First-line anti-tuberculosis drugs induce hepatotoxicity: A novel mechanism based on a urinary metabolomics platform
First-line anti-tuberculosis drugs induce hepatotoxicity: A novel mechanism based on a urinary metabolomics platform
复制标题
一线抗结核药物诱导肝毒性：基于尿液代谢组学平台的新机制。
DOI：
10.1016/j.bbrc.2018.02.030
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发表时间：
2018-03-04
影响因子：
3.1
通讯作者：
Miao, Liyan
中科院分区：
文献类型：
--
作者：
Cao, Jun;Mi, Yijun;Miao, Liyan
结核病已成为全球公共卫生和社会威胁。利福平、异烟肼作为临床一线用药，与吡嗪酰胺、乙胺丁醇联合使用（HRZE方案）常引起肝毒性。然而，这种现象背后的机制仍不清楚，研究HRZE方案联合治疗TB患者的代谢影响可以提供新的肝毒性证据。在这项研究中，使用高分辨率超高效液相色谱-质谱（UPLC-MS）平台分析了结核病患者的尿液代谢物。抗结核药物影响三羧酸循环、精氨酸和脯氨酸代谢以及嘌呤代谢途径。HRZE给药后，焦谷氨酸、异柠檬酸、柠檬酸和黄嘌呤的水平显著降低。药物性肝损伤（DILI）患者与非DILI患者的上述通路也不同。与非DILI组相比，DILI组的尿酸和顺式-4-辛烯二酸水平显著升高，而顺式乌头酸和次黄嘌呤水平显著降低。这些结果强调了超氧化物的产生可以加重HRZE方案的肝毒性作用。此外，我们的代谢组学方法能够预测临床应用的肝毒性。(C)2018爱思唯尔公司All rights reserved.
Tuberculosis (TB) has become a global public health and social threat. As clinical first-line drugs, rifampicin and isoniazid used in combination with pyrazinamide and ethambutol (the HRZE regimen) usually induce hepatotoxicity. However, the mechanisms underlying this phenomenon remain unclear, and studying the metabolic impact of co-treating TB patients with the HRZE regimen can provide new hepatotoxicity evidence. In this study, urine metabolites from TB patients were profiled using a high resolution ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) platform. The tricarboxylic acid circulation, arginine and proline metabolism and purine metabolic pathways were found to be affected by anti-TB drugs. The levels of pyroglutamate, isocitrate, citrate, and xanthine were significantly decreased after the administration of HRZE. The above mentioned pathways were also different between drug-induced liver injury (DILI) and non-DILI patients. Urate and cis-4-octenedioic acid levels in the DILI group were significantly increased compared to those in the non-DILI group, while the cis-aconitate and hypoxanthine levels were significantly decreased. These results highlight that superoxide generation can aggravate the hepatotoxic effects of the HRZE regimen. In addition, our metabolomic approach had the ability to predict hepatotoxicity for clinical applications. (C) 2018 Elsevier Inc. All rights reserved.