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.
Highlights
The liver is a very important organ in drug metabolism; it lies between absorption and systematic circulation in terms of its function and it is the primary location of metabolism and the discharge of external substances
Increased serum ALT/AST was an indicator of hepatotoxicity, and no change in ALP levels indicated a type of mixed liver injury via hepatocellular and cholestatic injury based on the clinical presentation [21]
Our results showed that CYP2C-catalyzed omeprazole 5-hydroxylation and CYP3A-mediated midazolam hydroxylation increased in response to RIF in a dose-dependent manner (Figure S1)
Summary
The liver is a very important organ in drug metabolism; it lies between absorption and systematic circulation in terms of its function and it is the primary location of metabolism and the discharge of external substances. Owing to these properties, the liver is considered the main target of drug toxicity. Drugs that most frequently cause DILI can be found in epidemiological data. According to an epidemiological study in China in 2013, the leading cause of DILI was tuberculosis drugs [3]. In Spain in 2005 and in the US in 2008, amoxicillin and clavulanate were classified as the major causes of DILI, and anti-tubercular drugs were ranked second and third, respectively [4,5]
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