Morello Judit, Derks Rico J E, Lopes Susana S, Steenvoorden Evelyne, Monteiro Emilia C, Mayboroda Oleg A, Pereira Sofia A
CEDOC, Chronic Diseases Research Centre, NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal.
Center for Proteomics and Metabolomics, Leiden University Medical Centre, Leiden, Netherlands.
Front Pharmacol. 2018 Oct 16;9:1193. doi: 10.3389/fphar.2018.01193. eCollection 2018.
Prevention and treatment of drug-induced renal injury (DIRI) rely on the availability of sensitive and specific biomarkers of early kidney injury and predictive animal models of human pathophysiology. This study aimed to evaluate the potential of zebrafish larvae as translational model in metabolic profiling of DIRI. Zebrafish larvae were exposed to the lethal concentration for 10% of the larvae (LC10) or ½ LC10 of gentamicin, paracetamol and tenofovir as tenofovir disoproxil fumarate (TDF) and tenofovir (TFV). Metabolites were extracted from whole larvae and analyzed by liquid chromatography-mass spectrometry. Principal component analysis showed that drug exposition to the LC10 of paracetamol, TFV, and TDF was the main source of the variance of the data. To identify the metabolites responsible for the toxic effects of the drugs, partial least squares discriminant analyses were built between the LC10 and ½ LC10 for each drug. Features with variable importance in projection> 1.0 were selected and Venn diagrams were built to differentiate between the common and drug specific metabolites of DIRI. Creatine, tyrosine, glutamine, guanosine, hypoxanthine were identified as common metabolites, adenosine and tryptophan as paracetamol-specific and xanthine and oxidized glutathione as tenofovir-specific. Those metabolic changes can be associated with alterations in energy metabolism, xenobiotic detoxification and protein catabolism, all described in the human pathophysiology of DIRI. Thus, zebrafish proved to be a suitable model to characterize the metabolic changes associated with DIRI. This information can be useful to early diagnose DIRI and to improve our knowledge on the mechanisms of DIRI.
药物性肾损伤（DIRI）的预防和治疗依赖于早期肾损伤敏感且特异的生物标志物以及人类病理生理学的预测性动物模型。本研究旨在评估斑马鱼幼体作为DIRI代谢谱分析转化模型的潜力。将斑马鱼幼体暴露于庆大霉素、对乙酰氨基酚和替诺福韦（以富马酸替诺福韦二吡呋酯（TDF）和替诺福韦（TFV）形式）的10%致死浓度（LC10）或1/2 LC10。从整个幼体中提取代谢物，并通过液相色谱 - 质谱法进行分析。主成分分析表明，对乙酰氨基酚、TFV和TDF的LC10药物暴露是数据变异的主要来源。为了确定导致药物毒性作用的代谢物，针对每种药物在LC10和1/2 LC10之间进行了偏最小二乘判别分析。选择投影中变量重要性>1.0的特征，并构建维恩图以区分DIRI的常见代谢物和药物特异性代谢物。肌酸、酪氨酸、谷氨酰胺、鸟苷、次黄嘌呤被确定为常见代谢物，腺苷和色氨酸为对乙酰氨基酚特异性代谢物，黄嘌呤和氧化型谷胱甘肽为替诺福韦特异性代谢物。这些代谢变化可能与能量代谢、外源性物质解毒和蛋白质分解代谢的改变有关，这些在DIRI的人类病理生理学中均有描述。因此，斑马鱼被证明是表征与DIRI相关代谢变化的合适模型。这些信息对于早期诊断DIRI以及增进我们对DIRI机制的了解可能有用。
