Wuhan Center of Magnetic Resonance, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences , Wuhan 430071, P. R. China.
J Proteome Res. 2012 Sep 7;11(9):4712-21. doi: 10.1021/pr300533a. Epub 2012 Aug 15.
Mequindox is used as an antibiotic drug in livestock; however, its toxicity remains largely unclear. Previously, we investigated metabolic responses of mice to mequindox exposure. In order to evaluate dependences of animal species in response to mequindox insult, we present the metabolic consequences of mequindox exposure in a rat model, by employing the combination of metabonomics and transcriptomics. Metabolic profiling of urine revealed that metabolic recovery is achieved for rats exposed to a low or moderate dose of mequindox, whereas high levels of mequindox exposure trigger liver dysfunction, causing no such recovery. We found that mequindox exposure causes suppression of the tricarboxylic acid cycle and stimulation of glycolysis, which is in contrast to a mouse model previously investigated. In addition, mequindox dosage induces promotion of β-oxidation of fatty acids, which was confirmed by elevated expressions of acox1, hsd17b2, and cpt1a in liver. Furthermore, altered levels of N-methylnicotinate, 1-methylnicotinamide, and glutathione disulfide highlighted the promotion of vitamin B3 antioxidative cycle in rats exposed to mequindox. Moreover, mequindox exposure altered levels of gut microbiotal related co-metabolites, suggesting a perturbation of the gut microflora of the host. Our work provides a comprehensive view of the toxicological effects of mequindox, which is important in the usage of mequindox in animal and human food safety.
美喹多司被用作牲畜中的抗生素药物；然而，其毒性在很大程度上仍不清楚。此前，我们研究了小鼠对美喹多司暴露的代谢反应。为了评估动物物种对美喹多司刺激的反应依赖性，我们通过代谢组学和转录组学的组合，在大鼠模型中评估了美喹多司暴露的代谢后果。尿液代谢谱分析表明，暴露于低剂量或中剂量美喹多司的大鼠可实现代谢恢复，而高剂量美喹多司暴露则会引发肝功能障碍，无法实现这种恢复。我们发现，美喹多司暴露会抑制三羧酸循环并刺激糖酵解，这与之前研究的小鼠模型相反。此外，美喹多司剂量会诱导脂肪酸的β-氧化，这可以通过肝脏中 acox1、hsd17b2 和 cpt1a 的高表达得到证实。此外，N-甲基烟酰胺、1-甲基烟酰胺和谷胱甘肽二硫化物水平的改变突出了美喹多司暴露促进了维生素 B3 抗氧化循环。此外，美喹多司暴露改变了肠道微生物群相关共代谢物的水平，表明宿主肠道微生物群受到了干扰。我们的工作提供了美喹多司毒理学效应的全面视图，这对于美喹多司在动物和人类食品安全中的使用非常重要。
