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首页> 外文期刊>Journal of mass spectrometry: JMS >Mass spectrometric studies on the in vitro generated metabolites of SIRT1 activating drugs for doping control purposes
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Mass spectrometric studies on the in vitro generated metabolites of SIRT1 activating drugs for doping control purposes

机译：用于兴奋剂控制目的的SIRT1活化药物的体外代谢产物的质谱研究

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摘要

The enzyme SIRT1 is a metabolic key regulator in mitochondrial biogenesis, fat and glucose metabolism. Its activation through pharmaceutical SIRT1 activators such as SRT2104 results in an increased deacetylation of substrates representing important targets for the treatment of metabolic diseases. Moreover, SRT1720 was found to enhance the physical performance of mice. As SIRT1 activators might therefore be relevant in a doping control context, metabolism studies of target substances need be conducted in order to develop a detection assay for SIRT1 activators in urine. In the present study, the in vitro metabolism of five SIRT1 activators was investigated using human liver microsomes. The mass spectrometric behavior of the resulting metabolites following positive electrospray ionization and collision-induced dissociation was elucidated by high-resolution/high-accuracy (tandem) mass spectrometry, and confirmation of the structure of a major metabolite of SRT1720 was accomplished by chemical synthesis. Subsequently, a screening procedure for urine samples was developed employing liquid-liquid-extraction and liquid chromatography/tandem mass spectrometry based on diagnostic ion transitions recorded in multiple reaction monitoring mode and the use of d_8-SRT1720 as deuterated internal standard. The method was validated with regard to specificity, sensitivity (limit of detection 0.5 ng/ml), recovery (88-99%) and imprecision (7-18%) aswell as ion suppression/enhancement effects (<10%), demonstrating its fitness-for-purpose for sports drug testing applications.
机译：SIRT1酶是线粒体生物发生，脂肪和葡萄糖代谢中的代谢关键调节剂。它通过药物SIRT1激活剂（例如SRT2104）的激活导致底物的脱乙酰化增加，这代表了治疗代谢性疾病的重要靶标。此外，发现SRT1720可以增强小鼠的身体机能。由于SIRT1激活剂可能因此在兴奋剂控制方面具有相关性，因此需要进行目标物质的代谢研究，以便开发尿液中SIRT1激活剂的检测方法。在本研究中，使用人肝微粒体研究了5种SIRT1激活剂的体外代谢。通过高分辨率/高精度（串联）质谱法阐明了正电喷雾电离和碰撞诱导的解离后所得代谢物的质谱行为，并通过化学合成确定了SRT1720主要代谢物的结构。随后，基于在多个反应监测模式下记录的诊断离子跃迁以及使用d_8-SRT1720作为氘代内标，使用液-液萃取和液相色谱/串联质谱开发了一种尿液样品的筛选程序。该方法在特异性，灵敏度（检出限0.5 ng / ml），回收率（88-99％）和不精密度（7-18％）以及离子抑制/增强效果（<10％）方面得到验证，证明了该方法的有效性。适用于运动药物测试应用。

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