Department of Forensic Pharmacology & Toxicology, Zurich Institute of Forensic Medicine , University of Zurich , 8057 Zurich , Switzerland.
Psychopharmacology Research, Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, Department of Clinical Research , University Hospital Basel, University of Basel , 4031 Basel , Switzerland.
J Proteome Res. 2018 Aug 3;17(8):2900-2907. doi: 10.1021/acs.jproteome.8b00438. Epub 2018 Jul 13.
The intake of 3,4-methylenedioxymethamphetamine (MDMA) is known to increase several endogenous substances involved in steroid and inflammation pathways. Untargeted metabolomics screening approaches can determine biochemical changes after drug exposure and can reveal new pathways, which might be involved in the pharmacology and toxicology of a drug of abuse. We analyzed plasma samples from a placebo-controlled crossover study of a single intake of MDMA. Plasma samples from a time point before and three time points after the intake of a single dose of 125 mg MDMA were screened for changes of endogenous metabolites. An untargeted metabolomics approach on a high-resolution quadrupole time-of-flight mass spectrometer coupled to liquid chromatography with two different chromatographic systems (reversed-phase and hydrophobic interaction liquid chromatography) was applied. Over 10 000 features of the human metabolome were detected. Hence, 28 metabolites were identified, which showed significant changes after administration of MDMA compared with placebo. The analysis revealed an upregulation of cortisol and pregnenolone sulfate 4 h after MDMA intake, suggesting increased stress and serotonergic activity. Furthermore, calcitriol levels were decreased after the intake of MDMA. Calcitriol is involved in the upregulation of trophic factors, which have protective effects on brain dopamine neurons. The inflammation mediators hydroxyeicosatetraenoic acid, dihydroxyeicosatetraenoic acid, and octadecadienoic acid were found to be upregulated after the intake of MDMA compared with placebo, which suggested a stimulation of inflammation pathways.
3,4-亚甲二氧基甲基苯丙胺（MDMA）的摄入已知会增加几种参与类固醇和炎症途径的内源性物质。非靶向代谢组学筛选方法可以确定药物暴露后的生化变化，并揭示新的途径，这些途径可能与滥用药物的药理学和毒理学有关。我们分析了一项单次摄入 MDMA 的安慰剂对照交叉研究的血浆样本。在单次摄入 125mg MDMA 之前和之后的三个时间点，对血浆样本进行了筛选，以寻找内源性代谢物的变化。我们应用了一种基于高分辨率四极杆飞行时间质谱仪与两种不同色谱系统（反相和疏水相互作用液相色谱）相结合的非靶向代谢组学方法。检测到了超过 10000 个人类代谢物的特征。因此，确定了 28 种代谢物，与安慰剂相比，这些代谢物在 MDMA 给药后发生了显著变化。分析表明，在 MDMA 摄入后 4 小时皮质醇和孕烯醇酮硫酸盐的水平升高，提示应激和 5-羟色胺能活性增加。此外，在摄入 MDMA 后，1,25-二羟维生素 D3 的水平降低。1,25-二羟维生素 D3 参与上调营养因子，这些营养因子对大脑多巴胺神经元具有保护作用。与安慰剂相比，炎症介质羟二十碳四烯酸、二羟二十碳四烯酸和十八碳二烯酸在 MDMA 摄入后被发现上调，这表明炎症途径被刺激。
