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.

Hepatotoxic effect of Rifampicin as an Anti-Tuberculosis drug on male Albino rat

“…The leaching of the intracellular enzymes occurred due to oxidative stress induced LPO mediated membrane damage. Similar type findings were also reported by Rana et al 15 and Kim et al 9 A scheme of proposed mechanism of rifampicin induced liver injury has been given in Figure 4 which indicates that hepatotoxicity is directly associated to cytochorome P450 dependent drug metabolism. Rifampicin is an agonist of xeno sensing pregnane X receptor (PXR) which is a member of nuclear receptor superfamily of ligand dependent transcription factors.…”

“…8 It causes hepatocellular dysfunction followed by hepatic lesions, cellular changes, lobular necrosis and hyperbilirubinemia. 9 Sensi et al 10 had isolated rifamycin from the culture of Streptomyces mediterranei which is the derivative [3-(4methyl-1-piperazinyl)-iminomethyl] of rifamycin. Rifampicin is a complex semisynthetic macrocyclic antibiotic 11 with empirical formula C43H58N4O12 and molar mass 822.953 g/mol.…”

Phytochemical analysis and Evaluation of hepatoprotective effect of Maytenus royleanus leaves extract against anti-tuberculosis drug induced liver injury in mice

“…Our finding is in parallel with previous reports on the toxic effect of anti-TB drug induced liver toxicity. They observed extreme hepatocyte hypertrophy characterized by a notable increase in cell size accompanied by binucleate hepatocytes with enlarged hepatocyte nuclei [45,46]. The liver tissue samples of MEM treated groups exhibited diminished necrosis, slight inflammatory cells without damage to cell membrane signifying its protective potential.…”

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

“…Treatment with rifampicin (200 mg/kg) in mice for 4 weeks results in elevated hepatic lipids caused by induction of PPARγ through rifampicin-mediated activation of pregnane X receptor (PXR) [30]. A recent toxico-proteomics study suggests that the PPARγ signaling pathway is involved in rifampicin-induced liver injury [31]. In the study, mice were treated with either a low dose (177 mg/kg) or a high dose (422.5 mg/kg) of rifampicin.…”

“…As an important receptor in lipid metabolism, the increase of PPARγ levels indicates a potential mechanism for rifampicin-induced liver injury. The study also identified that cytochrome P450, glutathione metabolism, chemical carcinogenesis, and related proteins increased in a dose-dependent manner in rifampicin-treated mouse livers [31]. Therefore, alterations of transcriptional regulatory functions of PXR and PPARγ may contribute to rifampicin-induced liver injury.…”