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Glutathione-dependent bioactivation of haloalkenes.
Several halogenated alkenes are nephrotoxic in rodents. A mechanism for the organ-specific toxicity of these compounds to the kidney has been elucidated. The mechanism involves hepatic glutathione conjugation to dihaloalkenyl or 1,1-difluoroalkyl glutathione S-conjugates, which are cleaved by gamma-glutamyltransferase and dipeptidases to cysteine S-conjugates. Haloalkene-derived cysteine S-conjugates may have four fates in the organism: (a) They may be substrates for renal cysteine conjugate beta-lyases, which cleave them to form reactive intermediates identified as thioketenes (chloroalkene-derived S-conjugates), thionoacyl halides (fluoroalkene-derived S-conjugates not containing bromide), thiiranes, and thiolactones (fluoroalkene-derived S-conjugates containing bromine); (b) cysteine S-conjugates may be N-acetylated to excretable mercapturic acids; (c) they may undergo transamination or oxidation to the corresponding 3-mercaptopyruvic acid S-conjugate; (d) finally, oxidation of the sulfur atom in halovinyl cysteine S-conjugates and corresponding mercapturic acids forms Michael acceptors and may also represent a bioactivation reaction. The formation of reactive intermediates by cysteine conjugate beta-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.[1]References
- Glutathione-dependent bioactivation of haloalkenes. Anders, M.W., Dekant, W. Annu. Rev. Pharmacol. Toxicol. (1998)
