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Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity II. Possible involvement of the gamma-glutamyl cycle.
Toxicol Appl Pharmacol 2005; 202(2):160-71TA

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+Show Affiliations

Toxicology Program, Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06268, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15629191

Citation

Stern, Stephan T., et al. "Contribution of Acetaminophen-cysteine to Acetaminophen Nephrotoxicity II. Possible Involvement of the Gamma-glutamyl Cycle." Toxicology and Applied Pharmacology, vol. 202, no. 2, 2005, pp. 160-71.
Stern ST, Bruno MK, Horton RA, et al. Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity II. Possible involvement of the gamma-glutamyl cycle. Toxicol Appl Pharmacol. 2005;202(2):160-71.
Stern, S. T., Bruno, M. K., Horton, R. A., Hill, D. W., Roberts, J. C., & Cohen, S. D. (2005). Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity II. Possible involvement of the gamma-glutamyl cycle. Toxicology and Applied Pharmacology, 202(2), pp. 160-71.
Stern ST, et al. Contribution of Acetaminophen-cysteine to Acetaminophen Nephrotoxicity II. Possible Involvement of the Gamma-glutamyl Cycle. Toxicol Appl Pharmacol. 2005 Jan 15;202(2):160-71. PubMed PMID: 15629191.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity II. Possible involvement of the gamma-glutamyl cycle. AU - Stern,Stephan T, AU - Bruno,Mary K, AU - Horton,Robert A, AU - Hill,Dennis W, AU - Roberts,Jeanette C, AU - Cohen,Steven D, PY - 2004/03/12/received PY - 2004/06/07/accepted PY - 2005/1/5/pubmed PY - 2005/3/15/medline PY - 2005/1/5/entrez SP - 160 EP - 71 JF - Toxicology and applied pharmacology JO - Toxicol. Appl. Pharmacol. VL - 202 IS - 2 N2 - 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. SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/15629191/Contribution_of_acetaminophen_cysteine_to_acetaminophen_nephrotoxicity_II__Possible_involvement_of_the_gamma_glutamyl_cycle_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(04)00300-X DB - PRIME DP - Unbound Medicine ER -