GLUTATHIONE-DEPENDENT BIOACTIVATION OF HALOALKENES

Several halogenated alkenes are nephrotoxic in rodents. A mechanism fo r the organ-specific toxicity of these compounds to the kidney has bee n elucidated. The mechanism involves hepatic glutathione conjugation t o dihaloalkenyl or 1,1-difluoroalkyl glutathione S-conjugates, which a re cleaved by gamma-glutamyltransferase and dipeptidases to cysteine S -conjugates. Haloalkene-derived cysteine S-conjugates may have four fa tes in the organism: (a) They may be substrates for renal cysteine con jugate beta-lyases, which cleave them to form reactive intermediates i dentified as thioketenes (chloroalkene-derived S-conjugates), thionoac yl halides (fluoroalkene-derived S-conjugates not containing bromide), thiiranes, and thiolactones (fluoroalkene-derived S-conjugates contai ning bromine); (b) cysteine S-conjugates may be N-acetylated to excret able mercapturic acids; (c) they may undergo transamination or oxidati on to the corresponding 3-mercaptopyruvic acid S-conjugate; (d) finall y, oxidation of the sulfur atom in halovinyl cysteine S-conjugates and corresponding mercapturic acids forms Michael accepters and may also represent a bioactivation reaction. The formation of reactive intermed iates by cysteine conjugate beta-lyase may play a role in the target-o rgan toxicity and in the possible renal tumorigenicity of several chlo rinated olefins widely used in many chemical processes.