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Open AccessArticle

Mechanism Investigation of Rifampicin-Induced Liver Injury Using Comparative Toxicoproteomics in Mice

BK21 PLUS Team for Creative Leader Program for Pharmacomics-Based Future Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Korea
BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea
Toxicological Research Center, Hoseo University, Asan 31499, Korea
College of Pharmacy, Chosun University, Gwangju 61452, Korea
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2017, 18(7), 1417;
Received: 22 March 2017 / Revised: 12 June 2017 / Accepted: 26 June 2017 / Published: 2 July 2017
(This article belongs to the Special Issue Molecular Research on Drug Induced Liver Injury)
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. View Full-Text
Keywords: rifampicin; drug-induced liver injury; anti-tuberculosis; proteomics rifampicin; drug-induced liver injury; anti-tuberculosis; proteomics
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Kim, J.-H.; Nam, W.S.; Kim, S.J.; Kwon, O.K.; Seung, E.J.; Jo, J.J.; Shresha, R.; Lee, T.H.; Jeon, T.W.; Ki, S.H.; Lee, H.S.; Lee, S. Mechanism Investigation of Rifampicin-Induced Liver Injury Using Comparative Toxicoproteomics in Mice. Int. J. Mol. Sci. 2017, 18, 1417.

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