Short communication Redox control of hepatic cell death Hannes Hentze a,b , Markus Latta a , Gerald Ku ¨ nstle a , Rudolf Lucas a , Albrecht Wendel a, * a Chair of Biochemical Pharmacology, Faculty of Biology, M-668, University of Konstanz, Universita ¨tsstrasse 10, D-78457 Konstanz, Germany b Institute of Molecular and Cell Biology (IMCB), Singapore, Singapore Abstract In necrotic liver failure like upon acetaminophen overdose, loss of the major intracellular thiol antioxidant glutathione was shown to be causal for hepatic dysfunction. In sharp contrast, fulminant apoptotic liver destruction upon overstimulation of the death receptors TNFR1 and CD95 was not associated with reduced hepatic glutathione levels. In view of the importance of the role of reactive oxygen intermediates versus antioxidants for apoptosis, we investigated the effect of phorone-induced enzymatic GSH depletion on the sensitivity of the liver towards CD95- or TNFR1-mediated hepatotoxicity. Our findings demonstrate in vivo that receptor-mediated hepatic apoptosis is disabled when glutathione is depleted, i.e. that an intact glutathione status is a critical determinant for the execution of apoptosis. In vitro, we did mechanistic studies in lymphoid cell lines and found that pro-caspase-8 at the CD95 death receptor and the mitochondrial activation of pro-caspase-9 are the enzyme targets that require sufficient intracellular reduced glutathione for their activation. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Glutathione; Apoptosis; Death receptors; Pro-caspase activation 1. Death receptor-mediated apoptosis in the liver The pathways activated upon stimulation of the death receptors (DR’s) TNF receptor 1 (TNFR1) and/or CD95 have been shown to be crucial in the apoptosis of hepatocytes, both in vitro and in vivo (Leist et al., 1995, 1996). Under physiological conditions, this form of cell death is important for hepatic tissue homeostasis and the mainte- nance of liver function. However, a diminished or an exaggerated apoptosis rate in the liver can be involved in the pathogenesis of toxic liver injury, alcohol hepatitis, hepatitis of autoimmune or viral origin and primary biliary cirrhosis (reviewed in McClain et al., 1999; Bradham et al., 1998; Benedetti and Marucci, 1999; Kaplowitz, 2000; Leist et al., 1998; Pinkoski et al., 2000; Galle and Krammer, 1998; Krammer et al., 1998; Streetz et al., 2000). A causal involvement of the two mentioned DR’s in liver disease due to their auto- or paracrine overactivation comes from the following experimental findings: (i) CD95 triggering was * Corresponding author. Tel.:  /49-753-188-2113; fax:  /49- 753-188-3099. E-mail address: albrecht.wendel@uni-konstanz.de (A. Wendel). Toxicology Letters 139 (2003) 111  /118 www.elsevier.com/locate/toxlet 0378-4274/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII:S0378-4274(02)00425-3