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: H Hentze, F Gantner, S A Kolb, A Wendel
• Journal: The American journal of pathology (Am J Pathol) Vol. 156 Issue 6 Pg. 2045-56 (Jun 2000) ISSN: 0002-9440 [Print] United States
• PMID: 10854226 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amanitins
• Antigens, CD
• Cytokines
• Nucleic Acid Synthesis Inhibitors
• Receptors, Tumor Necrosis Factor
• Receptors, Tumor Necrosis Factor, Type I
• Concanavalin A
• Dactinomycin
• Caspases
• Glutathione

Topics

• Amanitins (pharmacology)
• Animals
• Antigens, CD (metabolism)
• Apoptosis (physiology)
• Caspases (physiology)
• Cell Death (physiology)
• Concanavalin A (pharmacology)
• Cytokines (metabolism)
• Dactinomycin (pharmacology)
• Dose-Response Relationship, Drug
• Glutathione (deficiency)
• Liver (drug effects, metabolism, pathology, physiology)
• Male
• Mice
• Mice, Inbred BALB C
• Necrosis
• Nucleic Acid Synthesis Inhibitors (pharmacology)
• Receptors, Tumor Necrosis Factor (metabolism, physiology)
• Receptors, Tumor Necrosis Factor, Type I
• Shock, Septic (mortality, pathology)