Acetaminophen-induced suppression of hepatic AdoMet synthetase activity is attenuated by prodrugs of L-cysteine.
Administration of acetaminophen (ACP, 400 mg/kg, i.p.) to fasted, male Swiss-Webster mice caused a rapid 90% decrease in total hepatic glutathione (GSH) and a 58% decrease in mitochondrial GSH by 2 h post ACP. This was followed by a time-dependent decrease (72%) in hepatic AdoMet synthetase activity and rise in plasma ALT levels (>10000 U/l) at 24 h post ACP treatment. AdoMet synthetase activity was maintained at 82, 78 and 60% of controls, respectively, by the cysteine prodrugs PTCA, CySSME and NAC. Total hepatic and mitochondrial GSH levels were also protected from severe ACP-induced depletion by CySSME and MTCA. These results suggest that the maintenance of GSH homeostasis by cysteine prodrugs can protect mouse hepatic AdoMet synthetase, a sulfhydryl enzyme whose integrity is dependent on GSH, as well as the liver itself from the consequences of oxidative stress elicited by toxic metabolites of xenobiotics.
Shirota
Frances N
FN
Medical Research Laboratories (151), VA Medical Center, Minneapolis, MN 55417, USA.
DeMaster
Eugene G
EG
Shoeman
Don W
DW
Nagasawa
Herbert T
HT
D000082:Acetaminophen / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D003545:Cysteine / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008716:Methionine Adenosyltransferase / Q000037:antagonists & inhibitors*; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D011355:Prodrugs / Q000494:pharmacology*
D018712:Analgesics, Non-Narcotic; D011355:Prodrugs; D000082:Acetaminophen; D008716:Methionine Adenosyltransferase; D000410:Alanine Transaminase; D005978:Glutathione; D003545:Cysteine