Comparative studies on the hepatotoxic actions of chloroform and related halogenomethanes in normal and phenobarbital-pretreated animals.

Hepatotoxic action of CHCl3 was examined biochemically by comparing with those of CCl4 and other related halogenomethanes using normal and phenobarbital (PB)-pretreated animals. In the later stage (24 hr), in mice, PB pretreatment augmented CHCl3-induced liver damage as evidenced by an enhancement of elevation of plasma transaminase activities and a parallel rise in liver triglyceride content. In the earlier stage (1 hr), in normal rats, CCl4 (1.0 ml/kg, i.p.) decreased microsomal glucose-6-phosphatase (G-6-Pase) activity and cytochrome P-450 content, whereas no significant effect was observed with the same dose of CHCl3. PB pretreatment produced a significant loss of both enzymes by CHCl3, and enhanced the loss of cytochrome P-450 induced by CCl4, while G-6-Pase activity was little affected by CCl4 in PB-pretreated rats. Both hepatotoxins increased liver malondialdehyde (MDA) content. Some of these early changes in vivo were reproduced in the lipid peroxidation system in vitro. Diethyldithiocarbamate suppressed various toxic manifestations induced by CHCl3 in PB-pretreated rats, but did not protect against the loss of cytochrome P-450 induced by CHCl3 or CCl4. These results suggest that lipid peroxidation hypothesis proposed for CCl4 hepatotoxicity may be applied to the case of CHCl3 though there exist some qualitatively different characteristics between these hepatotoxins, and that the mechanisms of the loss of microsomal G-6-Pase and cytochrome P-450 by either of these hepatotoxins might be different.