PARTICIPATION OF P45O-DEPENDENT OXIDATION OF ISONIAZID IN ISONICOTINIC-ACID FORMATION IN RAT-LIVER

By determining the formation amount of isonicotinic acid (INA) from is onicotinic acid hydrazide (isoniazid: INH) in isolated rat hepatocytes , we were able to identify the involvement of the oxidative cleavage o f the acid hydrazide. INA formation from INH increased significantly u sing the isolated hepatocytes prepared from rats pretreated with pheno barbital (PB), 3-methylcholanthrene (3MC), dexamethazone (DEX) and rif ampicin (RIF), respectively, in comparison to the control group. On th e other hand, a remarkable decrease in INA formation from INH was obse rved by addition of such P450 inhibitor as metyrapone or cimetidine as well as an amidase inhibitor bis(p-nitrophenyl)phosphate (BNPP) to is olated hepatocytes prepared from PB-pretreated rats. By further experi ments using rat hepatic microsomes, the oxidative pathway of INA forma tion in INH metabolism was determined to be P450-dependent, since NADP H and oxygen were both essential for the oxidative pathway of INH to I NA and the amount of INA formation was also significantly increased by P450 inducers. Regarding acetylisoniazid (AcINH) and isonicotinic aci d amide (INAA), however, INA formation by P450 was little observed in the microsomal experiments.