Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1.
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.
Ludwiczek
Susanne
S
Department of General Internal Medicine, Clinical Immunology and Infectious Diseases, Innsbruck Medical University, Anichstr. 35, A-6020 Innsbruck, Austria.
Theurl
Igor
I
Muckenthaler
Martina U
MU
Jakab
Martin
M
Mair
Sabine M
SM
Theurl
Milan
M
Kiss
Judit
J
Paulmichl
Markus
M
Hentze
Matthias W
MW
Ritter
Markus
M
Weiss
Guenter
G
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
D002121:Calcium Channel Blockers; D027682:Cation Transport Proteins; D007501:Iron; D009543:Nifedipine; D000099236:Solute Carrier Family 11, Member 2