Effects of 2(RS)-n-propylthiazolidine-4(R)-carboxylic acid on extrahepaticsulfhydryl levels in mice treated with acetaminophena

The cysteine (Cys) precursor 2(RS)-n-propylthiazolidine-4(R)-carboxylic aci d (PTCA) has been shown to protect against acetaminophen (APAP)-induced hep atic GSH, GSSG, and Cys depletion and hepatic necrosis. The aim of this stu dy was to determine the effects of PTCA on the concentrations of sulfhydryl compounds in extrahepatic tissues, including renal cortex, whole blood, an d 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 wer e 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 d epleted by APAP. PTCA at 5 mmol/kg (i) attenuated the APAP-induced depletio n of GSH and Cys at 4 hr in renal cortex (78 and 65%, respectively, of vehi cle controls), (ii) prevented APAP-induced Cys depletion in blood (670% of vehicle controls) with no effect on GSH concentration (94% of vehicle contr ols), 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 lev els in extrahepatic tissues of APAP-treated mice. (C) 2001 Elsevier Science Inc. All rights reserved.