title: Redox control of hepatic cell death.
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.
authors.affiliation: Faculty of Biology, M-668, University of Konstanz, Universitätsstrasse 10, D-78457 Konstanz, Germany.
authors.forename: Hannes
authors.initials: H
authors.lastname: Hentze
authors.forename: Markus
authors.initials: M
authors.lastname: Latta
authors.forename: Gerald
authors.initials: G
authors.lastname: Künstle
authors.forename: Rudolf
authors.initials: R
authors.lastname: Lucas
authors.forename: Albrecht
authors.initials: A
authors.lastname: Wendel
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008107:Liver Diseases / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D010084:Oxidation-Reduction; D018000:Receptors, Peptide / Q000378:metabolism; D015398:Signal Transduction; D019014:fas Receptor / Q000378:metabolism
chemical_list: D018000:Receptors, Peptide; D019014:fas Receptor; C035560:glutathione receptor; D020169:Caspases; D005978:Glutathione