FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach

• Published in: Scientific reports 2015-01, Vol.5 (1), p.8114-8114, Article 8114
• Main Authors: Lu, Weiqiang, Cheng, Feixiong, Jiang, Jing, Zhang, Chen, Deng, Xiaokang, Xu, Zhongyu, Zou, Shien, Shen, Xu, Tang, Yun, Huang, Jin
• Format: Article
• Language: English
• Subjects: 38; 38/111; 631/114; 631/92; Analgesics; Anti-inflammatory agents; Anti-Inflammatory Agents, Non-Steroidal - adverse effects; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - pathology; Drug therapy; Gene expression; Genetic Predisposition to Disease; Hep G2 Cells; Humanities and Social Sciences; Humans; Ibuprofen; Ibuprofen - adverse effects; Indomethacin; Indomethacin - adverse effects; Inflammation; Liver; Luciferases - metabolism; Molecular modelling; multidisciplinary; Nonsteroidal anti-inflammatory drugs; Pharmacology; Phosphorylation; Phosphorylation - drug effects; Polymerase chain reaction; Protein Interaction Maps - drug effects; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Stat3 protein; STAT3 Transcription Factor - metabolism; Systems Biology; Transcription activation; Transcription, Genetic - drug effects; Transcriptional Activation - genetics; Two-Hybrid System Techniques
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep08114

Non-steroidal anti-inflammatory drugs (NSAIDs) are worldwide used drugs for analgesic, antipyretic and anti-inflammatory therapeutics. However, NSAIDs often cause several serious liver injuries, such as drug-induced liver injury (DILI) and the molecular mechanisms of DILI have not been clearly elucidated. In this study, we developed a systems pharmacology approach to explore the mechanism-of-action of NSAIDs. We found that the Farnesoid X Receptor (FXR) antagonism of NSAIDs is a potential molecular mechanism of DILI through systematic network analysis and in vitro assays. Specially, the quantitative real-time PCR assay reveals that indomethacin and ibuprofen regulate FXR downstream target gene expression in HepG2 cells. Furthermore, the western blot shows that FXR antagonism by indomethacin induces the phosphorylation of STAT3 (signal transducer and activator of transcription 3), promotes the activation of caspase9 and finally causes DILI. In summary, our systems pharmacology approach provided novel insights into molecular mechanisms of DILI for NSAIDs, which may propel the ways toward the design of novel anti-inflammatory pharmacotherapeutics.