title: Roles of oxidative stress and glutathione depletion in JP-8 jet fuel-induced apoptosis in rat lung epithelial cells.
abstract: The toxic jet fuel JP-8 induces morphological and biochemical changes characteristic of apoptosis in rat lung epithelial (RLE-6TN) cells. The mechanism of JP-8 toxicity in these cells was further investigated in an attempt to identify potential therapeutic interventions. Given that oxidative stress and changes in the concentrations of endogenous antioxidants, such as glutathione (GSH), have been associated with the cellular damage elicited by numerous toxicants, the possibility that JP-8 induces cellular oxidative stress was investigated. Experimentally induced depletion of intracellular GSH or exposure of cells to a low concentration of H(2)O(2) markedly enhanced JP-8-induced cell death. A significant reduction in intracellular concentrations of GSH was noted in RLE-6TN cells shortly after exposure to JP-8. Furthermore, JP-8 induced the generation of reactive oxygen species (ROS) in RLE-6TN cells. Consistent with the notion that JP-8 toxicity is mediated by generation of ROS and depletion of intracellular GSH, JP-8-induced cell death was inhibited by exogenous GSH or the thiol-containing antioxidant N-acetyl-cysteine. This protective effect was associated with marked inhibition of both the activation of caspase-3 and the loss of the mitochondrial membrane potential induced by JP-8. Inhibition of the JP-8-induced activation of poly(ADP-ribose) polymerase by 3-aminobenzamide did not protect cells against JP-8 toxicity. Together, these results indicate that thiol antioxidants are highly effective in rescuing cells from JP-8-induced cell death and that they may provide a basis for new therapeutic approaches to counteract JP-8 toxicity.
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, Washington, DC 20007, USA.
authors.forename: A Hamid
authors.initials: AH
authors.lastname: Boulares
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Contreras
authors.forename: Luis A
authors.initials: LA
authors.lastname: Espinoza
authors.forename: Mark E
authors.initials: ME
authors.lastname: Smulson
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000032:analysis / Q000096:biosynthesis; D004847:Epithelial Cells; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000172:deficiency / Q000378:metabolism*; D006838:Hydrocarbons / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D013723:Teratogens / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*
chemical_list: D001549:Benzamides; D016166:Free Radical Scavengers; D006838:Hydrocarbons; C098607:JP8 aviation fuel; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013723:Teratogens; D019328:Buthionine Sulfoximine; C025160:3-aminobenzamide; D006861:Hydrogen Peroxide; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione; D000111:Acetylcysteine