Transcription profiling of liver from wild type and Hfe-/- mice with hereditary hemochromatosis subjected to dietary iron overload and treatment with nifedipine to reverse iron overload

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 novel mechanism to reverse iron overload by 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. 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 1-100 uM. Mechanistically, nifedipine causes this effect by prolongation of the activity of DMT-1 to transport iron. 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 a novel pharmacological concept to treat iron overload disorders.

In this experiment mice were subjected to dietary iron overload before being treated with nifedipine at 5 ug/g bodyweight, or mock treated with the same volume of solvent.

INSTRUMENT(S): Axon GenePix 4000B scanning hardware

ORGANISM(S): Mus musculus

SUBMITTER: martina muckenthaler 

PROVIDER: E-MEXP-982 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress