p38 Mitogen-Activated Protein Kinase-Dependent Tumor Necrosis Factor-α-Converting Enzyme Is Important for Liver Injury in Hepatotoxic Interaction between Lipopolysaccharide and Ranitidine
- 4 April 2008
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Journal of Pharmacology and Experimental Therapeutics
- Vol. 326 (1), 144-152
- https://doi.org/10.1124/jpet.108.137497
Abstract
Ranitidine (RAN) is one of the drugs associated with idiosyncratic adverse drug reactions (IADRs) in human patients. In rats, cotreatment with nontoxic doses of lipopolysaccharide (LPS) and RAN causes liver injury. This is a potential animal model for RAN-induced IADRs in humans. Previous studies showed that RAN augmented serum tumor necrosis factor (TNF)-α production and hepatic neutrophil activation after LPS treatment and that both TNF-α and neutrophils are crucial for the liver pathogenesis. We tested the hypothesis that p38 mitogen-activated protein kinase activation is necessary for TNF-α production, neutrophil activation, and subsequent liver injury. LPS/RAN cotreatment caused more p38 activation compared with LPS alone. The p38 inhibitor SB 239063 [trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxypyridimidin-4-yl) imidazole] reduced liver injury in rats cotreated with LPS/RAN. This inhibitor also reduced neutrophil activation and attenuated hemostatic system activation. SB 239063 decreased serum TNF-α concentration after LPS/RAN treatment to the same level as LPS treatment. However, the inhibitor did not reduce TNF-α mRNA in liver, suggesting a post-transcriptional mode of action. This might occur through TNF-α-converting enzyme (TACE), which cleaves pro-TNF-α into its active form. Indeed, a TACE inhibitor administered just before RAN treatment reduced serum TNF-α protein. The TACE inhibitor also reduced liver injury and serum plasminogen activator inhibitor (PAI)-1. Furthermore, a PAI-1 inhibitor reduced neutrophil activation and liver injury after LPS/RAN treatment. In summary, RAN enhanced TNF-α production after LPS treatment through augmented p38 activation, and this seems to occur through TACE. The prolonged TNF-α production enhanced PAI-1 production after RAN cotreatment, and this is important for the hepatotoxicity.Keywords
This publication has 40 references indexed in Scilit:
- The Role of Tumor Necrosis Factor Alpha in Lipopolysaccharide/Ranitidine-Induced Inflammatory Liver InjuryToxicological Sciences, 2007
- Unique Gene Expression and Hepatocellular Injury in the Lipopolysaccharide-Ranitidine Drug Idiosyncrasy Rat Model: Comparison with FamotidineToxicological Sciences, 2006
- Differential Substrate and Inhibitory Activities of Ranitidine and Famotidine toward Human Organic Cation Transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3)Journal of Pharmacology and Experimental Therapeutics, 2005
- Characterization and comparative evaluation of a structurally unique PAI‐1 inhibitor exhibiting oral in‐vivo efficacyJournal of Thrombosis and Haemostasis, 2004
- Analysis of the mechanism regulating the stability of rat macrophage inflammatory protein‐2 mRNA in RBL‐2H3 cellsJournal of Cellular Biochemistry, 2003
- Ranitidine Treatment during a Modest Inflammatory Response Precipitates Idiosyncrasy-Like Liver Injury in RatsJournal of Pharmacology and Experimental Therapeutics, 2003
- Immunologic Detection and Measurement of Hypochlorite-Modified LDL With Specific Monoclonal AntibodiesArteriosclerosis, Thrombosis, and Vascular Biology, 1995
- Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigmCell, 1994
- Side Effects of RanitidineDrug Safety, 1991
- RANITIDINE HEPATOTOXICITY IN RENAL TRANSPLANT PATIENTThe Lancet, 1985