Whitehouse L W, Tryphonas L, Paul C J, Solomonraj G, Thomas B H, Wong L T
Can J Physiol Pharmacol. 1983 May;61(5):478-87. doi: 10.1139/y83-073.
Steatosis was induced in rabbits by subacute administration of isoniazid (INH, 50 mg/kg po). Concomitant treatment with pyridoxine (vitamin B6, 25 mg/kg po) antagonized both development of the hepatic lesions and the elevation of plasma concentrations of lipids. Rabbit acetylating ability was sixfold that of male Wistar rats, a species susceptible to hepatic cell necrosis, whereas hepatic cytochrome P-450 and NADPH-cytochrome c reductase were significantly lower than that observed in control or phenobarbital-induced rats. Examination of the hepatic hydrolysis of the amide bonds of INH and acetylisoniazid (AcINH) indicated that the isonicotinoyl bond of AcINH was the bond most susceptible to amidase hydrolysis in both species; but rabbits possessed the greater amidase activity: 5- to 20-fold greater than control rats and 2- to 7-fold greater than the phenobarbital-induced rats. Consequently, INH-induced hepatic fatty degeneration in rabbits was attributed to increased hepatic exposure to INH-derived primary amine functional groups, and its antagonism by vitamin B6 was attributed to the deactivation of the primary amine by pyridoxal hydrazone formation.
通过亚急性给予异烟肼（INH，50 mg/kg口服）在兔中诱导脂肪变性。同时用吡哆醇（维生素B6，25 mg/kg口服）治疗可对抗肝脏病变的发展以及血浆脂质浓度的升高。兔的乙酰化能力是雄性Wistar大鼠的六倍，Wistar大鼠是一种易发生肝细胞坏死的物种，而兔肝脏细胞色素P-450和NADPH-细胞色素c还原酶显著低于对照或苯巴比妥诱导的大鼠。对INH和乙酰异烟肼（AcINH）酰胺键的肝脏水解研究表明，AcINH的异烟酰基键是两种物种中最易被酰胺酶水解的键；但兔具有更高的酰胺酶活性：比对照大鼠高5至20倍，比苯巴比妥诱导的大鼠高2至7倍。因此，INH诱导的兔肝脏脂肪变性归因于肝脏对INH衍生的伯胺官能团的暴露增加，而维生素B6对其的拮抗作用归因于通过形成吡哆醛腙使伯胺失活。
