Nephrotoxicity of halogenated alkenyl cysteine-S-conjugates.
In 1916 a relationship was postulated between the occurrence of aplastic anaemia in cattle and the soy bean meal that they had been fed, which had been extracted with trichloroethylene. The toxic compound was later identified as S-(1,2-dichlorovinyl)-L-cysteine (DCV-Cys). In addition to effects on the hemopoietic system it also produced nephrotoxicity in calves. In rats only renal tubular necrosis was found. Further research demonstrated that other halogenated hydrocarbons produced similar nephrotoxicity. The haloalkenyl cysteine-S-conjugates (Cys-S-conjugates) have extensively been studied; this has provided new insight into the biochemical processes that lead to nephrotoxicity. It has been shown that a combination of transport processes and specific metabolic pathways, resulting in reactive intermediates that bind to cellular macromolecules, makes the kidney vulnerable to the noxious effects of the haloalkenyl Cys-S-conjugates. The first part of this review gives a brief overview of the bioactivation of the haloalkenes; in the second part the present knowledge of the underlying mechanisms of cytotoxicity will be outlined.
Division of Toxicology, Center for Bio-Pharmaceutical Sciences, Sylvius Laboratory, University of Leiden, The Netherlands.
J F
JF
Nagelkerke
P J
PJ
Boogaard
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D006846:Hydrocarbons, Halogenated / Q000378:metabolism / Q000633:toxicity*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects
D006846:Hydrocarbons, Halogenated; D003545:Cysteine; D002118:Calcium