Abstract
Nutrient iron entering the blood binds transferrin (TFN)d, which delivers iron to cells in the body. In healthy individuals, ∼30% of TFN is iron-bound while the remainder is unbound (apo-TFN). TFN saturates the plasma of individuals with iron-overload diseases such as hereditary hemochromatosis, prompting release of a poorly-defined low-molecular-mass (LMM) iron species called non-transferrin-bound iron (NTBI). An experiment was devised to directly detect NTBI in plasma of iron-deficient pigs and to assess the role of the liver which is known to bind NTBI. Catheters were surgically installed in the portal vein (PV) and either the caudal vena cava or the cranial vena cava. After the animals recovered, 57Fe II ascorbate was injected into the stomach via a feeding tube. Blood was removed through the catheters before and after injection; plasma became 57Fe-enriched after injection. 57Fe-enriched plasma was passed through a 10 kDa cutoff membrane and the flow-through solution (FTS) was subjected to size-exclusion liquid chromatography (LC). The eluent flowed into an ICP-MS where 56Fe and 57Fe were detected. Low-intensity iron peaks with masses of 400-1600 Da were observed, but none became enriched in 57Fe after injection. Rather, the injected 57Fe bound to apo-TFN. Viewed naively, this implies that nutrient-derived 57Fe in healthy mammals passes from the intestines to apo-TFN without first entering the blood as a LMM intermediate. In this case, nutrient iron exported from intestinal enterocytes of healthy individuals may quickly bind apo-TFN such that LMM iron species do not accumulate in blood plasma. Some 57Fe from the FTS may have adsorbed onto the column. In any event, the LMM iron species in plasma that eluted from the column must have originated from iron stored within the body, perhaps in macrophages - not directly from nutrient iron absorption. The liver absorbed and released LMM iron species, but the effect was modest, consistent with its role as a dynamic iron buffer. Passage through the liver also altered the distribution of different forms of TFN present in the PV.
Highlights
The majority of iron in humans is found in erythrocytes as iron-containing heme centers, but this transition metal is essential for many metalloenzymes and processes as diverse as mitochondrial energetics and DNA replication
Blood was removed through the catheters before and after injection; plasma became 57Fe-enriched after injection. 57Fe-enriched plasma was passed through a 10 kDa cutoff membrane and the flow-through solution (FTS) was subjected to size-exclusion liquid chromatography (LC)
We considered that the liver may have absorbed most non-transferrin-bound iron (NTBI) generated after a meal and so we may not have detected this species in general circulation blood
Summary
The majority of iron in humans is found in erythrocytes as iron-containing heme centers, but this transition metal is essential for many metalloenzymes and processes as diverse as mitochondrial energetics and DNA replication. The resulting nutrient-derived FeIII species are released into the PV and bind apo-transferrin (apo-TFN), an 80 kDa glycoprotein in blood that serves as an iron buffer. Individuals with the iron-overload disorder hereditary hemochromatosis generate insufficient hepcidin such that excessive iron enters the blood. In this case, TFN approaches saturation (100% holo-TFN).[5] The spillover hypothesis maintains that once TFN is saturated, further iron enters the blood as one or more toxic complexes called nontransferrin-bound-iron or NTBI.[5,6,7,8] FeIII citrate leads the list of NTBI candidates as the concentration of citrate in blood is high and FeIII citrate is stable.[9,10,11] NTBI is often defined operationally as the labile iron pool in blood plasma that is chelated by a particular chelator under specified conditions
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