Metabolomics reveals the formation of aldehydes and iminium in gefitinib metabolism
Metabolomics reveals the formation of aldehydes and iminium in gefitinib metabolism
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DOI：
10.1016/j.bcp.2015.07.010
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发表时间：
2015-09-01
影响因子：
5.8
通讯作者：
Li, Feng
中科院分区：
文献类型：
--
作者：
Liu, Xing;Lu, Yuanfu;Li, Feng
吉非替尼是一种表皮生长因子受体(EGFR)酪氨酸激酶的抑制剂，广泛用于癌症，特别是非小细胞肺癌的治疗。然而，它的临床应用受到与全球环境基金相关的多种不良反应的限制，如肝和肺损伤、严重恶心和腹泻。尽管全球环境基金不良反应的确切机制尚不清楚，但异种生物诱导的生物激活被认为在全球环境基金的毒性中起着重要作用。利用代谢组学方法，我们研究了全球环境基金在人和小鼠肝微粒体中的代谢途径。共鉴定了34种全环基金代谢物和加合物，其中一半为新化合物。潜在的活性代谢物，两个醛和一个亚胺，是第一次被鉴定。还观察到了以前报道的谷胱甘肽加合物和伯胺。以甲氧基胺和氰化钾为捕捉剂，进一步确认了醛和亚胺途径。利用重组的细胞色素P450亚型、细胞色素P3A4抑制剂和来自细胞色素P3A基因缺失小鼠的S9，我们证实了细胞色素P3A是在肝脏中促进醛、谷胱甘肽加合物和伯胺形成的主要酶。多种酶促进了亚胺的形成。这项研究为我们提供了更多关于环境基金生物活化和代谢途径中的酶的知识，这些知识可以用来理解与环境基金相关的不良反应的机制，并预测可能的药物-药物相互作用。建议进行进一步研究，以确定这些生物激活途径在全球环境基金毒性中的作用。(C)2015 Elsevier Inc.保留所有权利。
Gefitinib (GEF), an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, is widely used for the treatment of cancers, particularly non-small cell lung cancer. However, its clinical use is limited by multiple adverse effects associated with GEF, such as liver and lung injuries, severe nausea, and diarrhea. Although, the exact mechanism of GEF adverse effects are still unknown, xenobiotic-induced bioactivation is thought to play a significant role in GEF induced toxicity. Using a metabolomic approach, we investigated the metabolic pathways of GEF in human and mouse liver microsomes. Thirty four GEF metabolites and adducts were identified and half of them are novel. The potential reactive metabolites, two aldehydes and one iminium, were identified for the first time. The previously reported GSH adducts and primary amines were observed as well. The aldehyde and iminium pathways were further confirmed by using methoxylamine and potassium cyanide as trapping reagents. Using recombinant CYP450 isoforms, CYP3A4 inhibitor, and S9 from Cyp3a-null mice, we confirmed CYP3A is the major enzyme contributing to the formation of aldehydes, GSH adducts, and primary amines in liver. Multiple enzymes contribute to the formation of iminium. This study provided us more knowledge of GEF bioactivation and enzymes involved in metabolic pathways, which can be utilized for understanding the mechanism of adverse effects associated with GEF and predicting possible drug-drug interactions. Further studies are suggested to determine the roles of these bioactivation pathways in GEF toxicity. (C) 2015 Elsevier Inc. All rights reserved.