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TOXICOLOGY

p38 Mitogen-Activated Protein Kinase-Dependent Tumor Necrosis Factor--Converting Enzyme Is Important for Liver Injury in Hepatotoxic Interaction between Lipopolysaccharide and Ranitidine

Departments of Biochemistry and Molecular Biology (X.D., J.L.) and Pharmacology and Toxicology (P.E.G., R.A.R.), Michigan State University, East Lansing, Michigan; Discovery Toxicology, Bristol-Myers Squibb, Princeton, New Jersey (L.D.L.-M.); Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Graz, Austria (E.M.); and Wyeth Research, Philadelphia, Pennsylvania (D.L.C.)

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)- production and hepatic neutrophil activation after LPS treatment and that both TNF- and neutrophils are crucial for the liver pathogenesis. We tested the hypothesis that p38 mitogen-activated protein kinase activation is necessary for TNF- 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- concentration after LPS/RAN treatment to the same level as LPS treatment. However, the inhibitor did not reduce TNF- mRNA in liver, suggesting a post-transcriptional mode of action. This might occur through TNF--converting enzyme (TACE), which cleaves pro-TNF- into its active form. Indeed, a TACE inhibitor administered just before RAN treatment reduced serum TNF- 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- production after LPS treatment through augmented p38 activation, and this seems to occur through TACE. The prolonged TNF- production enhanced PAI-1 production after RAN cotreatment, and this is important for the hepatotoxicity.

Address correspondence to: Dr. Robert A. Roth, Department of Pharmacology and Toxicology, B347 Life Sciences Bldg., Michigan State University, East Lansing, MI 48824. E-mail: rothr{at}msu.edu

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