Studies on the role of acetylhydrazine in isoniazid hepatotoxicity

Abstract

Some factors affecting the metabolism of acetylhydrazine were studied in rats. This compound, a potent hepatotoxin, is a metabolite of isoniazid in man and is thought to be responsible for the hepatotoxicity of the drug. Isoniazid inhibited both the microsomal metabolism of acetylhydrazine, in vitro, and the acetylation to diacetylhydrazine in vivo. The overall effect of isoniazid in vivo was to increase metabolism of acetylhydrazine through the microsomal pathway leading to increased covalent binding of the toxic reactive intermediate to liver protein. The results suggest that the metabolism of acetylhydrazine produced as a metabolite of isoniazid may be quantitatively different from the metabolism of the compound alone. Preliminary studies in patients suffering isoniazid related liver damage indicated that acetylation of acetylhydrazine may be one of the factors involved in the hepatotoxicity of isoniazid in man.