title: Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity II. Possible involvement of the gamma-glutamyl cycle.
abstract: Acetaminophen (APAP) nephrotoxicity has been observed both in humans and research animals. Our recent investigations have focused on the possible involvement of glutathione-derived APAP metabolites in APAP nephrotoxicity and have demonstrated that administration of acetaminophen-cysteine (APAP-CYS) potentiated APAP-induced renal injury with no effects on APAP-induced liver injury. Additionally, APAP-CYS treatment alone resulted in a dose-responsive renal GSH depletion. This APAP-CYS-induced renal GSH depletion could interfere with intrarenal detoxification of APAP or its toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI) and may be the mechanism responsible for the potentiation of APAP nephrotoxicity. Renal-specific GSH depletion has been demonstrated in mice and rats following administration of amino acid gamma-glutamyl acceptor substrates for gamma-glutamyl transpeptidase (gamma-GT). The present study sought to determine if APAP-CYS-induced renal glutathione depletion is the result of disruption of the gamma-glutamyl cycle through interaction with gamma-GT. The results confirmed that APAP-CYS-induced renal GSH depletion was antagonized by the gamma-glutamyl transpeptidase (gamma-GT) inhibitor acivicin. In vitro analysis demonstrated that APAP-CYS is a gamma-glutamyl acceptor for both murine and bovine renal gamma-GT. Analysis of urine from mice pretreated with acivicin and then treated with APAP, APAP-CYS, or acetaminophen-glutathione identified a gamma-glutamyl-cysteinyl-acetaminophen metabolite. These findings are consistent with the hypothesis that APAP-CYS contributes to APAP nephrotoxicity by depletion of renal GSH stores through interaction with the gamma-glutamyl cycle.
authors.affiliation: Toxicology Program, Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06268, USA.
authors.forename: Stephan T
authors.initials: ST
authors.lastname: Stern
authors.forename: Mary K
authors.initials: MK
authors.lastname: Bruno
authors.forename: Robert A
authors.initials: RA
authors.lastname: Horton
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Hill
authors.forename: Jeanette C
authors.initials: JC
authors.lastname: Roberts
authors.forename: Steven D
authors.initials: SD
authors.lastname: Cohen
mesh_terms: D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity* / Q000652:urine; D000818:Animals; D002462:Cell Membrane / Q000473:pathology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003545:Cysteine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity* / Q000652:urine; D004151:Dipeptides / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007555:Isoxazoles / Q000494:pharmacology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008815:Mice, Inbred Strains; D008871:Microvilli / Q000473:pathology; D015394:Molecular Structure; D018675:Toxicity Tests / Q000379:methods; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D004151:Dipeptides; D007555:Isoxazoles; C497432:gamma-glutamylcysteinylacetominophen; D000082:Acetaminophen; C069744:acetaminophen cysteine; D005723:gamma-Glutamyltransferase; D005982:Glutathione Transferase; D005978:Glutathione; D003545:Cysteine; C006303:acivicin