title: Synergistic toxicity induced by prolonged glutathione depletion and inhibition of nuclear factor-kappaB signaling in liver cells.
abstract: TNF-alpha, GSH depletion and CYP2E1 are factors that play an important role in alcoholic liver disease. Activation of NF-kappaB prevents hepatocyte damage caused by TNF-alpha. This work describes the effect of NF-kappaB inhibition on toxicities caused by GSH depletion or arachidonic acid (AA) treatment in liver cells, and evaluates the possible influence of CYP2E1 overexpression. Cells were exposed to the NF-kappaB inhibitor BAY11-7082, in the absence or presence of l-buthionine sulfoximine (BSO) to block GSH synthesis. BSO toxicity was higher in CYP2E1-expressing E47 HepG2 cells compared to control cells; the incubation with BAY11-7082 potentiated BSO toxicity in both cell lines comparably. Several other agents which suppress activation of NF-kappaB increased BSO toxicity in E47 cells. NF-kappaB inhibition, however, did not sensitize E47 cells to AA toxicity. Suppressing activity of NF-kappaB also potentiated BSO, but not AA toxicity, in isolated rat hepatocytes. BAY11-7082 plus BSO induced a greater p38 MAPK activation as compared to BAY11-7082 or BSO alone, and a p38 MAPK inhibitor protected against the synergistic toxicity. In summary, inhibition of NF-kappaB sensitizes liver cells to toxicity linked to GSH depletion, probably accelerating the processes of thiol homeostasis deregulation and induction of apoptosis through a mechanism mediated by p38 MAPK.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA. jmajimen@ugr.es
authors.forename: Jose M
authors.initials: JM
authors.lastname: Jimenez-Lopez
authors.forename: Defeng
authors.initials: D
authors.lastname: Wu
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Cederbaum
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016718:Arachidonic Acid / Q000633:toxicity*; D019328:Buthionine Sulfoximine / Q000633:toxicity*; D045744:Cell Line, Tumor; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic; D005978:Glutathione / Q000187:drug effects* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013438:Sulfhydryl Compounds / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D016328:NF-kappa B; D013438:Sulfhydryl Compounds; D016718:Arachidonic Acid; D019328:Buthionine Sulfoximine; D019392:Cytochrome P-450 CYP2E1; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione