Mitchell J R, Zimmerman H J, Ishak K G, Thorgeirsson U P, Timbrell J A, Snodgrass W R, Nelson S D
Ann Intern Med. 1976 Feb;84(2):181-92. doi: 10.7326/0003-4819-84-2-181.
The clinical spectrum of isoniazid-induced liver injury seems to be clinically, biochemically, and histologically indistinguishable from viral hepatitis, except that the injury occurs primarily in persons older than 35 years. A possible relation between susceptibility of patients to isoniazid liver injury and rapid metabolism (acetylation) of the drug has been found. Examination of isoniazid metabolites showed that patients with rapid acetylator phenotype hydrolyze much more isoniazid to isonicotinic acid and the free hydrazine moiety than do slow acetylators. The hydrazine moiety liberated from isoniazid is primarily acetylhydrazine, and studies in animals show this metabolite to be converted to a potent acylating agent that produces liver necrosis. It seems likely that formation of chemically reactive metabolites is also the biochemical event initiating isoniazid liver injury in man. Recognition of the seriousness of isoniazid hepatic injury, not readily accepted at first, has led to revisions in the uses of isoniazid prophylaxis.
异烟肼所致肝损伤的临床谱在临床、生化和组织学上似乎与病毒性肝炎难以区分，只是这种损伤主要发生在35岁以上的人群中。已发现患者对异烟肼肝损伤的易感性与药物的快速代谢（乙酰化）之间可能存在关联。对异烟肼代谢产物的检测表明，快乙酰化表型的患者比慢乙酰化者将更多的异烟肼水解为异烟酸和游离肼基。从异烟肼释放出的肼基主要是乙酰肼，动物研究表明这种代谢产物会转化为一种产生肝坏死的强效酰化剂。化学反应性代谢产物的形成似乎也是人类异烟肼肝损伤起始的生化事件。起初人们并不容易接受对异烟肼肝损伤严重性的认识，这导致了异烟肼预防用途的修订。
