METABOLIC ACTIVATION OF TRICHLOROETHYLENE INTO A CHEMICALLY REACTIVE METABOLITE TOXIC TO LIVER

  • 1 January 1978
    • journal article
    • research article
    • Vol. 204  (3) , 714-723
Abstract
The mechanism for trichloroethylene hepatotoxicity was investigated in male Sprague-Dawley rats. Phenobarbital pretreatment increased and CoCl2 pretreatment decreased trichloroethylene hepatotoxicity. After [14C]trichloroethylene administration, a radioactive material became irreversibly bound to hepatic proteins, while negligible amounts were bound to muscle proteins. When [14C]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 CO 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 trichloroethylene is metabolized by cytochrome P-450 into a chemically reactive metabolite which reacts with, and binds to, either proteins or glutathione, binding to proteins produces liver lesions and binding to glutathione decreases the amount of reactive metabolite available for binding to proteins. Trichloroethylene, a halogenated hydrocarbon (CCl2 = CHCl), is used as an industrial solvent, as an household degreasing and cleaning agent, and as a volatile anesthetic; in addition, trichloroethylene is inhaled by an increasing number of solvent sniffers.

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