
AU  - Vadrot, Nathalie
AU  - Feldmann, Gérard
AU  - Berthon, Brigitte
AU  - Tordjmann, Thierry
AU  - Pessayre, Dominique
TI  - Toxicity of Alpidem, a Peripheral Benzodiazepine Receptor Ligand, but Not Zolpidem, in Rat Hepatocytes: Role of Mitochondrial Permeability Transition and Metabolic Activation
DP  - 2001 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 793--800
VI  - 299
IP  - 2
4099  - http://jpet.aspetjournals.org/content/299/2/793.short
4100  - http://jpet.aspetjournals.org/content/299/2/793.full
SO  - J Pharmacol Exp Ther2001 Nov 01; 299
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics