title: Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1.
abstract: Hereditary hemochromatosis and transfusional iron overload are frequent clinical conditions associated with progressive iron accumulation in parenchymal tissues, leading to eventual organ failure. We have discovered a new mechanism to reverse iron overload-pharmacological modulation of the divalent metal transporter-1 (DMT-1). DMT-1 mediates intracellular iron transport during the transferrin cycle and apical iron absorption in the duodenum. Its additional functions in iron handling in the kidney and liver are less well understood. We show that the L-type calcium channel blocker nifedipine increases DMT-1-mediated cellular iron transport 10- to 100-fold at concentrations between 1 and 100 microM. Mechanistically, nifedipine causes this effect by prolonging the iron-transporting activity of DMT-1. We show that nifedipine mobilizes iron from the liver of mice with primary and secondary iron overload and enhances urinary iron excretion. Modulation of DMT-1 function by L-type calcium channel blockers emerges as a new pharmacological therapy for the treatment of iron overload disorders.
authors.affiliation: Department of General Internal Medicine, Clinical Immunology and Infectious Diseases, Innsbruck Medical University, Anichstr. 35, A-6020 Innsbruck, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Ludwiczek
authors.forename: Igor
authors.initials: I
authors.lastname: Theurl
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
authors.forename: Martin
authors.initials: M
authors.lastname: Jakab
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Mair
authors.forename: Milan
authors.initials: M
authors.lastname: Theurl
authors.forename: Judit
authors.initials: J
authors.lastname: Kiss
authors.forename: Markus
authors.initials: M
authors.lastname: Paulmichl
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Hentze
authors.forename: Markus
authors.initials: M
authors.lastname: Ritter
authors.forename: Guenter
authors.initials: G
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D019556:COS Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D027682:Cation Transport Proteins / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004594:Electrophysiology; D006432:Hemochromatosis / Q000517:prevention & control*; D006801:Humans; D015151:Immunoblotting; D007501:Iron / Q000378:metabolism / Q000652:urine; D019190:Iron Overload / Q000188:drug therapy*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D009543:Nifedipine / Q000494:pharmacology* / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D002121:Calcium Channel Blockers; D027682:Cation Transport Proteins; D007501:Iron; D009543:Nifedipine; D000099236:Solute Carrier Family 11, Member 2