| 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. | |
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MedLine Citation:
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PMID: 1671599 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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F A Redegeld; G A Hofman; P G van de Loo; A S Koster; J Noordhoek |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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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:
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Created Date: 1991-03-21 Completed Date: 1991-03-21 Revised Date: 2003-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 665-9 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, Faculty of Pharmacy, University of Utrecht, The Netherlands. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Biological Transport / drug effects Isoxazoles / pharmacology Kidney / drug effects*, metabolism Male Perfusion Probenecid / pharmacology* Rats Rats, Inbred Strains Vitamin K / analogs & derivatives*, metabolism, toxicity gamma-Glutamyltransferase / physiology* |
| Chemical | |
Reg. No./Substance:
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0/Isoxazoles; 12001-79-5/Vitamin K; 481-85-6/menadiol; 52583-41-2/acivicin; 57-66-9/Probenecid; EC 2.3.2.2/gamma-Glutamyltransferase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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