Trichloroethylene, nephrotoxicity

Chakrabarti SK, Tuchweber B. 1988. Studies of acute nephrotoxic potential of trichloroethylene in Fischer-344 rats. J Toxicol Environ Health 23 147-158. 

Cojocel C, Beuter W, Muller W, et al. 1989. Lipid peroxidation A possible mechanism of trichloroethylene-induced nephrotoxicity. Toxicology 55 131-141. 

A variety of halogenated alkanes and alkenes such as hexachlorobutadiene, chlorotrifluoro-ethylene, tetrafluoroethylene, and trichloroethylene (Fig. 7.28) are nephrotoxic. Studies have shown that metabolic activation is necessary for toxicity, but this does not involve cytochromes P-450. Thus, hexachlorobutadiene (HCBD) is a potent nephrotoxin in a variety of mammalian species, and the kidney is the major target. 

Trichloroethylene is metabolized similarly and gives rise to dichlorovinyl cysteine. It has been found that S-(l,2-dichlorovinyl)-L-cysteine (DCVC) and S-(2-chloroethyl)-DL-cysteine (CEC) (Fig. 7.30) are both nephrotoxic when administered to animals causing renal proximal tubular necrosis. CEC does not require 3-lyase activation to be nephrotoxic, but can rearrange, possibly to a reactive episulfonium ion, by nucleophilic displacement of the chlorine atom. These compounds decrease the activity of the renal tubular anion and cation transport system. 

Other halogenated compounds such as trichloroethylene may be metabolized to similar cysteine conjugates, which are also nephrotoxic but may not all require p-lyase activation. 

Metabolomics has made remarkable inroads into the environmental research community. Here, a major emphasis is to understand the impact that environmental stress, such as pollution and climate change, has on wildlife. Indeed, many government organizations monitor the prevalence of pollutants in certain species of wildlife as indicators of the exposure risk within the environment. Studies of Japanese medaka have been conducted to investigate the effects of trichloroethylene, a common environmental pollutant, and the pesticide dinoseb, on the development of fish embryos (44, 45). Similarly, cadmium toxicity has been examined in the bank vole and rat and has revealed changes in lipid metabolism that preceded classical nephrotoxicity (46, 47). Another study investigated the effects of environmental toxins on earthworms (48). In particular, the analysis of earthworm tissue extracts by NMR spectroscopy identified maltose as a potential biomarker for ecotoxicity within a metal-contaminated site. 

Cytochrome P-450 and cysteine conjugate p-lyse are primarily localized in the proximal tubules, and these enzymes also contribute to the susceptibility of the proximal tubule to toxicant injury. Specifically, widely used industrial solvents such as chloroform produce tubular nephrotoxicity via cytochrome P-450 activation, and haloaUcanes and haloalkenes (e.g. trichloroethylene) are rendered toxic by cysteine conjugate (3-lyse activation [24,24a]. In addition, overdoses of acetaminophen (APAP) cause nephrotoxicity that is characterized by proximal tubular necrosis [25]. APAP undergoes cytochrome P-450-mediated activation to produce a toxic electrophile, N-acetyl-p-benzoquinon-eimine (NAPQI) [25a]. Although NAPQI is extremely reactive, it is detoxified by conjugation with reduced GSH unless NAPQI is formed in excess of the cellular capacity for GSH conjugation. The excess NAPQI is available to bind to critical cellular proteins and to induce oxidative stress, resulting in disruption of cellular homeostasis and tubular injury [26]. 

Trichloroethylene is a versatile chemical compound used extensively in vapour degreasing of metals, and to a more limited degree, as a solvent for dry-cleaning and for adhesives. Although the major rate of elimination of trichloroethylene, regardless of the method of exposure, in the rat is by exhalation through the pulmonary system (Daniel 1963), in man the nephrotoxic and genotoxic N-acetyl-S-dichlorovinyl-L-cysteine as an urinary metabolite was found after occupational exposure to 1,1,2-trichloroethylene (Birner et al. 1993). 

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