Glutathione-dependent metabolism of trichloroethylene in isolated liver and kidney cells of rats and its role in mitochondrial and cellular toxicity.
Metabolism of trichloroethylene (Tri) by the glutathione (GSH) conjugation pathway was studied in hepatocytes, renal cortical cells, and liver subcellular fractions from male Fischer 344 rats. Toxicity of Tri and some of its GSH- and cytochrome P450-dependent metabolites was then studied in isolated hepatocytes, kidney cells, and liver and kidney mitochondria to assess the relative role of these metabolites in toxicity. Tri metabolism to S-(1,2-dichlorovinyl)glutathione (DCVG), a nephrotoxic metabolite of Tri, was demonstrated in both isolated hepatocytes and kidney cells. This suggests that the first Tri bioactivation step that leads to nephrotoxicity in vivo occurs in both liver and kidney. Rates of DCVG formation in liver microsomes and cytosol were similar, although total activity was greater in cytosol. Only S-(1,2-dichlorovinyl)-L-cysteine (DCVC), but not Tri, DCVG, or the other oxidative metabolites examined (trichloroacetate, dichloroacetate, chloral hydrate, trichloroethanol, or oxalic acid) caused acute hepatotoxicity, whereas only DCVC and DCVG produced acute nephrotoxicity in isolated renal cortical cells. Tri and the metabolites examined, except trichloroacetate and DCVG, caused a loss of function of liver and kidney mitochondria. In liver mitochondria, DCVC produced the largest decrease in mitochondrial respiration, whereas Tri, trichloroethanol, and dichloroacetate were somewhat less toxic and chloral hydrate was the least toxic. In kidney mitochondria, in contrast, Tri, trichloroethanol, dichloroacetate, chloral hydrate, and DCVC caused similar decreases in mitochondrial respiration. These results suggest that, whereas both GSH conjugation and cytochrome P450-dependent metabolism of Tri generate mitochondrial toxicants, only the GSH-derived metabolites were cytotoxic.
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D005978:Glutathione / Q000502:physiology* / Q000633:toxicity; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000166:cytology / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D008930:Mitochondria, Liver / Q000187:drug effects; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D012997:Solvents / Q000378:metabolism* / Q000633:toxicity; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014241:Trichloroethylene / Q000378:metabolism* / Q000633:toxicity
D012997:Solvents; D014241:Trichloroethylene; D005978:Glutathione