Article abstract
Nature Medicine 13, 448 - 454 (2007)
Published online: 11 February 2007 | doi:10.1038/nm1542
Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1
Susanne Ludwiczek1, Igor Theurl1, Martina U Muckenthaler2, Martin Jakab3,4, Sabine M Mair1, Milan Theurl1, Judit Kiss2, Markus Paulmichl3,5, Matthias W Hentze6, Markus Ritter3,4 & Guenter Weiss1
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 
M. 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.
- Department of General Internal Medicine, Clinical Immunology and Infectious Diseases, Innsbruck Medical University, Anichstr. 35, A-6020 Innsbruck, Austria.
- Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Im Neuenheimer Feld 153, D-69120 Heidelberg, Germany.
- Department of Physiology and Medial Physics, Innsbruck Medical University, Fritz-Pregl Str. 3, A-6020 Innsbruck, Austria.
- Institute of Physiology, Paracelsus Medical University, Strubergasse 21, A-5020 Salzburg, Austria.
- Department of Biomolecular Sciences and Biotechnology, Universita degli Studi di Milano, Via Celoria 26, I-20133 Milano, Italy.
- European Molecular Laboratory (EMBL), Gene Expression Unit, Meyerhofstr. 1, D-69117 Heidelberg, Germany.
Correspondence to: Guenter Weiss1 e-mail: guenter.weiss@i-med.ac.at
Correspondence to: Matthias W Hentze6 e-mail: hentze@embl.de
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