Document Detail


Pro-inflammatory response and adverse drug reactions: mechanisms of action of ximelagatran on chemokine and cytokine activation in a monocyte in vitro model.
MedLine Citation:
PMID:  18640260     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Ylva Edling; Louise Sivertsson; Tommy B Andersson; Margareta Porsmyr-Palmertz; Magnus Ingelman-Sundberg
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-07-02
Journal Detail:
Title:  Toxicology in vitro : an international journal published in association with BIBRA     Volume:  22     ISSN:  0887-2333     ISO Abbreviation:  Toxicol In Vitro     Publication Date:  2008 Sep 
Date Detail:
Created Date:  2008-08-18     Completed Date:  2008-10-21     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8712158     Medline TA:  Toxicol In Vitro     Country:  England    
Other Details:
Languages:  eng     Pagination:  1588-94     Citation Subset:  IM    
Affiliation:
Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Nanna Svartz väg 2, Stockholm, Sweden. Ylva.Edling@ki.se
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MeSH Terms
Descriptor/Qualifier:
Amidines / metabolism
Anticoagulants / pharmacokinetics,  toxicity*
Azetidines / metabolism,  pharmacokinetics,  toxicity*
Benzylamines / metabolism,  pharmacokinetics,  toxicity*
Cell Line
Cell Survival / drug effects
Chemokines / drug effects*,  metabolism
Cytokines / drug effects*,  metabolism
Humans
Interleukin-8 / drug effects,  metabolism
JNK Mitogen-Activated Protein Kinases / drug effects,  metabolism
Mitogen-Activated Protein Kinase 1 / drug effects,  metabolism
Mitogen-Activated Protein Kinase 3 / drug effects,  metabolism
Models, Biological
Monocytes / drug effects,  metabolism
Chemical
Reg. No./Substance:
0/Amidines; 0/Anticoagulants; 0/Azetidines; 0/Benzylamines; 0/Chemokines; 0/Cytokines; 0/Interleukin-8; 0/N-hydroxymelagatran; 0/ximelagatran; 159776-70-2/melagatran; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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