Effect of cysteine, diethyl maleate, and phenobarbital treatments on the hepatotoxicity of [1H]chloroform.

The effects of cysteine, diethyl maleate and phenobarbital treatments and 2H-substitution on the hepatotoxicity of chloroform were investigated. Time course studies of covalent binding and hepatoxicity in phenobarbital-treated rats showed that covalent binding of 14C-label from [14C]chloroform was maximal at 6 h after chloroform administration while hepatotoxicity reached a peak at 18 h. Cysteine treatment reduced both covalent binding and hepatotoxicity, while diethyl maleate and phenobarbital treatments increased both the hepatotoxicity of chloroform and the covalent binding of chloroform metabolites to hepatic proteins. A deuterium isotope effect was present on chloroform-induced hepatotoxicity in diethyl maleate-treated rats suggesting that the previously reported inhibition of haloform metabolism by diethyl maleate occurs at a step in the reaction mechanism after phosgene production. These data support the concept that phosgene is the toxic intermediate in chloroform metabolism.