Organ-specific carcinogenicity of haloalkenes mediated by glutathione conjugation

Abstract

Several halogenated alkenes are nephrotoxic in rodents. A mechanism for the organ-specific toxicity to the kidney for these compounds has been elucidated. The mechanism involves hepatic glutathione conjugation to dihaloalkenyl or 1,1-difluoroalkyl glutathione S-conjugates, which are cleaved by γ-glutamyltransferase and dipeptidases to cysteine S-conjugates. Haloalkene-derived cysteine S-conjugates are substrates for renal cysteine conjugate β-lyases, which cleave them to form reactive intermediates identified as thioketenes (from chloroalkene-derived S-conjugates) or thionoacyl halides (from 1,1-difluoroalkyl S-conjugates). Alternatively, cysteine S-conjugates may be N-acetylated to excretable mercapturic acids. The formation of reactive intermediates by cysteine-conjugate β-lyase may play a role in the target-organ toxicity and in the possible renal tumorigenicity of several chlorinated olefins widely used in many chemical processes.