ROLE OF HYDRAZINE IN THE MECHANISM OF ISONIAZID HEPATOTOXICITY IN RABBITS

Isoniazid (INH) continues to be a highly effective drug in the chemopr ophylaxis and treatment of tuberculosis; however, its use is associate d with hepatotoxicity (predominantly hepatic necrosis) in 1-2% of indi viduals. The INH metabolites, acetylhydrazine and hydrazine, have each been implicated as the causative hepatotoxin in INH-induced hepatotox icity. Using a model of INH-induced hepatotoxicity in rabbits, in whic h INH-induced hepatotoxicity manifests as hepatic necrosis, hepatic st eatosis (hepatic fat accumulation) and hypertriglyceridaemia (elevated plasma triglycerides), we compared the severity of these measures of toxicity with plasma levels of INH, acetylhydrazine and hydrazine. Pla sma INH and acetylhydrazine were not correlated with markers of INH-in duced hepatic necrosis or fatty changes. Plasma hydrazine at 32 h was correlated significantly with plasma argininosuccinic acid lyase (ASAL , a sensitive marker of hepatic necrosis) activity as area under the c urve (r(2) = 0.54, P < 0.002) and log plasma ASAL activity at 48 h aft er the first dose of INH (r(2) = 0.53, p < 0.005), but not with fatty changes. These results show in this model of INH-induced hepatotoxicit y in rabbits that hydrazine, and not INH or acetylhydrazine, is most l ikely involved in the pathogenic mechanism of hepatic necrosis.