High hepatic glutathione stores alleviate Fas-induced apoptosis in mice.
OBJECTIVE
The agonistic Jo2 anti-Fas antibody reproduces human fulminant hepatitis in mice. We tested the hypothesis that enhancing hepatic glutathione (GSH) stores may prevent Jo2-induced apoptosis.


METHODS
We fed mice with a normal diet or a sulfur amino acid-enriched (SAA(+)) diet increasing hepatic GSH by 63%, and challenged these mice with Jo2.


RESULTS
The SAA(+) diet markedly attenuated the Jo2-mediated decrease in hepatic GSH and the increase in the oxidized glutathione (GSSG)/GSH ratio in cytosol and mitochondria. The SAA(+) diet prevented protein kinase Czeta (PKCzeta) and p47(phox) phosphorylations, Yes activation, Fas-tyrosine phosphorylation, Bid truncation, Bax, and cytochrome c translocations, the mitochondrial membrane potential collapse, caspase activation, DNA fragmentation, hepatocyte apoptosis, and mouse lethality after Jo2 administration. The protective effect of the SAA(+) diet was abolished by a small dose of phorone decreasing hepatic GSH back to the levels observed in mice fed the normal diet. Conversely, administration of GSH monoethyl ester after Jo2 administration prevented hepatic GSH depletion and attenuated toxicity in mice fed with the normal diet.


CONCLUSIONS
The SAA(+) diet preserves GSSG/GSH ratios, and prevents PKCzeta and p47(phox) phosphorylations, Yes activation, Fas-tyrosine phosphorylation, mitochondrial permeabilization, and hepatic apoptosis after Fas stimulation. GSH monoethyl ester is also protective, suggesting possible clinical applications.
Cazanave
Sophie
S
INSERM, U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, BP 416, F-75018 Paris, France.
Berson
Alain
A
Haouzi
Delphine
D
Vadrot
Nathalie
N
Fau
Daniel
D
Grodet
Alain
A
Lettéron
Philippe
P
Feldmann
Gérard
G
El-Benna
Jamel
J
Fromenty
Bernard
B
Robin
Marie-Anne
MA
Pessayre
Dominique
D
D000603:Amino Acids, Sulfur / Q000008:administration & dosage; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D004032:Diet; D019587:Dietary Supplements; D015536:Down-Regulation; D053222:Fas Ligand Protein / Q000819:agonists / Q000378:metabolism*; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000494:pharmacology; D019803:Glutathione Disulfide / Q000378:metabolism* / Q000494:pharmacology; D007659:Ketones / Q000008:administration & dosage; D008099:Liver / Q000378:metabolism* / Q000648:ultrastructure; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000178:diet therapy* / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000099221:Protein Kinase C zeta
D000603:Amino Acids, Sulfur; D000975:Antioxidants; D020169:Caspases; D053222:Fas Ligand Protein; D005978:Glutathione; D019803:Glutathione Disulfide; D007659:Ketones; D019255:NADPH Oxidases; D011493:Protein Kinase C; D051028:bcl-2-Associated X Protein; D000099221:Protein Kinase C zeta; C494827:Bax protein, mouse; C018637:phorone; C060505:neutrophil cytosolic factor 1