Ono Y, Wu X, Noda A, Noda H, Yoshitani T
Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Biol Pharm Bull. 1998 Apr;21(4):421-5. doi: 10.1248/bpb.21.421.
By determining the formation amount of isonicotinic acid (INA) from isonicotinic acid hydrazide (isoniazid:INH) in isolated rat hepatocytes, we were able to identify the involvement of the oxidative cleavage of the acid hydrazide. INA formation from INH increased significantly using the isolated hepatocytes prepared from rats pretreated with phenobarbital (PB), 3-methylcholanthrene (3MC), dexamethazone (DEX) and rifampicin (RIF), respectively, in comparison to the control group. On the other hand, a remarkable decrease in INA formation from INH was observed by the addition of such P450 inhibitor as metyrapone or cimetidine as well as an amidase inhibitor bis(p-nitrophenyl)phosphate (BNPP) to the isolated hepatocytes prepared from PB-pretreated rats. By further experiments using rat hepatic microsomes, the oxidative pathway of INA formation in INH metabolism was determined to be P450-dependent, since NADPH and oxygen were both essential for the oxidative pathway of INH to INA and the amount of INA formation was also significantly increased by P450 inducers. Regarding acetylisoniazid (AcINH) and isonicotinic acid amide (INAA), however, INA formation by P450 was little observed in the microsomal experiments.
通过测定分离的大鼠肝细胞中异烟肼（INH）生成异烟酸（INA）的量，我们能够确定酰肼的氧化裂解参与其中。与对照组相比，分别使用苯巴比妥（PB）、3-甲基胆蒽（3MC）、地塞米松（DEX）和利福平（RIF）预处理的大鼠制备的分离肝细胞，INH生成INA的量显著增加。另一方面，向PB预处理的大鼠制备的分离肝细胞中添加甲吡酮或西咪替丁等P450抑制剂以及酰胺酶抑制剂双（对硝基苯基）磷酸酯（BNPP）后，观察到INH生成INA的量显著减少。通过使用大鼠肝微粒体的进一步实验，确定INH代谢中INA生成的氧化途径是P450依赖性的，因为NADPH和氧气对于INH氧化为INA的途径都是必需的，并且P450诱导剂也显著增加了INA生成的量。然而，对于乙酰异烟肼（AcINH）和异烟酰胺（INAA），在微粒体实验中几乎未观察到P450介导的INA生成。
