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The genomic responses of mouse liver to diclofenac treatment reveals an immune mediated mechanism of liver injury


ABSTRACT: Diclofenac (DCL) is a non-steroidal anti-inflammatory drug. Its use can be associated with serious adverse drug reactions most notable myocardial infarction and drug-induced liver injury (DILI). The molecular causes leading to DILI remains unclear and it seems to be multifactorial. The aims of this study is to identify the molecular mechanisms involving immune mediated inflammatory reactions and its link to DILI through whole genome gene expression profiling. Diclofenac was given to mice at 30 mg/kg for 1, 3 and 14 days. Microarray experiments were performed with RNA extracts from liver samples. The performed gene expression studies showed >600 significantly regulated genes after single and repeated dosing for 3 and 14 days. The functional annotation revealed several genes were regulated in common coding for inflammatory, immune, stress and acute-phase responses. Immunohistochemistry, qRT-PCR as well as Western blotting were performed to evidence the regulation of key molecules in affected livers. In conclusion, the present study provides evidence for a mechanism of diclofenac induced liver injury that involves pro-inflammatory cytokine and acute phase responses. C57BL6- mice (males, 8 weeks old) (n=5) were administered daily by intraperitoneal injection of 30 mg/kg diclofenac sodium for up to 14 days. Control mice (n=5) were treated corresponding quantities of saline. The mice were euthanized at 24h (day 1), 72h (day 3) or 14 days after vehicle or diclofenac administration. The whole genome gene expression profiling studies of liver samples were performed to define the molecular mechanism of diclofenac induced immune mediated liver injury.

ORGANISM(S): Mus musculus

SUBMITTER: Jürgen Borlak 

PROVIDER: E-GEOD-75277 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Immunogenomics reveal molecular circuits of diclofenac induced liver injury in mice.

Lee Eun-Hee EH   Oh Jung-Hwa JH   Selvaraj Saravanakumar S   Park Se-Myo SM   Choi Mi-Sun MS   Spanel Reinhard R   Yoon Seokjoo S   Borlak Jürgen J  

Oncotarget 20160301 12


Diclofenac is a non-steroidal anti-inflammatory drug and its use can be associated with severe adverse reactions, notably myocardial infarction, stroke and drug-induced liver injury (DILI). In pursue of immune-mediated DILI mechanisms an immunogenomic study was carried out. Diclofenac treatment of mice at 30 mg/kg for 3 days caused significant serum ALT and AST elevations, hepatomegaly and degenerative changes including hepatic glycogen depletion, hydropic swelling, cholesterolosis and eosinophi  ...[more]

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