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Journal of metabolomics最新文献

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Bioactive lipid profiling reveals drug target engagement of a soluble epoxide hydrolase inhibitor in a murine model of tobacco smoke exposure. 生物活性脂质分析揭示了烟草烟雾暴露小鼠模型中可溶性环氧化物水解酶抑制剂的药物靶标参与。
Pub Date : 2015-04-01 Epub Date: 2015-04-04 DOI: 10.7243/2059-0008-1-1
Malin L Nording, Jun Yang, Laura Hoang, Vanessa Zamora, Dale Uyeminami, Imelda Espiritu, Kent E Pinkerton, Bruce D Hammock, Ayala Luria

The inflammatory process underlying chronic obstructive pulmonary disease (COPD) may be caused by tobacco smoke (TS) exposure. Previous studies show that epoxyeicosatrienoic acids (EETs) possess promising anti-inflammatory properties, therefore stabilization of EETs and other fatty acid epoxides through inhibition of soluble epoxide hydrolase (sEH) was investigated in mouse models of acute and sub-chronic inflammation caused by TS exposure. During the entire TS exposure, the potent sEH inhibitor 1-(1-methylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS) was given via drinking water. To assess drug target engagement of TUPS, a tandem mass spectrometry method was used for bioactive lipid profiling of a broad range of fatty acid metabolites, including EETs, and their corresponding diols (DHETs) derived from arachidonic acid, as well as epoxides and diols derived from other fatty acids. Several, but not all, plasma epoxide/diol ratios increased in mice treated with sEH inhibitor, compared to non-treated mice suggesting a wider role for sEH involving more fatty acid precursors besides arachidonic acid. This study supports qualitative use of epoxide/diol ratios explored by bioactive lipid profiling to indicate drug target engagement in mouse models of TS exposure relevant to COPD, which may have ramifications for future therapeutic interventions of sEH.

慢性阻塞性肺疾病(COPD)的炎症过程可能是由烟草烟雾(TS)暴露引起的。先前的研究表明,环氧二碳三烯酸(EETs)具有良好的抗炎特性,因此在TS暴露引起的急性和亚慢性炎症小鼠模型中,研究了EETs和其他脂肪酸环氧化物通过抑制可溶性环氧化物水解酶(sEH)来实现稳定。在整个TS暴露过程中,通过饮用水给予强效sEH抑制剂1-(1-甲基磺酰基-哌啶-4-酰基)-3-(4-三氟甲氧基-苯基)-尿素。为了评估up的药物靶标作用,采用串联质谱法对广泛的脂肪酸代谢产物进行生物活性脂质分析,包括花生四烯酸衍生的eet及其相应的二醇(DHETs),以及其他脂肪酸衍生的环氧化物和二醇。与未接受sEH抑制剂治疗的小鼠相比,接受sEH抑制剂治疗的小鼠血浆环氧化物/二醇比增加了几种,但不是全部,这表明sEH的作用更广泛,除了花生四烯酸外,还涉及更多的脂肪酸前体。该研究支持通过生物活性脂质谱研究的环氧化物/二醇比例的定性使用,以表明与COPD相关的TS暴露小鼠模型中的药物靶标参与,这可能对未来的sEH治疗干预产生影响。
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引用次数: 4
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Journal of metabolomics
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