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.
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.
Redegeld
F A
FA
Department of Pharmacology, Faculty of Pharmacy, University of Utrecht, The Netherlands.
Hofman
G A
GA
van de Loo
P G
PG
Koster
A S
AS
Noordhoek
J
J
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010477:Perfusion; D011339:Probenecid / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014812:Vitamin K / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D005723:gamma-Glutamyltransferase / Q000502:physiology*
D007555:Isoxazoles; D014812:Vitamin K; D005723:gamma-Glutamyltransferase; C006303:acivicin; D011339:Probenecid; C023885:menadiol