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  • Title: The role of l-thyroxine and hepatic reductase activity in isoniazid-induced hepatotoxicity in rabbits.
    Author: Sarich TC, Adams SP, Wright JM.
    Journal: Pharmacol Res; 1998 Sep; 38(3):199-207. PubMed ID: 9782070.
    Abstract:
    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.
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