title: Prolonged, but not acute, glutathione depletion promotes Fas-mediated mitochondrial permeability transition and apoptosis in mice.
abstract: Glutathione depletion either decreased or increased death-receptor-mediated apoptosis in previous studies. Comparison of the durations of glutathione depletion before death-receptor stimulation in these studies might suggest a different effect of prolonged versus acute thiol depletion. We compared the effects of the prolonged glutathione depletion caused by a sulfur amino acid-deficient (SAA(-)) diet and the acute depletion caused by a single dose of phorone on hepatic apoptosis triggered by the administration of an agonistic anti-Fas antibody. The chronic SAA(-) diet did not affect hepatic Fas or Bcl-XL, but increased p53 and Bax, and exacerbated Fas-mediated mitochondrial membrane depolarization, electron-microscopy-proven outer mitochondrial membrane rupture, cytochrome c translocation to the cytosol, and caspase 3 activation. These effects were prevented by cyclosporin A, an inhibitor of mitochondrial permeability transition. The SAA(-) diet increased internucleosomal DNA fragmentation, the percentage of apoptotic hepatocytes, serum alanine transaminase (ALT) activity, and mortality after Fas stimulation. Despite a similar decrease in hepatic glutathione, administration of a single dose of phorone 1 hour before the anti-Fas antibody did not change p53 or Bax, and did not enhance Fas-induced mitochondrial permeability transition and toxicity. However, 4 repeated doses of phorone (causing more prolonged glutathione depletion) increased Bax and Fas-mediated toxicity. In conclusion, a chronic SAA(-) diet, but not acute phorone administration, increases p53 and Bax, and enhances Fas-induced mitochondrial permeability transition and apoptosis. Thiol depletion could cause oxidative stress that requires several hours to increase p53; the latter induces Bax, which translocates to mitochondria after Fas stimulation.
authors.affiliation: INSERM U481 and Centre de Recherche sur les Hépatites Virales de l'Association Claude Bernard, Hôpital Beaujon, Clichy, France.
authors.forename: D
authors.initials: D
authors.lastname: Haouzi
authors.forename: M
authors.initials: M
authors.lastname: Lekehal
authors.forename: M
authors.initials: M
authors.lastname: Tinel
authors.forename: N
authors.initials: N
authors.lastname: Vadrot
authors.forename: L
authors.initials: L
authors.lastname: Caussanel
authors.forename: P
authors.initials: P
authors.lastname: Lettéron
authors.forename: A
authors.initials: A
authors.lastname: Moreau
authors.forename: G
authors.initials: G
authors.lastname: Feldmann
authors.forename: D
authors.initials: D
authors.lastname: Fau
authors.forename: D
authors.initials: D
authors.lastname: Pessayre
mesh_terms: D000596:Amino Acids / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D004032:Diet; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000172:deficiency*; D022781:Hepatocytes / Q000187:drug effects / Q000648:ultrastructure; D007659:Ketones / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000502:physiology; D010539:Permeability; D020011:Protective Agents / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D013455:Sulfur / Q000008:administration & dosage; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000494:pharmacology / Q000502:physiology*
chemical_list: D000596:Amino Acids; C494827:Bax protein, mouse; D003574:Cytochrome c Group; D007659:Ketones; D020011:Protective Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D013455:Sulfur; D016572:Cyclosporine; C018637:phorone; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione