Covalent Binding of14C-1,1,2-Trichloroethane to Hepatic Proteins Following Acetone Pretreatment

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Abstract
Pretreatment of rats with acetone potentiates both the hepatic glutathione (GSH) depletion and subsequent hepatotoxicity caused by 1,1,2-trichloroethane (TCEA). To determine if acetone treatment enhances the bioactivation of TCEA, the covalent binding of 14C-TCEA to tissue proteins was assessed both in vivo and in vitro. Male, Sprague-Dawley rats were treated with acetone (0.5 ml/kg; per os), fasted 16 h prior to dosing with 14C-TCEA (1.2 mmol/kg; i.p.) and killed 4 h later. Overnight fasting alone resulted in a 6-fold increase in covalent binding of 14C-TCEA to hepatic proteins compared to nonfasted rats. Acetone pretreatment, did not cause an increase in binding of 14C-TCEA 4 h after dosing compared to fasted controls, although it did produce a 30% further decrease in hepatic GSH. When microsomes from acetone treated rats were incubated with 14C-TCEA, covalent binding to protein was significantly increased (35%) over using microsomes from fasted control rats. The covalent binding of 14C-TCEA to microsomal protein was inhibited 80% by the addition of GSH (1 mM). Potentiation of TCEA hepatotoxicity by acetone may result, in part, from alterations of TCEA bioactivation and hepatic GSH concentrations.