Depletion of hepatic glutathione prevents death receptor-dependent apoptotic and necrotic liver injury in mice

The activation of the death receptors, tumor necrosis factor-receptor-1 (TN F-RI) or CD95, is a hallmark of inflammatory or viral liver disease. In dif ferent murine in vivo models, we found that livers depleted of gamma-glutam yl-cysteinyl-glycine (GSH) by endogenous enzymatic conjugation after phoron e treatment were resistant against death receptor-elicited injury as assess ed by transaminase release and histopathology. In apoptotic models initiate d by engagement of CD95, or by injection of TNF or lipopolysaccharide into galactosamine-sensitized mice, hepatic caspase-3-like proteases were not ac tivated in the GSH-depleted state. Under GSH depletion, also caspase-indepe ndent, TNF-R1-mediated injury (high-dose actinomycin D or alpha-amanitin), as well as necrotic hepatotoxicity (high-dose lipopolysaccharide) were enti rely blocked. In the T-cell-dependent model of concanavalin A-induced hepat otoxicity, GSH depletion resulted In a suppression of interferon-gamma rele ase, delay of systemic TNF release, hepatic nuclear factor-kappa B activati on, and an abrogation of sinusoidal endothelial cell detachment as assessed by electron microscopy, When GSH depletion was initiated 3 hours after con canavalin A injection, ie, after the peak of early proinflammatory cytokine s, livers were still protected. We conclude that sufficient hepatic GSH lev els are a prerequisite for the execution of death receptor-mediated hepatoc yte demise.