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Three common pathways of nephrotoxicity induced by halogenated alkenes

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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.

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Acknowledgments

AVS is supported by the Italian Ministero della Salute (GR-2011-02346985).

Conflict of interest statement

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Pathology Department, GlaxoSmithKline, Ware, UK

    Patrizia Cristofori

  2. San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy

    Aisha V. Sauer

  3. Department of Cardiologic, Thoracic and Vascular Sciences, University of Padova, Via Giustiniani 2, 35128, Padova, Italy

    Andrea Trevisan

Authors
  1. Patrizia Cristofori
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  2. Aisha V. Sauer
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  3. Andrea Trevisan
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Correspondence to Andrea Trevisan.

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Cristofori, P., Sauer, A.V. & Trevisan, A. Three common pathways of nephrotoxicity induced by halogenated alkenes. Cell Biol Toxicol 31, 1–13 (2015). https://doi.org/10.1007/s10565-015-9293-x

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  • DOI: https://doi.org/10.1007/s10565-015-9293-x

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