title: Depletion of hepatic glutathione prevents death receptor-dependent apoptotic and necrotic liver injury in mice.
abstract: The activation of the death receptors, tumor necrosis factor-receptor-1 (TNF-R1) or CD95, is a hallmark of inflammatory or viral liver disease. In different murine in vivo models, we found that livers depleted of gamma-glutamyl-cysteinyl-glycine (GSH) by endogenous enzymatic conjugation after phorone treatment were resistant against death receptor-elicited injury as assessed by transaminase release and histopathology. In apoptotic models initiated by engagement of CD95, or by injection of TNF or lipopolysaccharide into galactosamine-sensitized mice, hepatic caspase-3-like proteases were not activated in the GSH-depleted state. Under GSH depletion, also caspase-independent, TNF-R1-mediated injury (high-dose actinomycin D or alpha-amanitin), as well as necrotic hepatotoxicity (high-dose lipopolysaccharide) were entirely blocked. In the T-cell-dependent model of concanavalin A-induced hepatotoxicity, GSH depletion resulted in a suppression of interferon-gamma release, delay of systemic TNF release, hepatic nuclear factor-kappaB activation, and an abrogation of sinusoidal endothelial cell detachment as assessed by electron microscopy. When GSH depletion was initiated 3 hours after concanavalin A injection, ie, after the peak of early pro-inflammatory cytokines, livers were still protected. We conclude that sufficient hepatic GSH levels are a prerequisite for the execution of death receptor-mediated hepatocyte demise.
authors.affiliation: Department of Biochemical Pharmacology, University of Konstanz, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Hentze
authors.forename: F
authors.initials: F
authors.lastname: Gantner
authors.forename: S A
authors.initials: SA
authors.lastname: Kolb
authors.forename: A
authors.initials: A
authors.lastname: Wendel
mesh_terms: D000546:Amanitins / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000172:deficiency*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D012772:Shock, Septic / Q000401:mortality / Q000473:pathology
chemical_list: D000546:Amanitins; D015703:Antigens, CD; D016207:Cytokines; D019384:Nucleic Acid Synthesis Inhibitors; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D003208:Concanavalin A; D003609:Dactinomycin; D020169:Caspases; D005978:Glutathione