The transport of two iron chelators, desferrioxamine B and L1, across Caco‐2 monolayers

Abstract

The transport of two iron chelators, desferrioxamine B (DFO) and L1 (1,2-dimethyl-3 hydroxypyridin-4-one) has been studied in vitro using the human adenocarcinoma cell line, Caco-2. The transport of DFO and L1 has also been compared with that of their iron-bound complexes, ferrioxamine (FO) and L1(3)-Fe, respectively. We report an apparent permeability coefficient (Papp) value for DFO of 0.170 x 10(-7) +/- 0.080 cm s-1. The Papp value of L1 was 1.297 x 10(-5) +/- 0.133 cm s-1. The Papp values of their iron bound complexes FO and L1(3)-Fe are 0.230 x 10(-7) +/- 0.065 cm s-1 and 2.356 x 10(-6) +/- 0.365 cm s-1, respectively. We have shown that the transport of DFO and FO is similar in the Caco-2 cell system. The transport of L1, however, is greatly reduced when complexed to iron. The value for total uptake after 60 min for DFO into the Caco-2 cells was 1.49 +/- 0.09 x 10(-3) nmol per filter. The values for total uptake after 60 min for L1 and L1(3)-Fe were 0.37 +/- 0.03 nmol per filter and 0.04 +/- 0.01 nmol per filter, respectively. Our results indicate that the poor oral bioavailability of DFO can be attributed to the low epithelial permeability of the molecule coupled with its size (mol wt 656). In contrast, the oral bioavailability observed with L1 is due to the high lipophilicity and low molecular weight (mol wt 139) of the molecule. We believe that these differences between the two molecules account for L1 being better orally absorbed than DFO.

Effects of iron chelates on the transferrin-free culture of rat dermal fibroblasts through active oxygen generation

“…A similar phenomenon has been recently reported: transport of iron into human intestinal Caco-2 cells is greatly reduced if iron is combined with a membrane-penneable chelating agent, t.2-dimethyI-3 hydroxypyridin-4-one (17). A preliminary experiment confirmed that ~'Fe remained in a supernatant fraction of lhe serum-free medimn supplemented with IDA 100 and 14 times, at least, more than in the supernatant fractions of the media supplemented with GG and DHEG.…”

Deferiprone Reduces Amyloid-β and Tau Phosphorylation Levels but not Reactive Oxygen Species Generation in Hippocampus of Rabbits Fed a Cholesterol-Enriched Diet

“…It may be possible that doses higher than 50 mg/kg/day are necessary to fully reduce oxidative stress in the cholesterol diet-fed rabbits as plasma cholesterol levels remained more than ten times higher in the 50 mg/kg deferiprone treated, high-cholesterol group than in controls. Deferiprone has a low molecular weight, is known to penetrate the cells [80], crosses the blood brain barrier in less than 7 minutes after systemic administration [81], yields a peak plasma concentration one hour after oral administration [36], and its cellular uptake is superior to that of deferoxamine [82], another widely known metal chelator.…”

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

“…Nonetheless, as the NAD system comprises the major factor in intracellular antioxidant activity within the RBC, this observation suggests the prooxidant effect of DFO upon the cytosol of RBC[16]. 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].…”