Acetylhydrazine hepatotoxicity: the role of covalent binding

Acetylhydrazine, a human metabolite of isoniazid and a hepatotoxin, binds covalently to rat liver protein and to the proteins of other organs in vivo. The covalent binding to macromolecules in the liver, but not to those of other organs, was increased by pretreatment with phenobarbital. The time course of binding to total hepatic protein and to hepatic subcellular fractions was also altered by phenobarbital pretreatment. There was a concommitant time-dependent decline in cytochrome P-450 levels in the phenobarbital pretreated animals, but not controls. Acetylhydrazine did not produce detectable lesions in organs other than the liver, despite the occurrence of covalent binding to protein in those organs. The results suggest that only a critical fraction of the covalent binding to specific subcellular components is related to the subsequent development of tissue lesions.