Mechanism of protection by S-(1,2-dicarboxyethyl)glutathione triester against acetaminophen-induced hepatotoxicity in rat hepatocytes.
Treatment with the triester of S-(1,2-dicarboxyethyl)glutathione (DCE-GS) prevented the hepatotoxicity induced by acetaminophen via elevation of the glutathione (GSH) level in rat hepatocytes. This elevation of the GSH level in rat hepatocytes by DCE-GS triester was dose- and time-dependent (2.1-fold in 24 h with 0.5 mm). DCE-GS triester increased the GSH level much more effectively than GSH, DCE-GS, and DCE-GS monoester and diester. Furthermore, the activity of y-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme in GSH biosynthesis, was also increased by DCE-GS triester treatment (1.4-fold in 24 h with 1.0 mm). In contrast, with a rat liver homogenate, DCE-GS increased the y-GCS activity, whereas DCE-GS triester had no effect on this activity. These results suggested that DCE-GS triester, which is transported into hepatocytes much more effectively than DCE-GS and other DCE-GS esters due to its greater lipophilicity, was hydrolyzed to DCE-GS, and then the DCE-GS produced increased the GSH level via activation of gamma-GCS in rat hepatocytes.
Yasuda
M
M
Department of Biochemistry Faculty of Pharmaceutical Sciences, Okayama University, Japan.
Matsumoto
S
S
Matsushima
S
S
Murata
H
H
Shimoshinbara
T
T
Tsuboi
S
S
D000082:Acetaminophen / Q000037:antagonists & inhibitors* / Q000633:toxicity; D018712:Analgesics, Non-Narcotic / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control*; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use*; D022781:Hepatocytes / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D018712:Analgesics, Non-Narcotic; C041581:S-(1,2-dicarboxyethyl)glutathione; D000082:Acetaminophen; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione