Stable isotope- and mass spectrometry-based metabolomics as tools in drug metabolism: a study expanding tempol pharmacology.
Stable isotope- and mass spectrometry-based metabolomics as tools in drug metabolism: a study expanding tempol pharmacology.
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DOI：
10.1021/pr301023x
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发表时间：
2013-03-01
影响因子：
4.4
通讯作者：
Patterson AD
中科院分区：
文献类型：
--
作者：
Li F;Pang X;Krausz KW;Jiang C;Chen C;Cook JA;Krishna MC;Mitchell JB;Gonzalez FJ;Patterson AD
基于质谱的代谢组学在药物代谢领域的应用不仅对药物的代谢途径产生了重要的见解，而且为内源性代谢组学提供了公正的、全局的视角，可用于识别与作用机制、功效和毒性相关的生物标志物。在本报告中，描述了一种基于稳定同位素和质谱的代谢组学方法，该方法可以在单个实验中捕获药物代谢和内源性代谢组的变化。本文选择抗氧化药物tempol（4-羟基-2,2,6,6-四甲基哌啶- n -氧基），因为其作用机制尚未完全了解，其代谢命运尚未得到广泛研究。此外，其体积小（MW = 172.2）和化学成分（C9H18NO2）使其难以与内源性代谢物区分。在这项研究中，给小鼠注射了丹酚或氘化丹酚（C9D17HNO2），并使用超高效液相色谱-四极杆飞行时间质谱法对其尿液进行了分析。尿液代谢组学数据的主成分分析生成了一个y形散点图，其中包含药物代谢物（质子化和氘化），与内源性代谢物明显不同。共鉴定出10个坦普尔药物代谢物，其中8个为新代谢物。II期代谢是tempol在体内的主要代谢途径，包括葡萄糖醛酸化和葡萄糖苷化。坦宝处理显著升高的尿内源性代谢物包括2,8-二羟基喹啉（8.0倍，P<0.05）和2,8-二羟基喹啉-β- d -葡萄糖醛酸盐（6.8倍，P<0.05）。tempol处理显著降低了尿内源性代谢物，其中泛酸（1.3倍，P<0.05）和异丁基肉碱（5.3倍，P<0.01）。这项研究强调了基于稳定同位素和质谱的代谢组学在扩展药物药理学观点方面的力量。
The application of mass spectrometry-based metabolomics in the field of drug metabolism has yielded important insights not only into the metabolic routes of drugs but has provided unbiased, global perspectives of the endogenous metabolome that can be useful for identifying biomarkers associated with mechanism of action, efficacy, and toxicity. In this report, a stable isotope- and mass spectrometry-based metabolomics approach that captures both drug metabolism and changes in the endogenous metabolome in a single experiment is described. Here the antioxidant drug tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) was chosen because its mechanism of action is not completely understood and its metabolic fate has not been studied extensively. Furthermore, its small size (MW = 172.2) and chemical composition (C9H18NO2) makes it challenging to distinguish from endogenous metabolites. In this study, mice were dosed with tempol or deuterated tempol (C9D17HNO2) and their urine profiled using ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Principal component analysis of the urinary metabolomics data generated a Y-shaped scatter plot containing drug metabolites (protonated and deuterated) that were clearly distinct from the endogenous metabolites. Ten tempol drug metabolites, including eight novel metabolites, were identified. Phase II metabolism was the major metabolic pathway of tempol in vivo, including glucuronidation and glucosidation. Urinary endogenous metabolites significantly elevated by tempol treatment included 2,8-dihydroxyquinoline (8.0-fold, P<0.05) and 2,8-dihydroxyquinoline-β-D-glucuronide (6.8-fold, P<0.05). Urinary endogenous metabolites significantly attenuated by tempol treatment including pantothenic acid (1.3-fold, P<0.05) and isobutrylcarnitine (5.3-fold, P<0.01). This study underscores the power of a stable isotope- and mass spectrometry-based metabolomics in expanding the view of drug pharmacology.
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影响因子：
4.4
作者：
Patterson, Andrew D.;Slanar, Ondrej;Krausz, Kristopher W.;Li, Fei;Hoefer, Constance C.;Perlik, Frantisek;Gonzalez, Frank J.;Idle, Jeffrey R.
通讯作者：
Idle, Jeffrey R.
影响因子：
4.1
作者：
Chen, Chi;Krausz, Kristopher W.;Shah, Yatrik M.;Idle, Jeffrey R.;Gonzalez, Frank J.
通讯作者：
Gonzalez, Frank J.
影响因子：
6.9
作者：
Ebenezer, Philip J.;Mariappan, Nithya;Elks, Carrie M.;Haque, Masudul;Francis, Joseph
通讯作者：
Francis, Joseph
影响因子：
3.4
作者：
Hyland, Ruth;Osborne, Toby;Jones, Barry
通讯作者：
Jones, Barry
影响因子：
15.9
作者：
Samudio, Ismael;Harmancey, Romain;Andreeff, Michael
通讯作者：
Andreeff, Michael