Kinetic analysis of59Fe movement across the intestinal wall in duodenal rat segments ex vivo

Duodenal segments from iron-deficient and iron-adequate rats were luminally perfused ex vivo with solutions containing 1, 10, 50, 100, 200 and 500 μmol59Fe/l. When duodenal tissue load and mucosal-to-serosal transport had reached a steady state, perfusion was continued without luminal59Fe supply. Mobilization of59Fe from the duodenal tissue into the serosally released absorbate followed first-order rate kinetics, which permitted calculation of the asymptotic maximum, the rate constant, and the initial mobilization rate for tissue-to-absorbate transfer. There was no evidence for adaptation of59Fe tissue binding in iron-deficient segments.59Fe tissue-to-absorbate transfer increased in proportion to the mobilizable fraction of recently absorbed iron in the tissue, which is indicative of simple diffusion or carrier-mediated transport below saturation. Regulation of the mucosal uptake step appears to determine the mobilizable59Fe fraction and thus the adaptation of the overall iron absorption process to the demand. Iron retention in the duodenal tissue and iron transfer from here into the body appear not to be either regulated or rate limited.

Adaptive Response of Iron Absorption to Anemia, Increased Erythropoiesis, Iron Deficiency, and Iron Loading in β2-Microglobulin Knockout Mice

Recently, a novel gene of the major histocompatibility complex (MHC) class I family, HFE (HLA-H), has been found to be mutated in a large proportion of hereditary hemochromatosis (HH) patients. Further support for a causative role of HFE in this disease comes from the observation that β2-microglobulin knockout (β2m−/−) mice, that fail to express MHC class I products, develop iron overload. We have now used this animal model of HH to examine the capacity to adapt iron absorption in response to altered iron metabolism in the absence of β2m-dependent molecule(s). Mucosal uptake, mucosal transfer and retention of iron were measured in control and β2m−/−mice with altered iron metabolism. Mucosal uptake of Fe(III), but not of Fe(II), by the mutant mice was significantly higher when compared with B6 control mice. Mucosal transfer in the β2m−/−mice was higher, independent of the iron form tested. No significant differences were found in iron absorption between control and β2m−/− mice when anemia was induced either by repetitive bleeding or by hemolysis through phenylhydrazine treatment. However, iron absorption in mice made anemic by dietary deprivation of iron was significantly higher in the mutant mice. Furthermore, the β2m−/− mice manifested an impaired capacity to downmodulate iron absorption when dietary or parenterally iron-loaded. The expression of the defect in iron absorption in the β2m−/− mice is quantitative, with iron absorption being excessively high for the size of body iron stores. The higher iron absorption capacity in the β2m−/− mice may involve the initial step of ferric mucosal uptake and the subsequent step of mucosal transfer of iron to the plasma.