IDENTIFICATION OF S-(N-BUTYLCARBAMOYL)GLUTATHIONE, A REACTIVE CARBAMOYLATING AGENT, AS A BILIARY METABOLITE OF BENOMYL IN THE RAT

Treatment of rats with benomyl [methyl 1-(n-butylcarbamoyl)-2-benzimidazolecarbamate; 100 mg kg(-1) ip] led to the detection of a novel biliary metabolite of this widely used systemic fungicide. By means of on-line liquid chromatography-tandem mass spectrometry, this metabolite was identified as a carbamoylated derivative of glutathione, viz. S-(n-butylcarbamoyl)glutathione (SBuG), whose excretion in bile over 4:5 h accounted for ca. 1% of the dose. In vitro experiments demonstrated that SBuG and the corresponding cysteine adduct exhibited carbamoylating activity toward the thiol groups of free cysteine and glutathione when the elements of n-butyl isocyanate were transferred to the acceptor nucleophiles. SBuG also proved to be highly cytotoxic to isolated rat hepatocytes at a concentration of 1 mM. The results of this study raise the possibility that SBuG may serve as a latent form of n-butyl isocyanate in vivo and thereby mediate some of the adverse effects of benomyl.