Organ-specific carcinogenicity of haloalkenes mediated by glutathione conjugation.
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 gamma-glutamyltransferase and dipeptidases to cysteine S-conjugates. Haloalkene-derived cysteine S-conjugates are substrates for renal cysteine conjugate beta-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 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.
Dekant
W
W
Department of Toxicology, University of Würzburg, Germany. dekant@toxi.uni-wuerzburg.de
Henschler
D
D
D000818:Animals; D001711:Biotransformation; D013437:Carbon-Sulfur Lyases / Q000378:metabolism; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000493:pharmacokinetics* / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000139:chemically induced; D009928:Organ Specificity
D002273:Carcinogens; D006846:Hydrocarbons, Halogenated; D013437:Carbon-Sulfur Lyases; C019969:S-alkylcysteine lyase; D005978:Glutathione