Quadrupole linear ion-trap mass spectrometry studies on glutathione conjugates of nordihydroguaiaretic acid (NDGA) analogues reveals phenol-type analogues are without reactive metabolite-mediated toxic liability
Quadrupole linear ion-trap mass spectrometry studies on glutathione conjugates of nordihydroguaiaretic acid (NDGA) analogues reveals phenol-type analogues are without reactive metabolite-mediated toxic liability
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对去甲二氢愈创木酸 (NDGA) 类似物的谷胱甘肽缀合物的四极线性离子阱质谱研究表明，酚型类似物不存在反应性代谢物介导的毒性倾向
DOI：
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
E. Krol
中科院分区：
文献类型：
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作者：
I. Asiamah;E. Krol
摘要 反应性代谢物（RM）与许多药物引起的毒性有关，包括肝毒性。去甲二氢愈创木酸 (NDGA) 具有已知的药理学特性，但其使用也可能与 RM 介导的毒性有关。为了通过合理的结构修饰设计和制备具有更好安全性的NDGA类似物，我们首先评估了模拟儿茶酚型和苯酚型NDGA类似物的模型化合物的代谢活化潜力。我们在谷胱甘肽作为亲核捕获剂存在的情况下在大鼠肝微粒体（RLM）中孵育测试化合物。我们还研究了它们使用氧化银形成对醌甲基化物的潜力。通过电喷雾电离质谱 (ESI-MS) 在正离子模式下扫描中性丢失 (NL) 129 或 307 或在负离子模式下前体离子 (PI) 扫描 272 来检测谷胱甘肽缀合物，并通过液相色谱-串联质谱 (LC-MS/MS) 或在单次 LC-MS 运行中使用多反应监测 (MRM) 作为调查扫描来触发增强产物离子 (EPI) 数据的采集来进一步表征。我们的发现促使我们随后设计并合成了一系列 NDGA 类似物，用于评估其代谢激活潜力，以消除 RM 的责任。其中，我们发现儿茶酚型类似物被细胞色素 P450 转化为邻醌。我们没有看到细胞色素 P450 对苯酚型类似物产生 RM 的证据。这表明酚型 NDGA 类似物可能与反应性代谢物介导的毒性无关。尽管更广泛的药理学评估正在进行中，但我们的初步结果显示药理学特性并未受到损害。
Abstract Reactive metabolites (RMs) have been implicated in many drug-induced toxicities including hepatotoxicity. Nordihydroguaiaretic acid (NDGA) has known pharmacological properties but its use is also associated with toxicities possibly mediated by RMs. In our effort to design and prepare NDGA analogues with better safety profile through rational structural modification, we first evaluated metabolic activation potential of model compounds mimicking catechol- and phenol-type NDGA analogues. We incubated test compounds in rat liver microsomes (RLM) in the presence of glutathione as nucleophilic trapping agent. We also investigated their potential to form para-quinone methides using silver oxide. Glutathione conjugates were detected by electrospray ionization-mass spectrometry (ESI-MS) scanning for neutral loss (NL) 129 or 307 in positive ion mode or precursor ion (PI) scanning for 272 in negative ion mode and further characterized by liquid chromatography–tandem mass spectrometry (LC–MS/MS) or in a single LC-MS run using multiple reactions monitoring (MRM) as a survey scan to trigger acquisition of enhanced product ion (EPI) data. Our findings led us to subsequently design and synthesize a series of NDGA analogues for evaluating their metabolic activation potential with a goal of eliminating RMs liability. Among others, we found that catechol-type analogues were converted to ortho-quinones by cytochrome P450s. We saw no evidence of RMs by cytochrome P450s for phenol-type analogues. This suggest that phenol-type NDGA analogues might not be associated with reactive metabolites-mediated toxicities. Although a more extensive pharmacological evaluation is underway, our preliminary results revealed that pharmacological properties were not compromised.
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影响因子：
4.1
作者：
Bolton, JL;Wu, HM;Hu, LQ
通讯作者：
Hu, LQ
影响因子：
4.1
作者：
IVERSON, SL;HU, LQ;BOLTON, JL
通讯作者：
BOLTON, JL
影响因子：
4.7
作者：
Cavalieri, EL;Li, KM;Rogan, EG
通讯作者：
Rogan, EG
影响因子：
3.4
作者：
Baillie,TA;Pearson,PG;Rashed,MS;Howald,WN
通讯作者：
Howald,WN