Effects of 2(RS)-n-propylthiazolidine-4(R)-carboxylic acid on extrahepatic sulfhydryl levels in mice treated with acetaminophen.
The cysteine (Cys) precursor 2(RS)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA) has been shown to protect against acetaminophen (APAP)-induced hepatic GSH, GSSG, and Cys depletion and hepatic necrosis. The aim of this study was to determine the effects of PTCA on the concentrations of sulfhydryl compounds in extrahepatic tissues, including renal cortex, whole blood, and brain, in C57BL/6 mice treated with hepatotoxic doses of APAP. PTCA (1-5 mmol/kg, i.p.) was administered 30 min after the administration of APAP at a dose (800 mg/kg; 5.29 mmol/kg, i.p.) that depleted hepatic GSH and Cys at 4 hr by 95 and 86%, respectively. Tissue concentrations of GSH and Cys were determined by HPLC. At 4 hr following APAP administration, renal cortical GSH and Cys concentrations were decreased to 64 and 39%, respectively, of vehicle-treated control values, and blood concentrations were decreased to 87 and 30%, respectively, of vehicle controls. Brain GSH and Cys were not depleted by APAP. PTCA at 5 mmol/kg (i) attenuated the APAP-induced depletion of GSH and Cys at 4 hr in renal cortex (78 and 65%, respectively, of vehicle controls), (ii) prevented APAP-induced Cys depletion in blood (670% of vehicle controls) with no effect on GSH concentration (94% of vehicle controls), and (iii) increased GSH and Cys concentrations in brain (119 and 411%, respectively, of vehicle controls). The results demonstrate a high degree of tissue selectivity in the APAP-induced depletion of GSH and Cys, and in the effectiveness of PTCA in maintaining and even elevating sulfhydryl levels in extrahepatic tissues of APAP-treated mice.
Srinivasan
C
C
Department of Pharmacology and Toxicology, University of Louisville, School of Medicine, Louisville, KY 40292, USA.
Williams
W M
WM
Nagasawa
H T
HT
Chen
T S
TS
D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D004347:Drug Interactions; D005978:Glutathione / Q000172:deficiency / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011355:Prodrugs / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000097:blood / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D014018:Tissue Distribution
D018712:Analgesics, Non-Narcotic; D011355:Prodrugs; D013438:Sulfhydryl Compounds; D013844:Thiazoles; D000082:Acetaminophen; C101197:2-n-propylthiazolidine-4-carboxylic acid; D005978:Glutathione; D003545:Cysteine