Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1
- 11 February 2007
- journal article
- research article
- Published by Springer Nature in Nature Medicine
- Vol. 13 (4) , 448-454
- https://doi.org/10.1038/nm1542
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.Keywords
This publication has 46 references indexed in Scilit:
- Hereditary Hemochromatosis — A New Look at an Old DiseaseNew England Journal of Medicine, 2004
- Balancing Acts: Molecular Control of Mammalian Iron MetabolismPublished by Elsevier ,2004
- The orchestration of body iron intake: how and where do enterocytes receive their cues?Blood Cells, Molecules, and Diseases, 2003
- Mechanisms and Regulation of Intestinal Iron AbsorptionBlood Cells, Molecules, and Diseases, 2002
- HFE and non-HFE hemochromatosis.International Journal of Hematology, 2002
- Mechanisms of Iron Accumulation in Hereditary HemochromatosisAnnual Review of Physiology, 2002
- Secondary Iron OverloadHematology-American Society Hematology Education Program, 2001
- Duodenal metal-transporter (DMT-1, NRAMP-2) expression in patients with hereditary haemochromatosisThe Lancet, 1999
- Pathophysiology of Iron OverloadaAnnals of the New York Academy of Sciences, 1998
- A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosisNature Genetics, 1996