Desferrioxamine (DFO) conjugated with starch decreases NAD redox potential of intact red blood cells (RBC): Evidence for DFO as an extracellular inducer of oxidant stress in RBC

Abstract

Desferrioxamine (DFO) is an important iron-chelating agent. It has also been thought of as an agent with anti-oxidant potential as it chelates ferric iron in various parts of the body. However, there is evidence suggesting that it may paradoxically affect red blood cells (RBCs) by inducing intracellular oxidant stress. Recently we observed that incubation of RBCs with DFO decreases NAD redox potential in normal RBC. To further understand the mechanism of DFO's interaction with RBC, we conducted a study to determine the effect of extracellular DFO upon RBC's redox status. We examined NAD redox potential in intact RBC (N = 7) incubated with DFO conjugated to starch. RBCs were incubated with 4 mM DFO for 3(1/2) hr and with 6 mM DFO for 2 and 3(1/2) hr. Significant decreases in NAD redox potential were observed after the incubations. With 4 mM DFO at the 3 (1/2) hr time point the mean decrease was 12.37% +/- 9.96% (P < 0.0085). With 6 mM DFO, the mean decreases were 18.54% +/- 9.79% (P < 0.0013) and 19.16% +/- 8.78% (P < 0.0006) for the 2 and 3 (1/2) hr incubations, respectively. DFO by itself is very poorly permeable to RBC. Conjugation with starch further ensured impermeability of DFO. The data presented here confirm the oxidant effect of DFO on RBC. The data also demonstrate that the effect of DFO on RBC's NAD redox potential originates extracellularly.

Desferrioxamine decreases NAD redox potential of intact red blood cells: evidence for desferrioxamine as an inducer of oxidant stress in red blood cells

“…In regard to the mechanism of the prooxidant effect, because DFO is poorly permeable to RBC membrane [3], the action of DFO may primarily originate extracellularly to cause changes in the intracellular NAD redox potential. In fact, this concept of extracellular oxidant stress was confirmed in previously published data using DFO conjugated with starch to increase the molecular weight [13]. With conjugation with starch, it becomes impossible for the DFO to enter into RBC.…”

“…Previously, we have published the data demonstrating that DFO conjugated with starch leads to decrease in NAD redox potential[13]. As conjugation with starch makes DFO practically impossible to penetrate into RBC, it supported a notion that the oxidant stress was exerted from outside of RBC.…”

Pathophysiology of the Optic Neuropathy Associated With Friedreich Ataxia

“…7 Deferoxamine has been shown to increase oxidative stress in erythrocytes via an extracellular mechanism. 23 The mechanism by which this occurs is not clear, although there is evidence that chelating copper ions can also induce oxidative stress. 24 The presence of the extended GAA repeat, leading to reduced frataxin expression, will decrease intracytoplasmic iron levels 25 and shift the RGC redox state out of its optimum set point, thereby leading to early death and consequent optic neuropathy.…”

Atrial fibrillation in β‐thalassemia patients with a focus on the role of iron‐overload and oxidative stress: A review

“…It is also interesting that several recent studies have claimed that some iron chelators can exert oxidant effects (Lu, Chen, & Peng, 2011;Niihara et al, 2000Niihara et al, , 2002. Therefore, the combination of an iron chelator with an antioxidant can be beneficial.…”