Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity in CD-1 mice: I. Enhancement of acetaminophen nephrotoxicity by acetaminophen-cysteine.
Acetaminophen (APAP) nephrotoxicity has been observed both in humans and research animals. Recent studies suggest a contributory role for glutathione (GSH)-derived conjugates of APAP in the development of nephrotoxicity. Inhibitors of either gamma-glutamyl transpeptidase (gamma-GT) or the probenecid-sensitive organic anion transporter ameliorate APAP-induced nephrotoxicity but not hepatotoxicity in mice and inhibition of gamma-GT similarly protected rats from APAP nephrotoxicity. Protection against APAP nephrotoxicity by disruption of these GSH conjugate transport and metabolism pathways suggests that GSH conjugates are involved. APAP-induced renal injury may involve the acetaminophen-glutathione (APAP-GSH) conjugate or a metabolite derived from APAP-GSH. Acetaminophen-cysteine (APAP-CYS) is a likely candidate for involvement in APAP nephrotoxicity because it is both a product of the gamma-GT pathway and a probable substrate for the organic anion transporter. The present experiments demonstrated that APAP-CYS treatment alone depleted renal but not hepatic glutathione (GSH) in a dose-responsive manner. This depletion of renal GSH may predispose the kidney to APAP nephrotoxicity by diminishing GSH-mediated detoxification mechanisms. Indeed, pretreatment of male CD-1 mice with APAP-CYS before challenge with a threshold toxic dose of APAP resulted in significant enhancement of APAP-induced nephrotoxicity. This was evidenced by histopathology and plasma blood urea nitrogen (BUN) levels at 24 h after APAP challenge. APAP alone was minimally nephrotoxic and APAP-CYS alone produced no detectable injury. By contrast, APAP-CYS pretreatment did not alter the liver injury induced by APAP challenge. These data are consistent with there being a selective, contributory role for APAP-GSH-derived metabolites in APAP-induced renal injury that may involve renal-selective GSH depletion.
Stern
Stephan T
ST
Toxicology Program, Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06268, USA.
Bruno
Mary K
MK
Hennig
Gayle E
GE
Horton
Robert A
RA
Roberts
Jeanette C
JC
Cohen
Steven D
SD
D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism; D018675:Toxicity Tests / Q000379:methods
D013438:Sulfhydryl Compounds; D000082:Acetaminophen; C069744:acetaminophen cysteine; D005978:Glutathione; D003545:Cysteine