RT Journal Article
SR Electronic
T1 Toxicity of Alpidem, a Peripheral Benzodiazepine Receptor Ligand, but Not Zolpidem, in Rat Hepatocytes: Role of Mitochondrial Permeability Transition and Metabolic Activation
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 793
OP 800
VO 299
IS 2
A1 Alain Berson
A1 Véronique Descatoire
A1 Angela Sutton
A1 Daniel Fau
A1 Béatrice Maulny
A1 Nathalie Vadrot
A1 Gérard Feldmann
A1 Brigitte Berthon
A1 Thierry Tordjmann
A1 Dominique Pessayre
YR 2001
UL http://jpet.aspetjournals.org/content/299/2/793.abstract
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