Ascorbate status modulates reticuloendothelial iron stores and response to deferasirox iron chelation in ascorbate-deficient rats

TY - JOUR

T1 - Ascorbate status modulates reticuloendothelial iron stores and response to deferasirox iron chelation in ascorbate-deficient rats

AU - Brewer, Casey

AU - Otto-Duessel, Maya

AU - Lykkesfeldt, Jens

AU - Nick, Hanspeter

AU - Wood, John C

N1 - Copyright © 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

PY - 2012/10

Y1 - 2012/10

N2 - Iron chelation is essential to patients on chronic blood transfusions to prevent toxicity from iron overload and remove excess iron. Deferasirox (DFX) is the most commonly used iron chelator in the United States; however, some patients are relatively refractory to DFX therapy. We postulated that vitamin C supplementation would improve the availability of transfusional iron to DFX treatment by promoting iron's redox cycling, increasing its soluble ferrous form and promoting its release from reticuloendothelial cells. Osteogenic dystrophy rats (n = 54) were given iron dextran injections for 10 weeks. Cardiac and liver iron levels were measured after iron loading (n = 18), 12 weeks of sham chelation (n = 18), and 12 weeks of DFX chelation (n = 18) at 75 mg/kg/day. Ascorbate supplementation of 150 ppm, 900 ppm, and 2250 ppm was used in the chow to mimic a broad range of ascorbate status; plasma ascorbate levels were 5.4 ± 1.9, 8.2 ± 1.4, 23.6 ± 9.8 μM, respectively (p < 0.0001). The most severe ascorbate deficiency produced reticuloenthelial retention, lowering total hepatic iron by 29% at the end of iron loading (p < 0.05) and limiting iron redistribution from cardiac and hepatic macrophages during 12 weeks of sham chelation. Most importantly, ascorbate supplementation at 2250 ppm improved DFX efficiency, allowing DFX to remove 21% more hepatic iron than ascorbate supplementation with 900 ppm or 150 ppm (p < 0.05). We conclude that vitamin C status modulates the release of iron from the reticuloendothelial system and correlates positively with DFX chelation efficiency. Our findings suggest that ascorbate status should be probed in patients with unsatisfactory response to DFX.

AB - Iron chelation is essential to patients on chronic blood transfusions to prevent toxicity from iron overload and remove excess iron. Deferasirox (DFX) is the most commonly used iron chelator in the United States; however, some patients are relatively refractory to DFX therapy. We postulated that vitamin C supplementation would improve the availability of transfusional iron to DFX treatment by promoting iron's redox cycling, increasing its soluble ferrous form and promoting its release from reticuloendothelial cells. Osteogenic dystrophy rats (n = 54) were given iron dextran injections for 10 weeks. Cardiac and liver iron levels were measured after iron loading (n = 18), 12 weeks of sham chelation (n = 18), and 12 weeks of DFX chelation (n = 18) at 75 mg/kg/day. Ascorbate supplementation of 150 ppm, 900 ppm, and 2250 ppm was used in the chow to mimic a broad range of ascorbate status; plasma ascorbate levels were 5.4 ± 1.9, 8.2 ± 1.4, 23.6 ± 9.8 μM, respectively (p < 0.0001). The most severe ascorbate deficiency produced reticuloenthelial retention, lowering total hepatic iron by 29% at the end of iron loading (p < 0.05) and limiting iron redistribution from cardiac and hepatic macrophages during 12 weeks of sham chelation. Most importantly, ascorbate supplementation at 2250 ppm improved DFX efficiency, allowing DFX to remove 21% more hepatic iron than ascorbate supplementation with 900 ppm or 150 ppm (p < 0.05). We conclude that vitamin C status modulates the release of iron from the reticuloendothelial system and correlates positively with DFX chelation efficiency. Our findings suggest that ascorbate status should be probed in patients with unsatisfactory response to DFX.

KW - Animals

KW - Ascorbic Acid

KW - Ascorbic Acid Deficiency

KW - Benzoates

KW - Guinea Pigs

KW - Humans

KW - Iron

KW - Iron Chelating Agents

KW - Iron Overload

KW - Liver

KW - Mononuclear Phagocyte System

KW - Myocardium

KW - Rats

KW - Rats, Mutant Strains

KW - Triazoles

U2 - 10.1016/j.exphem.2012.06.005

DO - 10.1016/j.exphem.2012.06.005

M3 - Journal article

C2 - 22713799

SN - 0301-472X

VL - 40

SP - 820

EP - 827

JO - Experimental Hematology

JF - Experimental Hematology

IS - 10

ER -