help button home button Am J Pathol R & D Systems
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hentze, H.
Right arrow Articles by Wendel, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hentze, H.
Right arrow Articles by Wendel, A.
(American Journal of Pathology. 2000;156:2045-2056.)
© 2000 American Society for Investigative Pathology

Regular Articles

Depletion of Hepatic Glutathione Prevents Death Receptor-Dependent Apoptotic and Necrotic Liver Injury in Mice

Hannes Hentze*, Florian Gantner{dagger}, Stefan A. Kolb{ddagger} and Albrecht Wendel*

From the Department of Biochemical Pharmacology,*
Faculty of Biology, University of Konstanz, and Byk Gulden,{dagger}
Department of Biochemistry, Konstanz, Germany; and the Department of Pathology,{ddagger}
University Hospital Zürich, Zürich, Switzerland

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-{kappa}B 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.




This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
M. Latta, G. Kunstle, R. Lucas, H. Hentze, and A. Wendel
ATP-Depleting Carbohydrates Prevent Tumor Necrosis Factor Receptor 1-Dependent Apoptotic and Necrotic Liver Injury in Mice
J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 875 - 883.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
D. Han, N. Hanawa, B. Saberi, and N. Kaplowitz
Mechanisms of Liver Injury. III. Role of glutathione redox status in liver injury
Am J Physiol Gastrointest Liver Physiol, July 1, 2006; 291(1): G1 - G7.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
C. Muller, F. Dunschede, E. Koch, A. M. Vollmar, and A. K. Kiemer
{alpha}-Lipoic acid preconditioning reduces ischemia-reperfusion injury of the rat liver via the PI3-kinase/Akt pathway
Am J Physiol Gastrointest Liver Physiol, October 1, 2003; 285(4): G769 - G778.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. Chovolou, W. Watjen, A. Kampkotter, and R. Kahl
Resistance to Tumor Necrosis Factor-{alpha} (TNF-{alpha})-induced Apoptosis in Rat Hepatoma Cells Expressing TNF-{alpha} Is Linked to Low Antioxidant Enzyme Expression
J. Biol. Chem., August 8, 2003; 278(32): 29626 - 29632.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y.-Y. He, J.-L. Huang, D. C. Ramirez, and C. F. Chignell
Role of Reduced Glutathione Efflux in Apoptosis of Immortalized Human Keratinocytes Induced by UVA
J. Biol. Chem., February 28, 2003; 278(10): 8058 - 8064.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
L. Musallam, C. Ethier, P. S. Haddad, F. Denizeau, and M. Bilodeau
Resistance to Fas-induced apoptosis in hepatocytes: role of GSH depletion by cell isolation and culture
Am J Physiol Gastrointest Liver Physiol, September 1, 2002; 283(3): G709 - G718.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Hentze, I. Schmitz, M. Latta, A. Krueger, P. H. Krammer, and A. Wendel
Glutathione Dependence of Caspase-8 Activation at the Death-inducing Signaling Complex
J. Biol. Chem., February 8, 2002; 277(7): 5588 - 5595.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. Willuweit, G. Sass, A. Schoneberg, U. Eisel, G. Tiegs, and M. Clauss
Chronic Inflammation and Protection from Acute Hepatitis in Transgenic Mice Expressing TNF in Endothelial Cells
J. Immunol., October 1, 2001; 167(7): 3944 - 3952.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. Jahr, H. Hentze, S. Englisch, D. Hardt, F. O. Fackelmayer, R.-D. Hesch, and R. Knippers
DNA Fragments in the Blood Plasma of Cancer Patients: Quantitations and Evidence for Their Origin from Apoptotic and Necrotic Cells
Cancer Res., February 1, 2001; 61(4): 1659 - 1665.
[Abstract] [Full Text]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2000 by the American Society for Investigative Pathology.