Auto-oxidation of Isoniazid Leads to Isonicotinic-Lysine Adducts on Human Serum Albumin
Auto-oxidation of Isoniazid Leads to Isonicotinic-Lysine Adducts on Human Serum Albumin
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DOI：
10.1021/tx500285k
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发表时间：
2015-01-01
影响因子：
4.1
通讯作者：
Park, B. Kevin
中科院分区：
文献类型：
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作者：
Meng, Xiaoli;Maggs, James L.;Park, B. Kevin
异烟肼（INH）是一种广泛使用的抗结核药物，但其可引起严重的药物性肝损伤（DILI）。已提出INH修饰的蛋白质在INH DILI中发挥重要作用;然而，仍有待确定INH或反应性代谢物是否不可逆地与蛋白质结合。在这项研究中，质谱法被用来定义蛋白质修饰INH在体外和患者服用INH治疗。当INH与N-乙酰赖氨酸（NAL）孵育时，无论是否存在任何氧化酶，均检测到相同的异烟碱-NAL（IN-NAL）加合物，表明可能涉及自氧化。此外，我们发现INH也可以通过自氧化途径与人血清白蛋白（HSA）结合，与HSA中的赖氨酸残基形成异烟酰胺加合物。在从接受INH治疗的患者分离的血浆样品中检测到类似的加合物。我们的研究结果表明，INH在没有代谢的情况下形成蛋白加合物。
Isoniazid (INH), a widely used antituberculosis drug, has been associated with serious drug-induced liver injury (DILI). INH-modified proteins have been proposed to play important roles in INH DILI; however, it remains to be determined whether INH or reactive metabolites bind irreversibly to proteins. In this study, mass spectrometry was used to define protein modifications by INH in vitro and in patients taking INH therapy. When INH was incubated with N-acetyl lysine (NAL), the same isonicotinic-NAL (IN-NAL) adducts were detected irrespective of the presence or absence of any oxidative enzymes, indicating auto-oxidation may have been involved. In addition, we found that INH could also bind to human serum albumin (HSA) via an auto-oxidation pathway, forming isonicotinic amide adducts with lysine residues in HSA. Similar adducts were detected in plasma samples isolated from patients taking INH therapy. Our results show that INH forms protein adducts in the absence of metabolism.