(The FASEB Journal. 2008;22:1192.2.)
© 2008 FASEB
A role for the divalent metal-ion transporter (DMT1) is doubtful in the mechanism by which calcium-channel blockers reverse iron overload
Bryan Mackenzie1,
Ali Shawki1,
Andrew J Ghio2,
Jacqueline D Stonehuerner2,
Lin Zhao3,
Saied Ghadersohi3,
Laura M Garrick3 and
Michael D Garrick3
1 Dept Molecular & Cellular Physiology, Univ Cincinnati, Cincinnati, OH
2 US Environmental Protection Agency, Chapel Hill, NC
3 Dept Biochemistry, SUNY at Buffalo, Buffalo, NY
ABSTRACT
Fueling speculation about a connection between transferrin-independent Fe uptake and Ca channels, Ludwiczek et al (Nat Med 13, 448 [2007]) concluded that dihydropyridine-type Ca-channel blockers (e.g. nifedipine) can reverse Fe overload by stimulating DMT1 activity and mobilizing tissue Fe. Since the paper disagrees with two others (Biochem J 398, 539 [2006]; Biochem J 403, 59 [2007]) on the transport activity of DMT1 isoforms, studies were undertaken to resolve that issue and explore the effect of nifedipine on DMT1, using doxycycline-induced expression of DMT1 in permanently-transfected HEK293 cell lines and expression of DMT1 in Xenopus oocytes. We confirmed our cited studies that the isoforms have very similar activities. Nifedipine did not stimulate DMT1 activity in any assay. Morgan & Savigni (Biochem Pharmacol 51, 1701 [1996]) observed that photodegraded nifedipine (PDN) stimulated Fe uptake by erythrocytes and suggested that PDN was an Fe-specific ionophore. We confirmed this property of PDN in our preparations and found that it was independent of DMT1 since: (1) PDN stimulated uptake of Fe, but not of Mn, whereas each are DMT1 substrates; (2) The effect of PDN on Fe uptake was less apparent when cells over-expressed DMT1 than when DMT1 levels were lower or minimal. The report by Ludwiczek et al is of clinical significance because of the need for ways to increase Fe excretion, but how nifedipine leads to such an increase remains unclear.
