Direct oxidation and covalent binding of isoniazid to rodent liver and human hepatic microsomes: humans are more like mice than rats.
Direct oxidation and covalent binding of isoniazid to rodent liver and human hepatic microsomes: humans are more like mice than rats.
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DOI：
10.1021/tx300341r
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发表时间：
2012-11-19
影响因子：
4.1
通讯作者：
Uetrecht J
中科院分区：
文献类型：
--
作者：
Metushi IG;Nakagawa T;Uetrecht J
异烟肼（INH）与严重的肝损伤和自身免疫有关。大鼠中的经典研究表明，乙酰肼的反应性代谢产物负责INH的共价结合和毒性。对兔子的研究表明，肼可能是有毒物质。然而，这些模型涉及高剂量INH的急性毒性，并且INH诱导的人类肝损伤与这些动物模型具有非常不同的特征。在这项研究中，我们证明了INH本身的反应性代谢产物可以在小鼠肝脏中共价结合，也可以与人肝微粒体结合。大鼠也有共价结合，但远低于小鼠。我们能够在与人肝微粒体孵育中用N-α-乙酰基-L-赖氨酸捕获INH的反应性代谢物。这表明导致共价结合的INH的反应性中间体是重氮氢氧化物而不是自由基或碳阳离子，因为这些反应性代谢物的反应性太强而不能以这种方式捕获。用INH治疗小鼠或大鼠长达5周未产生严重的肝损伤。丙氨酸转氨酶（ALT）被INH抑制，而谷氨酸和山梨醇脱氢酶（SDH）是INH诱导的肝损伤的更好的生物标志物。高剂量INH（200和400 mg/kg/天）给药一周，可导致大鼠脂肪变性和SDH增加，这表明它可导致线粒体损伤。然而，当以较低剂量给予小鼠或大鼠较长时间时，未观察到脂肪变性。我们认为，母体药物的共价结合可能有助于异烟肼诱导的肝毒性和自身免疫。我们还提出这些是免疫介导的反应，并且有临床数据支持这些假设。
Isoniazid (INH) is associated with serious liver injury and autoimmunity. Classic studies in rats indicated that a reactive metabolite of acetylhydrazine is responsible for the covalent binding and toxicity of INH. Studies in rabbits suggested that hydrazine might be the toxic species. However, these models involved acute toxicity with high doses of INH, and INH-induced liver injury in humans has very different features than such animal models. In this study, we demonstrated that a reactive metabolite of INH itself can covalently bind in the liver of mice and also to human liver microsomes. Covalent binding also occurred in rats, but it was much less than that in mice. We were able to trap the reactive metabolite of INH with N-α-acetyl-l-lysine in incubations with human liver microsomes. This suggests that the reactive intermediate of INH that leads to covalent binding is a diazohydroxide rather than a radical or carbocation because those reactive metabolites would be too reactive to trap in this way. Treatment of mice or rats with INH for up to 5 weeks did not produce severe liver injury. The alanine transaminase assay (ALT) is inhibited by INH, and other assays such as glutamate and sorbitol dehydrogenase (SDH) were better biomarkers of INH-induced liver injury. High doses of INH (200 and 400 mg/kg/day) for one week produced steatosis in rats and an increase in SDH, which suggests that it can cause mitochondrial injury. However, steatosis was not observed when INH was given at lower doses for longer periods of time to either mice or rats. We propose that covalent binding of the parent drug can contribute to INH-induced hepatotoxicity and autoimmunity. We also propose that these are immune-mediated reactions, and there are clinical data to support these hypotheses.
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影响因子：
13.5
作者：
Huang, YS;Chern, HD;Lee, SD
通讯作者：
Lee, SD
影响因子：
6.7
作者：
Metushi, I. G.;Cai, P.;Uetrecht, J. P.
通讯作者：
Uetrecht, J. P.
影响因子：
3
作者：
Bernhardt, PV;Chin, P;Richardson, DR
通讯作者：
Richardson, DR
影响因子：
39.2
作者：
MADDREY, WC;BOITNOTT, JK
通讯作者：
BOITNOTT, JK
影响因子：
2.6
作者：
Sodhi, CP;Rana, SV;Mehta, S
通讯作者：
Mehta, S