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

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.

• Authors: Ju-Hyun Kim, Woong Shik Nam, Sun Joo Kim, Oh Kwang Kwon, Eun Ji Seung, Jung Jae Jo, Riya Shresha, Tae Hee Lee, Tae Won Jeon, Sung Hwan Ki, Hye Suk Lee, Sangkyu Lee
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 18 Issue 7 (Jul 02 2017) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 28671602 (Publication Type: Journal Article)

Chemical References

• Antibiotics, Antitubercular
• Biomarkers
• Proteome
• Rifampin

Topics

• Animals
• Antibiotics, Antitubercular (adverse effects)
• Biomarkers
• Biopsy
• Chemical and Drug Induced Liver Injury (genetics, metabolism, pathology)
• Computational Biology (methods)
• Disease Models, Animal
• Gene Ontology
• Lethal Dose 50
• Liver (drug effects, metabolism, pathology)
• Male
• Mice
• Proteome
• Proteomics (methods)
• Rifampin (adverse effects)