Timbrell J A, Mitchell J R, Snodgrass W R, Nelson S D
J Pharmacol Exp Ther. 1980 May;213(2):364-9.
The relationship between the hepatotoxicity and metabolism of isoniazid and its metabolites, acetylisoniazid and acetylhydrazine, has been investigated. Toxic doses of acetylisoniazid and acetylhydrazine, radiolabeled in the acetyl group, were found to bind covalently to liver protein in vivo. This binding was mediated by the microsomal enzyme system as indicated by the effects of pretreatments altering the activity of these enzymes. Metabolic studies revealed that the pretreatments increased the metabolism of the acetylhydrazine moiety of acetyl-labeled acetylisoniazid and of acetylhydrazine itself by the microsomal enzyme system. Pretreatment with the acyl amidase inhibitor, bis-p-nitrophenyl phosphate, inhibited the hydrolysis of acetylisoniazid to isonicotinic acid plus acetylhydrazine and concomitantly decreased the covalent binding of acetyl-labeled acetylisoniazid. The changes in the metabolism of isoniazid, acetylisoniazid and acetylhydrazine effected by various pretreatments paralleled changes in the severity of the hepatic necrosis caused by the compounds. These results strongly suggest that acetylhydrazine is the metabolite responsible for the hepatic necrosis caused by isoniazid and that mirosomal metabolism of acetylhydrazine in vivo leads to the production of a reactive acylating species capable of reacting covalently with tissue macromolecules.
已对异烟肼及其代谢产物乙酰异烟肼和乙酰肼的肝毒性与代谢之间的关系进行了研究。发现乙酰基带有放射性标记的乙酰异烟肼和乙酰肼的毒性剂量在体内与肝脏蛋白发生共价结合。如通过改变这些酶活性的预处理效果所示，这种结合是由微粒体酶系统介导的。代谢研究表明，预处理增加了微粒体酶系统对乙酰标记的乙酰异烟肼的乙酰肼部分以及乙酰肼本身的代谢。用酰基酰胺酶抑制剂对硝基苯基磷酸酯进行预处理，可抑制乙酰异烟肼水解为异烟酸加乙酰肼，并同时降低乙酰标记的乙酰异烟肼的共价结合。各种预处理对异烟肼、乙酰异烟肼和乙酰肼代谢的影响与这些化合物引起的肝坏死严重程度的变化平行。这些结果有力地表明，乙酰肼是导致异烟肼引起肝坏死的代谢产物，并且乙酰肼在体内的微粒体代谢导致产生能够与组织大分子发生共价反应的活性酰化物质。
