NDLI: Three common pathways of nephrotoxicity induced by halogenated alkenes

Content Provider	Springer Nature Link
Author	Cristofori, Patrizia Sauer, Aisha V. Trevisan, Andrea
Copyright Year	2015
Abstract	Glutathione-dependent bioactivation is a common pathway in nephrotoxicity caused by haloalkanes and haloalkenes. Glutathione conjugation forms the link between halogenated hydrocarbons, based on the formation of an episulfonium ion (vicinal halomethanes) or a cysteine conjugate (haloalkenes). Herein, we review the metabolic pathways underlying the nephrotoxic effects of the three well-known haloalkenes trichloroethylene, tetrachloroethylene, and hexachloro-1:3-butadiene to emphasize the role of cysteine-conjugate β-lyase and the oxidative metabolism in renal toxicity. Activation by cysteine-conjugate β-lyase is the best-characterized mechanism causing toxicity due to haloalkene treatment in experimental models. However, the severity of toxicity differs considerably, with S-(1,2,2-trichlorovinyl)-l-cysteine being more toxic than S-(1,2-dichlorovinyl)-l-cysteine, which is in turn more toxic than S-(1,2,3,4,4-pentachloro-1:3-butadienyl)-l-cysteine. Moreover, two oxidative pathways involving cysteine S-conjugates (mediated by flavin-containing monooxigenase 3) and N-acetyl-l-cysteine conjugates (mediated by cytochrome P-450 3A) form derived sulfoxides, which represent alternative metabolites with toxic effects. In vitro and in vivo studies showed that sulfoxide metabolites are more toxic than 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, haloalkenes are highly nephrotoxic in vivo and in vitro and their toxicity mechanisms are well documented experimentally. However, little information is available on their toxicity in humans, except for the carcinogenic effects established for high exposure levels of trichloroethylene and tetrachloroethylene.
Starting Page	1
Ending Page	13
Page Count	13
File Format	PDF
ISSN	07422091
Journal	Cell Biology and Toxicology
Volume Number	31
Issue Number	1
e-ISSN	15736822
Language	English
Publisher	Springer Netherlands
Publisher Date	2015-02-11
Publisher Place	Dordrecht
Access Restriction	Subscribed
Subject Keyword	Trichloroethylene Tetrachloroethylene Hexachloro-1:3-butadiene Sulfoxide β-Lyase Nephrotoxicity Cell Biology Pharmacology/Toxicology Biochemistry
Content Type	Text
Resource Type	Article
Subject	Cell Biology Health, Toxicology and Mutagenesis Toxicology

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