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.

journal_name

Nat Med

journal_title

Nature medicine

authors

Ludwiczek S,Theurl I,Muckenthaler MU,Jakab M,Mair SM,Theurl M,Kiss J,Paulmichl M,Hentze MW,Ritter M,Weiss G

doi

10.1038/nm1542

subject

Has Abstract

pub_date

2007-04-01 00:00:00

pages

448-54

issue

4

eissn

1078-8956

issn

1546-170X

pii

nm1542

journal_volume

13

pub_type

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