Abstract
An acyl-linked mercapturic acid metabolite of clofibrate has been identified in human urine. The identification is based on comparison of fast-atom bombardment mass spectra and high-pressure liquid chromatograms with those of synthesized material. This represents the first acyl-linked mercapturate found in man. The mechanism proposed for its formation involves transacylation of clofibrate acyl glucuronide by glutathione, hydrolysis, and acetylation to produce clofibryl mercapturic acid. Synthetic clofibrate glucuronide is shown to be electrophilic; it reacts covalently with ethanethiol and p-nitro-benzylpyridine. We propose that clofibrate acyl glucuronide is an electrophilic metabolite which reacts with sulfhydryl groups and therefore may be responsible for the human hepatotoxicity of clofibrate.