Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity in CD-1 mice: I. Enhancement of acetaminophen nephrotoxicity by acetaminophen-cysteine
- Toxicology Program, Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06268 (United States)
- Toxicology Program, Department of Pathobiology, University of Connecticut, Storrs, CT 06268 (United States)
- Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112 (United States)
- Toxicology Program, Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06268 (United States) and Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Worcester, MA 01608 (United States)
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.
- OSTI ID:
- 20634834
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 202, Issue 2; Other Information: DOI: 10.1016/j.taap.2004.06.030; PII: S0041-008X(04)00301-1; Copyright (c) 2004 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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