Inhibition of isoniazid-induced hepatotoxicity in rabbits by pretreatment with an amidase inhibitor

Isoniazid (INH), a widely used drug in the prophylaxis and treatment of tub erculosis, is associated with a 1 to 2% risk of severe and potentially fata l hepatotoxicity. There is evidence that the INH metabolite hydrazine plays an important role in the mechanism of this toxicity. Metabolism of INH lea ds to the production of hydrazine via both direct and indirect pathways. In both cases, the activity of an INH amidase is required to hydrolyze an ami de bond. In the present study, using a model of INH-induced hepatotoxicity in rabbits, pretreatment of rabbits with the amidase inhibitor bis-p-nitrop henyl phosphate 30 min before injection of INH inhibited the formation of I NH-derived hydrazine and decreased measures of hepatocellular damage, hepat ic triglyceride accumulation, and hypertriglyceridemia. Bis-p-nitrophenyl p hosphate also potently inhibited the production of hydrazine from INH in in vitro microsomal incubations (IC50 2 mu M). Although hepatic glutathione s tores are decreased, they are not depleted in animals with INH-induced hepa totoxicity. Significant effects on hepatic microsomal cytochrome P-450 1A1/ 2 and cytochrome P-450 2E1 activities suggest that these isozymes may be in volved in the mechanism of the toxicity. In conclusion, this study demonstr ates the importance of amidase activity in this rabbit model of hepatotoxic ity and provides additional evidence in support of the role of hydrazine in the mechanism of INH-induced hepatotoxicity.