In vivo reversal of glutathione deficiency and susceptibility to in vivo dexamethasone-induced apoptosis by N-acetylcysteine and L-2-oxothiazolidine-4-carboxylic acid, but not ascorbic acid, in thymocytes from gamma-glutamyltranspeptidase-deficient knockout mice.
Cellular glutathione is released during apoptosis and may play a role in the regulation of the mitochondrial permeability transition pore. The question of whether only cytosolic glutathione is important in apoptosis, or whether mitochondrial glutathione also plays a role, was investigated using gamma-glutamyltranspeptidase-deficient knockout mice. Thymocytes from these mice were found to have both glutathione pools diminished and they were more susceptible to dexamethasone (DEX)-induced apoptosis. Supplementation with N-acetylcysteine (NAC) and L-2-oxothiazolidine-4-carboxylic acid replenished both glutathione pools and provided protection from apoptosis. Ascorbate supplementation was beneficial to the mitochondrial glutathione pool, but apoptosis was not prevented. NAC supplementation caused an increase in reactive oxygen species formation and cardiolipin oxidation, but had no adverse affect on the amount of apoptotic cells. Our results suggest that the glutathione status is an important factor in apoptosis and indirect evidence indicates that the cytosolic pool of glutathione may be important in DEX-induced apoptosis, with mitochondrial events being secondary, and may reflect the execution phase.
Will
Yvonne
Y
Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon 97330, USA.
Kaetzel
Rhonda S
RS
Brown
Marda K
MK
Fraley
Tamara S
TS
Reed
Donald J
DJ
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001205:Ascorbic Acid / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005978:Glutathione / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011761:Pyrrolidonecarboxylic Acid; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*; D005723:gamma-Glutamyltransferase / Q000172:deficiency*
D013844:Thiazoles; D053778:Thiazolidines; D003907:Dexamethasone; D005723:gamma-Glutamyltransferase; D005978:Glutathione; D001205:Ascorbic Acid; D011761:Pyrrolidonecarboxylic Acid; D000111:Acetylcysteine; C029536:2-oxothiazolidine-4-carboxylic acid