Centrolobular hepatic necrosis related to covalent binding of metabolites of halogenated aromatic hydrocarbons

Abstract

The mechanism of centrolobular hepatic necrosis produced by treating rats or mice with 14C-labeled halogenated aromatic hydrocarbons was studied as an animal model of drug-induced tissue lesions. The development of hepatic necrosis was associated with the covalent binding of substantial amounts of radiolabeled material to liver proteins, and autoradiograms revealed that most of the covalently bound material was localized within the necrotic centrolobular hepatocytes. Prior induction of hepatic microsomal enzymes by phenobarbital administration potentiated the covalent binding and necrosis, whereas prior inhibition of hydrocarbon metabolism had the opposite effect, suggesting that the binding and necrosis are caused by toxic metabolites of the hydrocarbons. A positive correlation between the amount of covalent binding and the severity of centrolobular necrosis was obtained after various drug treatments and with several different halogenated benzene derivatives of varying hepatotoxicity. These results suggest that covalent binding of toxic metabolites may be an important mechanism in the pathogenesis of tissue lesions elicited by a variety of foreign compounds.