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Int. J. Mol. Sci. 2017, 18(7), 1417; doi:10.3390/ijms18071417

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

1
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
2
BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea
3
Toxicological Research Center, Hoseo University, Asan 31499, Korea
4
College of Pharmacy, Chosun University, Gwangju 61452, Korea
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
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)
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Abstract

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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MDPI and ACS Style

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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