Dexamethasone-Induced Perturbations in Tissue Metabolomics Revealed by Chemical Isotope Labeling LC-MS Analysis
Dexamethasone-Induced Perturbations in Tissue Metabolomics Revealed by Chemical Isotope Labeling LC-MS Analysis
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DOI：
10.3390/metabo10020042
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发表时间：
2020-02-01
期刊：
影响因子：
4.1
通讯作者：
Rahman, Anas M. Abdel
中科院分区：
文献类型：
--
作者：
Dahabiyeh, Lina A.;Malkawi, Abeer K.;Rahman, Anas M. Abdel
地塞米松（Dex）是一种合成糖皮质激素（GC）药物，临床上常用于治疗多种炎症和免疫介导的疾病。尽管其适应症范围广泛，但已知长期使用Dex与几种组织和器官的特定异常相关。在本研究中，使用化学同位素标记液相色谱-质谱（CIL LC-MS）平台，以胺/酚亚代谢物组为目标，研究了Dex长期给药对Sprague-Dawley大鼠模型中5个不同器官的代谢物组学影响。与对照组相比，Dex的长期摄入分别导致脑、骨骼肌、肝、肾和心脏组织中492、442、300、186和105种代谢物水平的显著扰动。阳性鉴定的代谢物被映射到不同器官中的不同分子途径。在大脑中，蛋白质生物合成，氨基酸代谢和单胺神经递质合成的扰动被确定，而在心脏中，嘧啶代谢和支链氨基酸生物合成是最显着受损的途径。在肾脏中，几种氨基酸途径失调，这反映了几种生物学功能的损害，包括胚胎发育和尿素生成。β-丙氨酸代谢和尿苷稳态在肝组织中受到深刻的影响，而谷胱甘肽，精氨酸，谷氨酰胺和氮代谢的改变指向肌肉代谢的调节和骨骼肌中能量产生和肌肉质量的干扰。多种二肽的差异表达在肝脏（下调）、脑（上调）和肾组织中最显著，但在心脏或骨骼肌组织中不显著。临床相关途径的识别提供了对Dex诱导的组织分子反应的整体见解，并了解了与其副作用相关的潜在机制。我们的数据表明，谷胱甘肽补充剂和二肽调节剂作为新型治疗干预措施，以减轻Dex治疗引起的副作用的潜在作用。
Dexamethasone (Dex) is a synthetic glucocorticoid (GC) drug commonly used clinically for the treatment of several inflammatory and immune-mediated diseases. Despite its broad range of indications, the long-term use of Dex is known to be associated with specific abnormalities in several tissues and organs. In this study, the metabolomic effects on five different organs induced by the chronic administration of Dex in the Sprague-Dawley rat model were investigated using the chemical isotope labeling liquid chromatography-mass spectrometry (CIL LC-MS) platform, which targets the amine/phenol submetabolomes. Compared to controls, a prolonged intake of Dex resulted in significant perturbations in the levels of 492, 442, 300, 186, and 105 metabolites in the brain, skeletal muscle, liver, kidney, and heart tissues, respectively. The positively identified metabolites were mapped to diverse molecular pathways in different organs. In the brain, perturbations in protein biosynthesis, amino acid metabolism, and monoamine neurotransmitter synthesis were identified, while in the heart, pyrimidine metabolism and branched amino acid biosynthesis were the most significantly impaired pathways. In the kidney, several amino acid pathways were dysregulated, which reflected impairments in several biological functions, including gluconeogenesis and ureagenesis. Beta-alanine metabolism and uridine homeostasis were profoundly affected in liver tissues, whereas alterations of glutathione, arginine, glutamine, and nitrogen metabolism pointed to the modulation of muscle metabolism and disturbances in energy production and muscle mass in skeletal muscle. The differential expression of multiple dipeptides was most significant in the liver (down-regulated), brain (up-regulation), and kidney tissues, but not in the heart or skeletal muscle tissues. The identification of clinically relevant pathways provides holistic insights into the tissue molecular responses induced by Dex and understanding of the underlying mechanisms associated with their side effects. Our data suggest a potential role for glutathione supplementation and dipeptide modulators as novel therapeutic interventions to mitigate the side effects induced by Dex therapy.