Mechanism Investigation of Rifampicin-Induced Liver Injury Using Comparative Toxicoproteomics in Mice.
Mechanism Investigation of Rifampicin-Induced Liver Injury Using Comparative Toxicoproteomics in Mice.
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DOI：
10.3390/ijms18071417
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发表时间：
2017-07-02
影响因子：
5.6
通讯作者：
Lee S
中科院分区：
文献类型：
--
作者：
Kim JH;Nam WS;Kim SJ;Kwon OK;Seung EJ;Jo JJ;Shresha R;Lee TH;Jeon TW;Ki SH;Lee HS;Lee S
结核病是可治愈的传染病中最主要的死亡原因之一;它是一种空气传播的传染病，2010年在全世界造成110万人死亡。抗结核药物性肝损伤是药物性肝损伤（DILI）的主要原因。利福平是最常见的抗结核疗法之一，具有众所周知的肝毒性。为了了解利福平诱导的肝损伤的机制，我们在小鼠模型中经口给予177和442.5 mg/kg利福平（LD 10和LD 25）14天后，通过LC-MS/MS对肝脏蛋白进行了整体蛋白质组学分析。根据利福平处理后血浆中的生化参数，将利福平在小鼠肝脏中的肝毒性作用定义为混合性肝损伤。在本研究中，我们鉴定了1101种蛋白质，并定量了1038种蛋白质。分别在177和442.5 mg/kg利福平组中，共有29和40种蛋白质上调，27和118种蛋白质下调。此外，我们进行了基因本体论（GO）和京都基因和基因组百科全书（KEGG）途径富集分析，以表征利福平诱导的肝毒性机制。在分子功能类别中，谷胱甘肽转移酶活性上调，花生四烯酸代谢相关蛋白下调。在基于KEGG途径富集的聚类分析中，在利福平处理的肝脏中，过氧化物酶体增殖物激活受体-γ（PPARγ）信号通路、细胞色素P450、谷胱甘肽代谢、化学致癌作用和相关蛋白呈剂量依赖性增加。本研究通过比较毒理蛋白质组学方法，深入探讨了利福平致肝损伤的分子机制。
Tuberculosis is one of the top causes of death among curable infectious diseases; it is an airborne infectious disease that killed 1.1 million people worldwide in 2010. Anti-tuberculosis drug-induced liver injury is the primary cause of drug-induced liver injury (DILI). Rifampicin is one of the most common anti-tuberculosis therapies and has well-known hepatotoxicity. To understand the mechanism of rifampicin-induced liver injury, we performed a global proteomic analysis of liver proteins by LC-MS/MS in a mouse model after the oral administration of 177 and 442.5 mg/kg rifampicin (LD10 and LD25) for 14 days. Based on the biochemical parameters in the plasma after rifampicin treatment, the hepatotoxic effect of rifampicin in the mouse liver was defined as a mixed liver injury. In the present study, we identified 1101 proteins and quantified 1038 proteins. A total of 29 and 40 proteins were up-regulated and 27 and 118 proteins were down-regulated in response to 177 and 442.5 mg/kg rifampicin, respectively. Furthermore, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to characterize the mechanism of rifampicin-induced hepatotoxicity. In the molecular function category, glutathione transferase activity was up-regulated and proteins related to arachidonic acid metabolism were down-regulated. In the KEGG pathway enrichment-based clustering analysis, the peroxisome proliferator-activated receptor-γ (PPARγ) signaling pathway, cytochrome P450, glutathione metabolism, chemical carcinogenesis, and related proteins increased dose-dependently in rifampicin-treated livers. Taken together, this study showed in-depth molecular mechanism of rifampicin-induced liver injury by comparative toxicoproteomics approach.
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影响因子：
7.7
作者：
Dalen, KT;Schoonjans, K;Nebbl, HI
通讯作者：
Nebbl, HI
影响因子：
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作者：
Holt, Michael;Ju, Cynthia
通讯作者：
Ju, Cynthia
影响因子：
14.5
作者：
Brewer, C. Trent;Chen, Taosheng
通讯作者：
Chen, Taosheng
DOI：
10.1111/j.1440-1746.2012.07279.x
发表时间：
2013-01-01
影响因子：
4.1
作者：
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通讯作者：
Balaraju, Girisha
影响因子：
3.2
作者：
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通讯作者：
Gomez-Lechon, M. J.