ISONIAZID HEPATOTOXICITY - THE RELATIONSHIP BETWEEN COVALENT BINDING AND METABOLISM INVIVO

  • 1 January 1980
    • journal article
    • research article
    • Vol. 213  (2) , 364-369
Abstract
The relationship between the hepatotoxicity and metabolism of isoniazid and its metabolites, acetylisoniazid and acetylhydrazine, was investigated. Toxic doses of acetylisoniazid and bound covalently to live protein in vivo. This binding was mediated by the microsomal enzyme system as indicated by the effects of pretreatments altering the activity of the enzymes. Metabolic studies revealed that the pretreatments increased the metabolism of the acetylhydrazine moiety of acetyllabled acetylisoniazid and of acetylhydrazine itself by the microsomal enzyme system. Pretreatment with the acyl amidase inhibitor, bis-p-nitrophenyl phosphate, inhibited the hydrolysis of acetylisoniazid to isonicotinic acid plus acetylhydrazine and concomitantly decreased the covalent binding of acetyl-labeled acetylisoniazid. The changes in the metabolism of isoniazid, acetylisoniazid and acetylhydrazine effected by various pretreatments paralleled changes in the severity of the hepatic necrosis caused by the compounds. Acetylhydrazine is the metabolite responsible for the hepatic necrosis caused by isoniazid and that microsomal metabolism of acetylhydrazine in vivo leads to the production of a reactive acylating species capable of reacting covalently with tissue macromolecules.