title: FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach.
abstract: 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.
authors: 1] Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China [2] Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors: Weiqiang
authors: W
authors: Lu
authors: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors: Feixiong
authors: F
authors: Cheng
authors: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors: Jing
authors: J
authors: Jiang
authors: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors: Chen
authors: C
authors: Zhang
authors: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors: Xiaokang
authors: X
authors: Deng
authors: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors: Zhongyu
authors: Z
authors: Xu
authors: Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China.
authors: Shien
authors: S
authors: Zou
authors: 1] Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China [2] Shanghai Institute of Materia Medica, 555 Zuchongzhi Road, Shanghai 201203, China.
authors: Xu
authors: X
authors: Shen
authors: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors: Yun
authors: Y
authors: Tang
authors: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors: Jin
authors: J
authors: Huang
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000473:pathology*; D020022:Genetic Predisposition to Disease; D056945:Hep G2 Cells; D006801:Humans; D007052:Ibuprofen / Q000009:adverse effects; D007213:Indomethacin / Q000009:adverse effects; D008156:Luciferases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D060066:Protein Interaction Maps / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D049490:Systems Biology; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000235:genetics; D020798:Two-Hybrid System Techniques; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007052:Ibuprofen; D007213:Indomethacin; D008156:Luciferases; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D050796:STAT3 Transcription Factor; D000099150:Receptor, Farnesoid X-Activated
references: Singapore Med J. 2004 Nov;45(11):530-2
references: 15510325
references: Sci Transl Med. 2012 Mar 14;4(125):125ra31
references: 22422992
references: Annu Rev Pharmacol Toxicol. 2012;52:505-21
references: 22235860
references: J Biochem. 2012 Dec;152(6):577-86
references: 22969091
references: Clin Pharmacol Ther. 2013 May;93(5):379-81
references: 23598453
references: PLoS One. 2012;7(7):e41064
references: 22815915
references: Mol Syst Biol. 2010;6:343
references: 20087340
references: Clin Pharmacokinet. 1994 Jan;26(1):16-43
references: 8137596
references: J Chem Inf Model. 2013 Apr 22;53(4):753-62
references: 23527559
references: Nat Genet. 2008 Feb;40(2):124-5
references: 18227866
references: Nat Biotechnol. 2014 Jun;32(6):583-91
references: 24837663
references: Hepatology. 2012 Dec;56(6):2336-43
references: 22711662
references: Mol Cell. 2000 Sep;6(3):507-15
references: 11030331
references: Hepatology. 2006 Oct;44(4):976-82
references: 17006946
references: J Pharmacol Exp Ther. 2005 Oct;315(1):58-68
references: 15980055
references: PLoS Comput Biol. 2012;8(5):e1002503
references: 22589709
references: BMJ. 1992 Oct 10;305(6858):865-8
references: 1422399
references: Expert Opin Drug Metab Toxicol. 2011 Jul;7(7):817-28
references: 21473713
references: Am J Physiol Gastrointest Liver Physiol. 2012 Dec 1;303(11):G1245-53
references: 23042943
references: World J Gastroenterol. 2010 Dec 7;16(45):5651-61
references: 21128314
references: Semin Liver Dis. 2002;22(2):169-83
references: 12016548
references: Hepatology. 1981 May-Jun;1(3):255-63
references: 7286906
references: Am J Gastroenterol. 1990 Jul;85(7):898-9
references: 2371992
references: Nucleic Acids Res. 2011 Jan;39(Database issue):D1067-72
references: 20864448
references: QJM. 2003 Nov;96(11):787-91
references: 14566034
references: Nucleic Acids Res. 2013 Jan;41(Database issue):D8-D20
references: 23193264
references: Cell Signal. 2008 Dec;20(12):2180-97
references: 18634871
references: J Chem Inf Model. 2013 Apr 22;53(4):744-52
references: 23521697
references: Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41
references: 21059682
references: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D267-70
references: 14681409
references: Br J Clin Pharmacol. 1982 Aug;14(2):286-9
references: 7104182
references: Methods Mol Biol. 2001;176:359-76
references: 11554336
references: Nucleic Acids Res. 2008 Jan;36(Database issue):D913-8
references: 18032438
references: J Steroid Biochem Mol Biol. 2008 May;110(1-2):150-6
references: 18455388
references: Nucleic Acids Res. 2005 Jan 1;33(Database issue):D514-7
references: 15608251
references: Ann Pharmacother. 1999 Sep;33(9):945-7
references: 10492497
references: Crit Rev Toxicol. 1995;25(3):207-35
references: 7576152
references: Cell Signal. 2012 Aug;24(8):1658-64
references: 22560881
references: Curr Top Med Chem. 2013;13(11):1273-89
references: 23675935
references: Mol Biosyst. 2012 Sep;8(9):2373-84
references: 22751809
references: Annu Rev Physiol. 2006;68:159-91
references: 16460270
references: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W94-8
references: 15980589
references: Contrib Nephrol. 2011;170:209-16
references: 21659773
references: BMJ. 2003 Jul 5;327(7405):18-22
references: 12842950
references: Sci Rep. 2014;4:5576
references: 24992957
references: Planta Med. 2012 Mar;78(5):472-9
references: 22281717
references: Hepatol Res. 2013 Sep;43(9):959-69
references: 23369163
references: J Biol Chem. 2001 Aug 3;276(31):28857-65
references: 11387316
references: Biochim Biophys Acta. 2011 Aug;1812(8):888-92
references: 21167938
references: Curr Mol Med. 2010 Aug;10(6):579-95
references: 20642438
references: Mol Endocrinol. 2010 May;24(5):886-97
references: 20211986
references: Biomed Environ Sci. 2007 Dec;20(6):465-9
references: 18348404
references: J Chem Inf Model. 2010 Jun 28;50(6):1134-46
references: 20481574
references: Lancet. 2004 Aug 21-27;364(9435):665-74
references: 15325831
references: Arthritis Rheum. 1985 Jun;28(6):686-92
references: 4004978
references: Genome Biol. 2009;10(9):238
references: 19723347
references: Diabetes. 2007 Oct;56(10):2485-93
references: 17660268
references: Aliment Pharmacol Ther. 2010 Jul;32(1):3-13
references: 20374223
references: PLoS Comput Biol. 2011 Mar;7(3):e1002016
references: 21483481
references: Fundam Clin Pharmacol. 2008 Apr;22(2):141-58
references: 18353109
references: Mol Biosyst. 2013 Jun;9(6):1316-25
references: 23455869
references: J Hepatol. 2009 Aug;51(2):380-8
references: 19501927