Sarich T C, Youssefi M, Zhou T, Adams S P, Wall R A, Wright J M
Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada.
Arch Toxicol. 1996;70(12):835-40. doi: 10.1007/s002040050347.
Isoniazid (INH) continues to be a highly effective drug in the chemoprophylaxis and treatment of tuberculosis; however, its use is associated with hepatotoxicity (predominantly hepatic necrosis) in 1-2% of individuals. The INH metabolites, acetylhydrazine and hydrazine, have each been implicated as the causative hepatotoxin in INH-induced hepatotoxicity. Using a model of INH-induced hepatotoxicity in rabbits, in which INH-induced hepatotoxicity manifests as hepatic necrosis, hepatic steatosis (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. Plasma INH and acetylhydrazine were not correlated with markers of INH-induced 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 curve (r2 = 0.54, P < 0.002) and log plasma ASAL activity at 48 h after the first dose of INH (r2 = 0.53, p < 0.005), but not with fatty changes. These results show in this model of INH-induced hepatotoxicity in rabbits that hydrazine, and not INH or acetylhydrazine, is most likely involved in the pathogenic mechanism of hepatic necrosis.
异烟肼（INH）在结核病的化学预防和治疗中仍然是一种高效药物；然而，在1%-2%的个体中，其使用与肝毒性（主要是肝坏死）相关。INH的代谢产物乙酰肼和肼，均被认为是INH诱导肝毒性的致病肝毒素。利用兔INH诱导肝毒性模型（其中INH诱导的肝毒性表现为肝坏死、肝脂肪变性（肝脏脂肪堆积）和高甘油三酯血症（血浆甘油三酯升高）），我们将这些毒性指标的严重程度与INH、乙酰肼和肼的血浆水平进行了比较。血浆INH和乙酰肼与INH诱导的肝坏死或脂肪变化指标无关。32小时时的血浆肼与血浆精氨琥珀酸裂解酶（ASAL，肝坏死的敏感标志物）活性的曲线下面积显著相关（r2 = 0.54，P < 0.002），与首次给予INH后48小时的血浆ASAL活性对数相关（r2 = 0.53，p < 0.005），但与脂肪变化无关。这些结果表明，在该兔INH诱导肝毒性模型中，最有可能参与肝坏死致病机制的是肼，而非INH或乙酰肼。
