Research Database PMU-SQQUID

PMU-Authors

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.

Useful keywords (using NLM MeSH Indexing)

Animals

Biological Transport, Active/drug effects

COS Cells

Calcium Channel Blockers/pharmacology*

Calcium Channel Blockers/therapeutic use

Cation Transport Proteins/metabolism*

Cercopithecus aethiops

Electrophysiology

Hemochromatosis/prevention*

control*

Humans

Immunoblotting

Iron/metabolism

Iron/urine

Iron Overload/drug therapy*

Liver/metabolism

Mice

Mice, Knockout

Microarray Analysis

Nifedipine/pharmacology*

Nifedipine/therapeutic use

Reverse Transcriptase Polymerase Chain Reaction