Document Detail

Nephrotoxicity of the glutathione conjugate of menadione (2-methyl-1, 4-naphthoquinone) in the isolated perfused rat kidney. Role of metabolism by gamma-glutamyltranspeptidase and probenecid-sensitive transport.
MedLine Citation:
PMID:  1671599     Owner:  NLM     Status:  MEDLINE    
The renal processing of the glutathione conjugate of menadione, 2-methyl-3-S-glutathionyl-1,4-naphthoquinone (thiodione) was studied in the isolated perfused rat kidney. Thiodione at an initial concentration of 600 microM was eliminated rapidly from the perfusate (clearance = 6.0 ml/min). Renal disposition could be ascribed to metabolism and transport of the glutathione conjugate. Renal metabolism by gamma-glutamyltranspeptidase was inhibited by AT-125 [L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid] (0.5 mM) resulting in a reduction of the thiodione clearance to 0.86 ml/min. Further reduction of the renal clearance of thiodione was achieved by a combination of AT-125 (0.5 mM) and probenecid (0.5 mM), resulting in a renal clearance of 0.58 ml/min which equalled glomerular filtration rate. Addition of thiodione to the perfusate caused loss of renal function and cellular damage, as reflected by a decreased glucose reabsorption and an increased urinary secretion of lactate dehydrogenase, respectively. Thiodione-induced nephrotoxicity was ameliorated by AT-125 and prevented completely by a combination of AT-125 and probenecid. Aminooxyacetic acid (0.5 mM), an inhibitor of beta-lyase, did not afford protection against the nephrotoxic action of thiodione. From our results it can be concluded that the thiodione-mediated toxicity in the isolated perfused rat kidney can be linked to cellular uptake by anionic transport systems and metabolism by gamma-glutamyltranspeptidase.
F A Redegeld; G A Hofman; P G van de Loo; A S Koster; J Noordhoek
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  256     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  1991 Feb 
Date Detail:
Created Date:  1991-03-21     Completed Date:  1991-03-21     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  665-9     Citation Subset:  IM    
Department of Pharmacology, Faculty of Pharmacy, University of Utrecht, The Netherlands.
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MeSH Terms
Biological Transport / drug effects
Isoxazoles / pharmacology
Kidney / drug effects*,  metabolism
Probenecid / pharmacology*
Rats, Inbred Strains
Vitamin K / analogs & derivatives*,  metabolism,  toxicity
gamma-Glutamyltransferase / physiology*
Reg. No./Substance:
0/Isoxazoles; 12001-79-5/Vitamin K; 481-85-6/menadiol; 52583-41-2/acivicin; 57-66-9/Probenecid; EC

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