The toxic interaction between carbon tetrachloride (CCl4) and chloroform (CHCl3) was investigated in rats chronically pretreated with ethanol, and in rat liver microsomes. A combined exposure to 10 ppm CCl4 and 50 ppm CHCl3 increased plasma alanine aminotransferase (ALT) activity to a level similar to that by a single exposure to 50 ppm CCl4. The single exposure decreased liver reduced glutathione (GSH) and cytochrome P450 (CYP) content, and N-nitrosodimethylamine N-demethylase (NDMAD) activity. The effects of combined exposure, however, were little or less than those of the single exposure. Immunoblot analysis with monoclonal antibody to CYP2E1 indicated that CYP2E1 was appreciably decreased after the single exposure but the enzyme remained after the combined exposure. The antibody inhibited CCl4-induced lipid peroxidation in microsomes from ethanol-treated rats. Ethanol pretreatment increased the metabolic rate of CCl4 and CCl4-induced lipid peroxidation, but the coexistence of CHCl3 and other hydrocarbons such as trichloroethylene and 1,1,1-trichloroethane did not increase the in vitro metabolic rate or the lipid peroxidation. The addition of GSH decreased CCl4-induced lipid peroxidation, and the effect reached its maximum at 0.3 mM of GSH, so that the hepatotoxic interaction between CCl4 and CHCl3 at low dose exposure is more than additive when judged by the plasma ALT activity, but this is not true of the changes in drug-metabolizing enzyme activity and GSH depletion.
- Carbon tetrachloride
- Cytochrome P450
- Lipid peroxidation
ASJC Scopus subject areas
- Public Health, Environmental and Occupational Health