Linked Life Data

15629191

Source:http://linkedlifedata.com/resource/pubmed/id/15629191

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2005-1-4
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0041-008X
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
202
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
160-71
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:15629191-Acetaminophen, pubmed-meshheading:15629191-Animals, pubmed-meshheading:15629191-Cell Membrane, pubmed-meshheading:15629191-Chromatography, High Pressure Liquid, pubmed-meshheading:15629191-Cysteine, pubmed-meshheading:15629191-Dipeptides, pubmed-meshheading:15629191-Dose-Response Relationship, Drug, pubmed-meshheading:15629191-Glutathione, pubmed-meshheading:15629191-Glutathione Transferase, pubmed-meshheading:15629191-Injections, Intraperitoneal, pubmed-meshheading:15629191-Isoxazoles, pubmed-meshheading:15629191-Kidney Diseases, pubmed-meshheading:15629191-Kidney Tubules, Proximal, pubmed-meshheading:15629191-Male, pubmed-meshheading:15629191-Mass Spectrometry, pubmed-meshheading:15629191-Mice, pubmed-meshheading:15629191-Mice, Inbred Strains, pubmed-meshheading:15629191-Microvilli, pubmed-meshheading:15629191-Molecular Structure, pubmed-meshheading:15629191-Toxicity Tests, pubmed-meshheading:15629191-gamma-Glutamyltransferase
pubmed:year
2005
pubmed:articleTitle
Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity II. Possible involvement of the gamma-glutamyl cycle.
pubmed:affiliation
Toxicology Program, Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06268, USA.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't