Covalent binding of 14C-1,1,2-trichloroethane to hepatic proteins following acetone pretreatment.
We have recently reported that 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; po), fasted 15 hr prior to dosing with 14C-TCEA (1.2 mmole/kg; ip), and killed 4 hr later. Overnight fasting alone resulted in a six fold increase in covalent binding of 14C-TCEA to hepatic proteins compared to non-fasted rats. Acetone pretreatment, however, did not cause an increase in binding of 14C-TCEA 4 hr 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). The data suggest that potentiation of TCEA hepatotoxicity by acetone may result in part, from alterations of TCEA bioactivation and hepatic GSH concentrations.
D000096:Acetone / Q000494:pharmacology*; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006843:Hydrocarbons, Chlorinated / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000378:metabolism; D014240:Trichloroethanes / Q000378:metabolism*
D006843:Hydrocarbons, Chlorinated; D014240:Trichloroethanes; D000096:Acetone; C024567:1,1,2-trichloroethane; D005978:Glutathione