Effect of isoniazid administration on selected rat and mouse hepatic microsomal mixed-function oxidases and in vitro [14C]acetylhydrazine-derived covalent binding.

The effect of isoniazid on selected microsomal mixed-function oxidase activities and on the microsomal metabolism of its own metabolite, acetylhydrazine, to a highly reactive compound which covalently binds to intracellular macromolecules was characterized in male C57BL6 mice and male Sprague-Dawley rats. In comparison with controls, isoniazid pretreatment of rats significantly increased the sp. act. of acetanilide 4-hydroxylase and the in vitro [14C]acetylhydrazine-derived covalent binding to hepatic microsomes but significantly decreased the sp. act. of benzo[a]pyrene hydroxylase and testosterone 16 alpha-hydroxylase. Isoniazid treatment of mice had no effect on any of these parameters except for a significant reduction in sp. act. of testosterone 7 alpha-hydroxylase. Thus the pathway of isoniazid metabolism leading to the formation of reactive metabolites of acetylhydrazine is enhanced by isoniazid pretreatment in rats but not in mice. The presence of similar routes of isoniazid metabolism in man may account for the 8.7-24% incidence of subclinical hepatocellular damage observed in patients receiving isoniazid alone in the chemoprophylaxis of tuberculosis.