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A number of chemicals are known to potentiate the hepatotoxicity of carbon tetrachloride. The halocarbon trichloroethylene was shown in a previous study to enhance both carbon tetrachloride-induced toxicity and lipid peroxidation in isolated hepatocytes. In this study three other chlorocarbons have been investigated in order to determine whether this interaction was peculiar to trichloroethylene or common to chlorinated solvents. Hepatocyte suspensions were exposed to carbon tetrachloride at subthreshold levels of toxicity and various concentrations of 1,1,1-trichloroethane, tetrachloroethylene, and chloroform over an eightfold concentration range. Plasma membrane preparations were exposed to tetrachloroethylene and carbon tetrachloride and effects on Mg 2+ - and Na + -K + -ATPase activities determined. None of the treatments alone caused statistically significant toxicity. Combined treatments resulted in toxicity as demonstrated by potassium ion, alanine aminotransferase, and lactate dehydrogenase leakage from the cells on coincubation of carbon tetrachloride with each of the other halocarbons studied. Only tetrachloroethylene and chloroform were found to potentiate lipid peroxidation, however. In liver plasma membranes no changes in Na + -K + -ATPase were observed with any of the treatments and only the highest dose of tetrachloroethylene was able to inhibit Mg 2+ -ATPase activity. There was no increase in this inhibition on coincubation with carbon tetrachloride, which does not support involvement of ATPases in combined halocarbon toxicity. In conclusion, the data suggest a mechanism of action common to this class of chemical although its specific nature remains to be established.

Hepatocytes isolated from Sprague-Dawley rats were exposed to carbon tetrachloride together with various concentrations of trichloroethylene over a 40-fold range. A potentiation of carbon tetrachloride-induced lipid peroxidation by trichloroethylene and an enhanced toxicity on combined exposure were clearly demonstrated. Additionally, rats were treated 2.5 hr before isolation of hepatocytes, which were then exposed to carbon tetrachloride. Lipid peroxidation and potassium ion leakage were increased in these cells. Some incubations included the antioxidant N,N′ -diphenyl- p -phenylenediamine (DPPD) while others contained dithiothreitol (DTT), a thiol reducing compound. DPPD inhibited lipid peroxidation while DTT did not. Neither, however, was able to inhibit the toxicity. Assays to estimate total and nonprotein bound sulfhydryl groups were also performed. There was no indication of a causative role for cellular sulfhydryl groups in the enhanced toxicity. Therefore, our data show that lipid peroxidation is not responsible for the trichloroethylene-induced enhancement of toxicity in hepatocytes due to carbon tetrachloride. Furthermore, there is no evidence to indicate a role for sulfhydryl groups in this response.