他莫昔芬及其代谢物的脱靶相互作用和毒性机制,Chemical Research in Toxicology

当前位置： X-MOL 学术 › Chem. Res. Toxicol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

他莫昔芬及其代谢物的脱靶相互作用和毒性机制
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2017-06-14 00:00:00 , DOI: 10.1021/acs.chemrestox.7b00112
Maria Flynn ₁ , Kali Amelia Heale ₁ , Laleh Alisaraie _{1,

2}

Affiliation

他莫昔芬是一种雌激素调节剂，可竞争性抑制内源性雌激素的结合。广泛用于治疗乳腺癌；然而，与许多抗肿瘤药类似，他莫昔芬也有许多不良反应，最突出的是恶心。我们已经确定了他莫昔芬的几种脱靶受体及其 22 种代谢物，包括组胺 H1 和 H3、毒蕈碱 M1、M4 和 M5 亚型，以及多巴胺 D2 受体。我们已经通过对其相互作用模式的全面计算分析展示了它们如何与他莫昔芬及其代谢物的毒性相关，并将其与每个受体的相关内源性底物进行比较。使用现有的体内和体外数据进一步评估结果数据。所呈现的工作为确定恶心诱导的精确机制，特别是他莫昔芬及其代谢物与参与该生物分子途径的受体的相互作用提供了基础知识。这项研究可以帮助预测具有常见药效团或与他莫昔芬及其代谢物相似的片段的化学物质的潜在不良影响，并为药物发现研究提供服务，以开发更有效和可耐受的他莫昔芬类似物或化疗药物。

"点击查看英文标题和摘要"

Mechanism of Off-Target Interactions and Toxicity of Tamoxifen and Its Metabolites

Tamoxifen is an estrogen modulator that acts to competitively inhibit the binding of endogenous estrogens. It is widely used for treatment of breast cancer; however, analogous with many antineoplastic agents, tamoxifen is associated with numerous adverse effects, most prominently nausea. We have identified several off-target receptors of tamoxifen and 22 of its metabolites that include histamine H1 and H3, and muscarinic M1, M4, and M5 subtypes, and dopamine D2 receptor. We have shown how they are associated with tamoxifen and its metabolites’ toxicity through a comprehensive computational analysis of their interaction modes, which were also compared to that of the related endogenous substrates of each receptor. The results were further evaluated using available in vivo and in vitro data. The presented work provides foundational knowledge toward the determination of the precise mechanism of nausea induction, and in particular, interactions of tamoxifen and its metabolites with the receptors involved in that biomolecular pathway. This study can assist in predicting the potential undesired effects of the chemicals with common pharmacophores or similar fragments to that of tamoxifen and its metabolites and serve drug discovery research in developing more effective and tolerable tamoxifen analogues or chemotherapeutic agents.

更新日期：2017-06-14

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南