In vivo modulation of total and mitochondrial glutathione in rat liver. Depletion by phorone and rescue by N-acetylcysteine.
The aim of the present work was to modulate in vivo the level of hepatic mitochondrial glutathione (GSH). Rats were given phorone (diisopropylidene acetone), which in vivo becomes enzymatically conjugated to GSH, and were subsequently treated with N-acetylcysteine (NAC) to rescue GSH. In liver homogenate, a rapid and biphasic (T1/2 less than or equal to 15 min and 1.5 hr) drop of GSH was observed upon phorone administration. NAC treatment led to a restoration (T1/2 about 1 hr) of GSH in the homogenate above control values within 3 hr. The mitochondrial GSH level decreased with T1/2 of about 1.5 hr upon phorone treatment, and was 75% restored by NAC treatment within 3 hr. Hydroperoxide-induced mitochondrial pyridine nucleotide oxidation and Ca2+ release were impeded in GSH-depleted organelles, and NAC treatment restored these processes. The GSH status had no influence on mitochondrial pyridine nucleotide oxidation and Ca2+ released induced by alloxan, which reacts directly and non-enzymatically with pyridine nucleotides. It is concluded that NAC is able to rescue mitochondrial GSH in vivo and restore important mitochondrial functions. The data suggest that NAC may be a useful antidote in oxidative stress-related diseases.
Traber
J
J
Laboratory of Biochemistry I, Swiss Federal Institute of Technology (ETH), Zürich.
Suter
M
M
Walter
P
P
Richter
C
C
D000111:Acetylcysteine / Q000494:pharmacology*; D000496:Alloxan / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007659:Ketones / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D009711:Nucleotides / Q000378:metabolism; D010545:Peroxides / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D020122:tert-Butylhydroperoxide
D007659:Ketones; D009711:Nucleotides; D010545:Peroxides; D000496:Alloxan; C018637:phorone; D020122:tert-Butylhydroperoxide; D005978:Glutathione; D002118:Calcium; D000111:Acetylcysteine