Acute hepatoxicity of vinyl chloride and ethylene: Modification by trichloropropene oxide, diethylmaleate, and cysteine

Abstract

We have reported that vinyl chloride (VC) and ethylene are acutely hepatotoxic in rats pretreated with polychlorinated biphenyl (PCB). The present study used several chemical treatments to investigate the mechanisms of acute VC and ethylene toxicity in PCB-pretreated rats. Trichloropropene oxide (TCPO) depletes hepatic glutathione (GSH) and inhibits hepatic epoxide hydrase (EH). Diethylmaleate (DEM) also depletes hepatic GSH. Cysteine is a rate-limiting precursor in hepatic GSH synthesis. Effects of these various treatments on VC and ethylene toxicity were compared with their influence on hepatic GSH concentrations. Exposures to VC and ethylene were by inhalation at 1000 to 50,000 ppm. TCPO significantly increased VC toxicity in fasted but not in fed rats. Ethylene toxicity was not affected by TCPO. These actions of TCPO were not attributable to changes in hepatic GSH. DEM significantly lowered GSH during exposure, but did not increase the hepatotoxicity of either VC or ethylene. This suggests either that hepatic GSH concentrations are not an important determinant of the acute response to VC and ethylene or that DEM has important effects in addition to hepatic GSH depletion. Cysteine protected significantly, though incompletely, against acute VC hepatotoxicity. There was no effect of cysteine on the toxicity of ethylene. These data indicate that in PCB-treated rats, hepatic GSH and EH influence the acute hepatotoxicity of VC, but not that of ethylene.