In vivo nephrotoxic action of an isomeric mixture of S-(1-phenyl-2-hydroxyethyl)glutathione and S-(2-phenyl-2-hydroxyethyl)glutathione in Fischer-344 rats.
An isomeric mixture of S-[(1 and 2)-phenyl-2-hydroxyethyl]glutathione (PHEG), a glutathione conjugate of styrene, is moderately nephrotoxic. Its in vivo nephrotoxicity was characterized by significant elevations in the urinary excretion of glucose, gamma-glutamyl transpeptidase, glutamate dehydrogenase, N-acetyl-beta-D-glucosaminidase and lactic dehydrogenase 24 h after an i.v. administration of PHEG (0.5 mmol/kg) in male Fischer-344 rats. The histologic alterations consisted of moderate tubular damage with proximal tubule vacuolization and accumulation of tubular cast material, indicating an early sign of tubular necrosis. The data suggest that nephrotoxic injury induced by PHEG lies preferentially at the tubular region of the rat kidney involving several subcellular targets. The nephrotoxicity of PHEG was blocked by acivicin, a specific inhibitor of gamma-glutamyl transpeptidase, by phenylalanylglycine, an inhibitor of cysteinylglycine dipeptidase, as well as by probenecid, a competitive inhibitor of renal organic anion transport system. On the other hand, pretreatment with aminooxyacetic acid, a specific inhibitor of renal cysteine conjugate beta-lyase, failed to inhibit the nephrotoxicity of this glutathione conjugate. Similarly, prior administration of alpha-ketobutyrate, an inducer of renal cysteine conjugate beta-lyase, failed to potentiate its nephrotoxicity, suggesting an insignificant role of beta-lyase in such toxicity. A modest decline in renal cellular GSH due to PHEG but without any concomitant oxidation of GSH to GSSG and without any increase in lipid peroxidation indicates that oxidative stress may not be an important mechanism of its nephrotoxicity. Therefore, the following steps at least, are involved in the development of its nephrotoxicity: (1) renal tubular accumulation of PHEG via a probenecid-sensitive transport process; and (2) its renal metabolism via gamma-glutamyl transpeptidase and cysteinylglycine dipeptidase to the corresponding cysteine-S-conjugate.
Chakrabarti
S
S
Département de médecine du travail et d'hygiène du milieu, Faculté de médecine, Université de Montréal, Québec, Canada.
Malick
M A
MA
D000118:Acetylglucosaminidase / Q000652:urine; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D005969:Glutamate Dehydrogenase / Q000652:urine; D005978:Glutathione / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism / Q000633:toxicity; D006029:Glycosuria / Q000139:chemically induced; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000652:urine; D008297:Male; D010084:Oxidation-Reduction; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D005723:gamma-Glutamyltransferase / Q000652:urine
D000963:Antimetabolites; D002087:Butyrates; D004151:Dipeptides; D007555:Isoxazoles; D000625:Aminooxyacetic Acid; C040500:phenylalanylglycine; C005087:alpha-ketobutyric acid; C068332:S-(1-phenyl-2-hydroxyethyl)glutathione; C068333:S-(2-phenyl-2-hydroxyethyl)glutathione; D007770:L-Lactate Dehydrogenase; D005969:Glutamate Dehydrogenase; D005723:gamma-Glutamyltransferase; D000118:Acetylglucosaminidase; D005978:Glutathione; C006303:acivicin; D011339:Probenecid