Sarich T C, Adams S P, Wright J M
Departments of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
Pharmacol Res. 1998 Sep;38(3):199-207. doi: 10.1006/phrs.1998.0347.
There is evidence that hydrazine, a metabolite of isoniazid, plays an important role in the mechanism of isoniazid-induced hepatotoxicity. Hydrazine has been reported to be metabolised by NADPH cytochrome P-450 reductase (reductase) to reactive and potentially toxic intermediates. The present study was designed, using a model of isoniazid-induced hepatotoxicity in rabbits, to determine whether or not reductase plays a role in this toxicity. Although pretreating rabbits with l-thyroxine increased hepatic reductase activity (54% greater than controls), the severity of isoniazid-induced hepatic cell damage (plasma argininosuccinic acid lyase activity) was lower in thyroxine pre-treated animals than in animals treated with isoniazid alone (31.3+/-20 vs 56.0+/-20 Takahara Units, respectively). In addition, pre-treatment with l-thyroxine completely prevented isoniazid-induced hepatic steatosis. In conclusion, contrary to our hypothesis, an increase in reductase activity achieved by pre-treatment with l-thyroxine was associated with a decrease in the severity of isoniazid-induced hepatic cell damage and steatosis in rabbits.
有证据表明，异烟肼的代谢产物肼在异烟肼诱导的肝毒性机制中起重要作用。据报道，肼可被NADPH细胞色素P - 450还原酶（还原酶）代谢为具有反应活性且可能有毒的中间体。本研究采用异烟肼诱导的兔肝毒性模型，旨在确定还原酶是否在这种毒性中起作用。尽管用L - 甲状腺素预处理兔可增加肝脏还原酶活性（比对照组高54%），但在甲状腺素预处理的动物中，异烟肼诱导的肝细胞损伤严重程度（血浆精氨酸琥珀酸裂解酶活性）低于仅用异烟肼处理的动物（分别为31.3±20和56.0±20高桥单位）。此外，L - 甲状腺素预处理完全预防了异烟肼诱导的肝脂肪变性。总之，与我们的假设相反，用L - 甲状腺素预处理使还原酶活性增加，这与兔中异烟肼诱导的肝细胞损伤和脂肪变性严重程度降低有关。
