School of Forensic Medicine, China Medical University, No. 77, Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, People's Republic of China.
School of Fundamental Sciences, China Medical University, Shenyang, 110014, People's Republic of China.
Sci Rep. 2021 Jan 14;11(1):1454. doi: 10.1038/s41598-021-81109-7.
Tramadol is an opioid used as an analgesic for treating moderate or severe pain. The long-term use of tramadol can induce several adverse effects. The toxicological mechanism of tramadol abuse is unclear. Limited literature available indicates the change of proteomic profile after chronic exposure to tramadol. In this study, we analyzed the proteomic and metabolomic profile by TMT-labeled quantitative proteomics and untargeted metabolomics between the tramadol and the control group. Proteomic analysis revealed 31 differential expressed serum proteins (9 increased and 22 decreased) in tramadol-treated mice (oral, 50 mg/kg, 5 weeks) as compared with the control ones. Bioinformatics analysis showed that the dysregulated proteins mainly included: enzyme inhibitor-associated proteins (i.e. apolipoprotein C-III (Apoc-III), alpha-1-antitrypsin 1-2 (Serpina 1b), apolipoprotein C-II (Apoc-II), plasma protease C1 inhibitor, inter-alpha-trypsin inhibitor heavy chain H3 (itih3)); mitochondria-related proteins (i.e. 14-3-3 protein zeta/delta (YWHAZ)); cytoskeleton proteins (i.e. tubulin alpha-4A chain (TUBA4A), vinculin (Vcl)). And we found that the differential expressed proteins mainly involved in the pathway of the protein digestion and absorption. Metabolomics analysis revealed that differential expressed metabolites mainly involved in protein ingestion and absorption, fatty acid biosynthesis, steroid hormone biosynthesis and bile secretion. Our overall findings revealed that chronic exposure to tramadol changed the proteomic and metabolomic profile of mice. Moreover, integrated proteomic and metabolomic revealed that the protein digestion and absorption is the common enrichment KEGG pathway. Thus, the combination of proteomics and metabolomics opens new avenues for the research of the molecular mechanisms of tramadol toxicity.
曲马多是一种阿片类药物，用作治疗中度或重度疼痛的镇痛药。长期使用曲马多会引起几种不良反应。曲马多滥用的毒理学机制尚不清楚。有限的可用文献表明，慢性暴露于曲马多后蛋白质组谱会发生变化。在这项研究中，我们通过 TMT 标记定量蛋白质组学和非靶向代谢组学分析了曲马多组和对照组之间的蛋白质组和代谢组学图谱。蛋白质组学分析显示，与对照组相比，经口给予 50mg/kg 曲马多（5 周）的小鼠血清中存在 31 种差异表达的血清蛋白（9 种上调和 22 种下调）。生物信息学分析表明，失调蛋白主要包括：酶抑制剂相关蛋白（如载脂蛋白 C-III（Apoc-III）、α-1-抗胰蛋白酶 1-2（Serpina 1b）、载脂蛋白 C-II（Apoc-II）、血浆蛋白酶 C1 抑制剂、α-胰蛋白酶抑制剂重链 H3（itih3））；与线粒体相关的蛋白（如 14-3-3 蛋白 ζ/δ（YWHAZ））；细胞骨架蛋白（如微管蛋白 α-4A 链（TUBA4A）、连接蛋白（Vcl））。并且我们发现差异表达蛋白主要参与蛋白质消化吸收途径。代谢组学分析显示，差异表达代谢物主要涉及蛋白质摄取和吸收、脂肪酸生物合成、类固醇激素生物合成和胆汁分泌。我们的综合研究结果表明，慢性暴露于曲马多会改变小鼠的蛋白质组学和代谢组学图谱。此外，蛋白质组学和代谢组学的综合分析表明，蛋白质消化吸收是常见的富集 KEGG 途径。因此，蛋白质组学和代谢组学的结合为曲马多毒性的分子机制研究开辟了新途径。
