Is isoniazid-hepatotoxicity induced by the metabolite, hydrazine?

The effects of rifampicin (RMP) on isoniazid (INH) metabolism in rabbits were examined from the viewpoint of extensive hepatitis. After the RMP pretreatment, no remarkable changes were observed in the plasma levels of INH as well as its metabolites, acetylisoniazid (AcINH), acetylhydrazine (AcHz) and diacetylhydrazine (DAcHz) with the exception of hydrazine (Hz). After an oral administration of INH or Hz hydrate, the stochastic examination showed that the AUC0-8hr values of Hz plasma levels in RMP pretreated groups were significantly less than those in the control rabbits. RMP treatment was also shown to induce rabbit liver cytochrome P-450 activity. Histological studies demonstrated that Hz causes more remarkable hepatic necrosis in rabbits pretreated with RMP than in the control rabbits. These observations could suggest that Hz is a key intermediate of INH-hepatitis through the transformation of some hepatotoxic species by microsomal oxidation that is facilitated by RMP.