title: Dicumarol is a potent reversible inhibitor of gap junctional intercellular communication.
abstract: Dicumarol [3,3'-methylene-bis(4-hydroxycoumarin)] is a potent inhibitor of NAD(P)H:quinone oxidoreductase-1. Exposure of rat liver epithelial cells or of human skin fibroblasts to dicumarol resulted in a rapid and complete inhibition of connexin-43-dependent gap junctional intercellular communication (GJC). GJC was restored within 60min following removal of dicumarol. The concentration of dicumarol required for half maximal inhibition of GJC was 3muM, making dicumarol about 10-fold more effective in blocking GJC than 1-octanol and flufenamic acid, known inhibitors of GJC. Warfarin, a related coumarin derivative, also attenuated GJC, yet very high concentrations of 5-10mM were required. Dicumarol-induced downregulation of GJC was found not to be due to an interference with pathways enhancing the phosphorylation of connexin-43, such as epidermal growth factor receptor and extracellular signal-regulated kinase pathways. Rather, inhibition of GJC by dicumarol was paralleled by a reversible loss of a phosphorylated form ("P2") of connexin-43.
authors.affiliation: Institut für Biochemie und Molekularbiologie I, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Kotb
authors.initials: K
authors.lastname: Abdelmohsen
authors.forename: Dominik
authors.initials: D
authors.lastname: Stuhlmann
authors.forename: Felicitas
authors.initials: F
authors.lastname: Daubrawa
authors.forename: Lars-Oliver
authors.initials: LO
authors.lastname: Klotz
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015153:Blotting, Western; D002450:Cell Communication; D002460:Cell Line; D004396:Coloring Agents / Q000494:pharmacology; D018031:Connexin 43 / Q000494:pharmacology; D001728:Dicumarol / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005439:Flufenamic Acid / Q000494:pharmacology; D017629:Gap Junctions; D007546:Isoquinolines / Q000494:pharmacology; D008099:Liver / Q000187:drug effects; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008956:Models, Chemical; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D014475:Uncoupling Agents / Q000494:pharmacology; D014859:Warfarin / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D004396:Coloring Agents; D018031:Connexin 43; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D014475:Uncoupling Agents; D014859:Warfarin; D005439:Flufenamic Acid; D001728:Dicumarol; C017475:lucifer yellow; D048052:Mitogen-Activated Protein Kinase 3