Prevention of acetaminophen-induced liver toxicity by 2(R,S)-n-propylthiazolidine-4(R)-carboxylic acid in mice.
The cysteine (Cys) precursor 2(R,S)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA) was shown previously to maintain near normal levels of hepatic GSH and GSSG at 24 hr and to protect against hepatic necrosis and mortality at 48 hr after toxic doses of acetaminophen (APAP) in mice. Studies were performed in C57BL/6 mice to determine: (a) the time course of APAP-induced hepatic sulfhydryl depletion, and (b) the effectiveness of PTCA in preventing APAP-induced decreases in sulfhydryl concentrations at the time of maximal depletion. APAP (400-800 mg/kg in 50% propylene glycol; 2.65-5.29 mmol/kg) and PTCA (1-5 mmol/kg 30 min after APAP) were administered i.p. Hepatic GSH, GSSG, and Cys concentrations were determined by HPLC. Hepatocellular damage was assessed by elevations in serum glutamate-pyruvate transaminase (SGPT) activity and histopathologic examination. APAP and PTCA produced dose-dependent effects. At 4 hr after the highest dose of APAP, hepatic GSH and Cys concentrations were reduced to 5 and 14%, respectively, of values in vehicle-treated controls, and the GSSG concentration was below the sensitivity of the analytical method. At 24 hr, recovery of hepatic sulfhydryls was incomplete, and there was hepatic necrosis with an approximately 100-fold increase in SGPT activity. At the highest dose of PTCA, the concentrations of GSH, Cys, and GSSG at 4 hr after APAP (800 mg/kg) were 66, 116, and 111%, respectively, of vehicle controls. PTCA in doses of 1.75 to 5 mmol/kg attenuated the APAP-induced increases in SGPT activity. It was concluded that the protective effect of PTCA is most likely related to prevention of hepatic sulfhydryl depletion.
Srinivasan
C
C
Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, KY 40292, USA.
Williams
W M
WM
Ray
M B
MB
Chen
T S
TS
D000082:Acetaminophen / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000447:Aldehydes / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D003545:Cysteine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D008099:Liver / Q000187:drug effects; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011355:Prodrugs / Q000627:therapeutic use; D020011:Protective Agents / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*
D000447:Aldehydes; D018712:Analgesics, Non-Narcotic; D011355:Prodrugs; D020011:Protective Agents; D013844:Thiazoles; D000082:Acetaminophen; C101197:2-n-propylthiazolidine-4-carboxylic acid; D005978:Glutathione; C018475:butyraldehyde; D003545:Cysteine; D019803:Glutathione Disulfide