Metabolic activation of trichloroethylene into a chemically reactive metabolite toxic to the liver.
The mechanism for trichloroethylene hepatotoxicity was investigated in male Sprague-Dawley rats. Phenobarbital pretreatment increased and CoCl2 pretreatment decreased trichloroethylene hepatotoxicity. After administration of 1(14)C]trichloroethylene, a radioactive material became irreversibly bound to hepatic proteins, while negligible amounts were bound to muscle proteins. When 1(14)C]trichloroethylene was incubated under air with hepatic microsomes and a NADPH-generating system, a radioactive material became irreversibly bound to microsomal proteins; binding was negligible when the NADPH-generating system was omitted; binding was inhibited by carbon monoxide and by piperonyl butoxide; the amount of bound material was greater with microsomes from phenobarbital-pretreated rats and lower with microsomes from CoCl2-pretreated rats than with microsomes from nonpretreated rats. Trichloroethylene administration decreased hepatic glutathione in normal rats but not in piperonyl butoxide-pretreated rats; in vitro, glutathione decreased the amount of trichloroethylene material that bound to microsomal proteins. The reported results are consistent with the view that 1) trichloroethylene is metabolized by cytochrome P-450 into a chemically reactive metabolite which reacts with, and binds to, either proteins or glutathione, 2) binding to proteins produces liver lesions and 3) binding to glutathione decreases the amount of reactive metabolite available for binding to proteins.
D000818:Animals; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D003035:Cobalt / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D014241:Trichloroethylene / Q000009:adverse effects* / Q000378:metabolism
D009124:Muscle Proteins; D014241:Trichloroethylene; D003035:Cobalt; D005978:Glutathione; D010634:Phenobarbital