Isoniazid (INH), a widely used
drug in the prophylaxis and treatment of
tuberculosis, is associated with a 1 to 2% risk of severe and potentially fatal hepatotoxicity. There is evidence that the INH metabolite
hydrazine plays an important role in the mechanism of this toxicity. Metabolism of INH leads 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
amide bond. In the present study, using a model of INH-induced hepatotoxicity in rabbits, pretreatment of rabbits with the
amidase inhibitor
bis-p-nitrophenyl phosphate 30 min before injection of INH inhibited the formation of INH-derived
hydrazine and decreased measures of hepatocellular damage, hepatic
triglyceride accumulation, and
hypertriglyceridemia.
Bis-p-nitrophenyl phosphate also potently inhibited the production of
hydrazine from INH in in vitro microsomal incubations (IC50 2 microM). Although hepatic
glutathione stores are decreased, they are not depleted in animals with INH-induced hepatotoxicity. Significant effects on hepatic microsomal
cytochrome P-450 1A1/2 and
cytochrome P-450 2E1 activities suggest that these
isozymes may be involved in the mechanism of the toxicity. In conclusion, this study demonstrates the importance of
amidase activity in this rabbit model of hepatotoxicity and provides additional evidence in support of the role of
hydrazine in the mechanism of INH-induced hepatotoxicity.