Dicumarol is a potent reversible inhibitor of gap junctional intercellular communication.
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.
Abdelmohsen
Kotb
K
Institut für Biochemie und Molekularbiologie I, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
Stuhlmann
Dominik
D
Daubrawa
Felicitas
F
Klotz
Lars-Oliver
LO
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
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