Identification of the 1-cyano-3,4-epithiobutane-derived urinary mercapturic acid N-acetyl-S-(4-cyano-2-thio-1-butyl)cysteine in male Fischer 344 rats

1-Cyano-3,4-epithiobutane (CEB), a naturally occurring nitrile derived from cruciferous plants, causes nephrotoxicity in male Fischer 344 rats. Nephro toxicity induced by CEB is dependent on glutathione (GSH) conjugation and b ioactivation, Conjugation with GSH and subsequent metabolism leads to the f ormation of specific urinary metabolites. The objectives of the present stu dy were to identify CEB-derived urinary metabolites and quantify urinary no n-protein thiols and thioethers in male Fischer 344 rats. Animals received 125 mg kg(-1) of CEB alone or following pretreatment with one of three sele ctive inhibitors of GSH metabolism: acivicin, probenecid or aminooxyacetic acid. Total non-protein urinary thiol and urinary thioether concentrations were elevated in all treated groups at 12 and 24 h; however, elevations in non-protein thiols were not significantly greater in rats administered CEB alone as compared to negative controls. A single predominant urinary metabo lite was identified as the CEB-derived mercapturic acid N-acetyl-S-(4-cyano -thio-1-butyl)-cysteine. Evidence for other CEB-derived metabolites was als o demonstrated. These findings represent the identification of a unique com pound and provide further evidence for the importance of GSH conjugation as a significant pathway in CEB metabolism. Copyright (C) 2000 John Wiley & S ons, Ltd.