Three common pathways of nephrotoxicity induced by halogenated alkenes

Glutathione-dependent bioactivation is a common pathway in nephrotoxicitycaused by haloalkanesand haloalkenes. Glutathione conjugation forms the link between halogenated hydrocarbons, based on the formation of an episulfonium ion (vicinal halomethanes) or a cysteineconjugate ( haloalkenes). Herein, we review the metabolic pathways underlying the nephrotoxiceffects of the three well-known haloalkenes trichloroethylene, tetrachloroethylene, and hexachloro-1:3-butadiene to emphasize the role of cysteine-conjugate β- lyaseand the oxidative metabolism in renal toxicity. Activation by cysteine-conjugate β- lyaseis the best-characterized mechanism causing toxicitydue to haloalkenetreatment in experimental models. However, the severity of toxicitydiffers considerably, with S-(1,2,2-trichlorovinyl)-l- cysteinebeing more toxicthan S-(1,2-dichlorovinyl)-l- cysteine, which is in turn more toxicthan S-(1,2,3,4,4-pentachloro-1:3-butadienyl)-l- cysteine. Moreover, two oxidative pathways involving cysteineS-conjugates (mediated by flavin-containing monooxigenase 3) and N-acetyl-l-cysteineconjugates (mediated by cytochrome P-450 3A) form derived sulfoxides, which represent alternative metabolites with toxiceffects. In vitro and in vivo studies showed that sulfoxide metabolites are more toxicthan cysteine-conjugate derivates. The cytochrome P-450 3A family, on the other hand, is sex specific, and its expression has only been reported in adult male rats and rabbits. In summary, haloalkenesare highly nephrotoxicin vivo and in vitro and their toxicitymechanisms are well documented experimentally. However, little information is available on their toxicityin humans, except for the carcinogenic effects established for high exposure levels of trichloroethyleneand tetrachloroethylene.