Chloroform toxicity in mice: correlation of renal and hepatic necrosis with covalent binding of metabolites to tissue macromolecules

Chloroform (CHCl₃) treatment caused centrolobular hepatic necrosis in mice of both sexes whereas renal necrosis was observed only in male mice. Following administration of ¹⁴CHCl₃ to mice, substantial amounts (about 3 mmole/g) of radiolabeled material were covalently bound to proteins in the liver and kidney. The amount of convalent binding paralleled the extent of renal and hepatic necrosis both in normal animals and in male mice pretreated with either phenobarbital or piperonyl butoxide, agents which induce or block, respectively, microsomal drug metabolizing enzymes. These results suggest that the covalent binding is due to a metabolite of CHCl₃. Evidence that the covalent binding is causally related to the tissue necrosis was obtained from autoradiograms showing that the radioactivity is located mainly in the necrotic lesions.