他克莫司(Tac)是一种常用的器官移植免疫抑制剂。然而,它的治疗指数狭窄,而且容易产生副作用,随着毒性风险的增加,即,心脏-,肾-,肝-,和神经毒性。先前涉及Tac驱动毒性的代谢组学研究主要集中在单个器官的变化。然而,对多个矩阵的广泛研究并不常见。因此,在这项研究中,作者系统地评估了Tac介导的主要器官毒性,即,血清,大脑,心,肝脏,肺,肾,和肠子,使用气相色谱-质谱(GC-MS)。作者还采用了多变量分析,包括对潜在结构的正交投影(OPLS)和t检验,筛选8种血清代谢物,即,D-脯氨酸,甘油,D-果糖,D-葡萄糖醇,亚硫酸,1-monopalmitin(MG(16:0/0:0/0:0)),甘油单硬脂酸酯(MG(0:0/18:0/0:0)),和胆固醇。大脑内的代谢变化涉及丁酰胺水平的改变,tartronicacid,氨基丙二酸,scyllo-肌醇,二氢吗啡,肌醇,和11-十八烯酸。在心里,丙酮和D-果糖代谢产物发生改变。在肝脏中,D-葡萄糖醇,L-山梨糖,棕榈酸,肌醇,和尿苷被改变。在肺部,L-乳酸,L-5-氧代脯氨酸,L-苏氨酸,磷酸,磷酸乙醇胺,D-Allose,胆固醇也改变了.最后,在肾脏,L-缬氨酸和D-葡萄糖改变。我们的发现将对Tac驱动的毒性小鼠模型中靶器官的代谢改变进行系统评估。
Tacrolimus (Tac) is a common immunosuppressant that used in organ transplantation. However, its therapeutic index is narrow, and it is prone to adverse side effects, along with an increased risk of toxicity, namely, cardio-, nephro-, hepato-, and neurotoxicity. Prior metabolomic investigations involving Tac-driven toxicity primarily focused on changes in individual organs. However, extensive research on multiple matrices is uncommon. Hence, in this research, the authors systemically evaluated Tac-mediated toxicity in major organs, namely, serum, brain, heart, liver, lung, kidney, and intestines, using gas chromatography-mass spectrometry (GC-MS). The authors also employed multivariate analyses, including orthogonal projections to the latent structure (OPLS) and t-test, to screen 8 serum metabolites, namely, D-proline, glycerol, D-fructose, D-glucitol, sulfurous acid, 1-monopalmitin (MG (16:0/0:0/0:0)), glycerol monostearate (MG (0:0/18:0/0:0)), and cholesterol. Metabolic changes within the brain involved alterations in the levels of butanamide, tartronic acid, aminomalonic acid, scyllo-inositol, dihydromorphine, myo-inositol, and 11-octadecenoic acid. Within the heart, the acetone and D-fructose metabolites were altered. In the liver, D-glucitol, L-sorbose, palmitic acid, myo-inositol, and uridine were altered. In the lung, L-lactic acid, L-5-oxoproline, L-threonine, phosphoric acid, phosphorylethanolamine, D-allose, and cholesterol were altered. Lastly, in the kidney, L-valine and D-glucose were altered. Our findings will provide a systematic evaluation of the metabolic alterations in target organs within a Tac-driven toxicity mouse model.