title: Pro-inflammatory response and adverse drug reactions: mechanisms of action of ximelagatran on chemokine and cytokine activation in a monocyte in vitro model.
abstract: There is a lack of suitable human in vitro systems which can predict drug hepatotoxicity that in many cases involves inflammatory responses mediated by macrophages. In the present investigation we used an in vitro model based on human THP-1 cells to evaluate the inflammatory cytokine/chemokine activation properties of ximelagatran, a drug previously shown to cause elevation of liver transferases in a subset of patients. Treatment of the cells with ximelagatran caused an intracellular accumulation of the metabolites hydroxymelagatran and melagatran. A decreased viability and increased release of the pro-inflammatory cytokines and chemokines IL-8, VEGF and MCP-1 was seen. Ximelagatran exposure caused activation of ERK1/2 and JNK as evident from determination of the phosphorylation status. In accordance, the release of IL-8 was attenuated by inhibitors of the ERK- and JNK-pathways. It is concluded that human monocytes might constitute a valuable additional in vitro model for monitoring the basis for cytotoxic action of drugs.
authors.affiliation: Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Nanna Svartz väg 2, Stockholm, Sweden. Ylva.Edling@ki.se
authors.forename: Ylva
authors.initials: Y
authors.lastname: Edling
authors.forename: Louise
authors.initials: L
authors.lastname: Sivertsson
authors.forename: Tommy B
authors.initials: TB
authors.lastname: Andersson
authors.forename: Margareta
authors.initials: M
authors.lastname: Porsmyr-Palmertz
authors.forename: Magnus
authors.initials: M
authors.lastname: Ingelman-Sundberg
mesh_terms: D000578:Amidines / Q000378:metabolism; D000925:Anticoagulants / Q000493:pharmacokinetics / Q000633:toxicity*; D001384:Azetidines / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D001596:Benzylamines / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018925:Chemokines / Q000187:drug effects* / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism
chemical_list: D000578:Amidines; D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D018925:Chemokines; D016207:Cytokines; D016209:Interleukin-8; C479417:N-hydroxymelagatran; C109573:melagatran; C426686:ximelagatran; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3