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首页> 外文期刊>Biochemical Pharmacology >Metabolomics reveals the formation of aldehydes and iminium in gefitinib metabolism
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Metabolomics reveals the formation of aldehydes and iminium in gefitinib metabolism

机译：代谢组学揭示了吉非替尼代谢中醛和亚胺的形成

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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.
机译：吉非替尼（GEF）是一种表皮生长因子受体（EGFR）酪氨酸激酶的抑制剂，被广泛用于治疗癌症，特别是非小细胞肺癌。但是，其临床应用受到与GEF相关的多种不良反应的限制，例如肝和肺损伤，严重的恶心和腹泻。尽管仍不清楚GEF不良反应的确切机制，但异种生物诱导的生物活化被认为在GEF诱导的毒性中起重要作用。使用代谢组学方法，我们研究了人和小鼠肝微粒体中GEF的代谢途径。鉴定了34种GEF代谢产物和加合物，其中一半是新颖的。首次确定了潜在的反应性代谢物，两个醛和一个亚胺。还观察到了先前报道的GSH加合物和伯胺。通过使用甲氧基胺和氰化钾作为捕集剂进一步证实了醛和亚胺鎓的途径。使用CYP3a-null小鼠的重组CYP450同工型，CYP3A4抑制剂和S9，我们证实CYP3A是主要酶，有助于肝脏中醛，GSH加合物和伯胺的形成。多种酶有助于亚胺的形成。这项研究为我们提供了有关GEF生物活化和代谢途径中涉及的酶的更多知识，这些知识可用于了解与GEF相关的不良反应的机理并预测可能的药物相互作用。建议进行进一步的研究以确定这些生物激活途径在GEF毒性中的作用。 （C）2015 Elsevier Inc.保留所有权利。

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