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

FA Redegeld, GA Hofman, PG van de Loo, AS Koster and J Noordhoek

Department of Pharmacology, Faculty of Pharmacy, University of Utrecht, The Netherlands.

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.

Volume 256, Issue 2, pp. 665-669, 02/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics