Effect of iron status on the intestinal absorption of aluminum: a reappraisal.

Clinical and experimental studies have shown that serum aluminum (Al) is bound to transferrin and that cellular uptake of Al appears to be mediated by transferrin receptors. Based on these findings it is widely believed that intestinal Al absorption occurs via iron-specific, transferrin-dependent pathways and that iron (Fe) deficiency increases the intestinal absorption of Al. However, since no transferrin receptors are expressed on the absorptive surface of small intestinal epithelial cells this notion is doubtful. To further clarify the issue the present study investigated the effect of marked alterations of body Fe stores on the intestinal absorption of Al using three different rat models. (I) Serum Al concentrations and urinary excretion rates of Al were measured in iron-overloaded (Fe+) or iron-deficient (Fe-) rats with either normal (C) or impaired (5/6 nephrectomy) renal function (Nx) employing oral A1 loads in single dose studies. (II) Tissue A1 accumulation as well as serum and urine A1 were determined in respective experimental groups exposed to a prolonged (41 days) dietary Al load. (III) To assess the effect of Fe status on the intestinal absorption of Al directly at the organ level perfusions of in situ rat gut preparations were performed. In the single dose studies administration of Al resulted in similar urinary excretion rates of Al in intact kidney groups (C+Fe-, 229 +/- 85 nmol/5 days; C+Fe+, 240 +/- 59 nmol/5 days) despite marked differences in liver Fe (C+Fe-, 1.34 +/- 0.16 vs. C+Fe+, 55.69 +/- 13.20 mumol/g) and duodenal mucosal Fe (C+Fe-, 0.68 +/- 0.11 vs. C+Fe+, 3.17 +/- 0.82 mumol/g). In addition, mucosal Al concentration 24 hours after the load was not affected by the Fe status (C+Fe-, 37 +/- 16 nmol/g, C+Fe+, 56 +/- 19 nmol/g). Regardless of the Fe status post-load Al excretion was enhanced in Nx rats (Nx+Fe-, 533 +/- 234 nmol/five days, Nx+Fe+, 536 +/- 201 nmol/five days). Irrespective of Fe status a prolonged dietary Al load resulted in a similar increase in tissue Al concentration (nmol/g) in liver (baseline, 159 +/- 22; C+Fe-, 276 +/- 125; C+Fe+, 251 +/- 71; Nx+Fe-, 330 +/- 119; Nx+Fe+, 437 +/- 67) and in bone (baseline, 219 +/- 119; C+Fe-, 433 +/- 174, C+Fe+, 485 +/- 141; Nx+Fe-, 504 +/- 185; Nx+Fe+, 548 +/- 215). The increase in spleen Al was significantly larger in Fe-overloaded rats (baseline, 194 +/- 20; C+Fe+, 511 +/- 129 vs. C+Fe-, 308 +/- 62, P < 0.05; Nx+Fe+, 514 +/- 67 vs. Nx+Fe-, 389 +/- 119, P < 0.05). Brain Al tended to rise in Nx rats only (baseline, 96 +/- 33; Nx+Fe+, 174 +/- 100, Nx+Fe-, 156 +/- 78, P = NS). Analogous results were obtained in in situ intestinal perfusion studies: Fe deficiency and Fe overload both did not affect the time-dependent increase in serum Al in either systemic or portal vein blood. When paracellular intestinal permeability was assessed mannitol absorption was significantly higher in uremic animals as compared to controls. Pharmacological blockade (2 mM kinetin) of the paracellular permeability substantially reduced the time-dependent increase in serum Al in uremic rats but had little effect in control animals, suggesting that even the excess absorption of Al observed in uremia occurs via a paracellular rather than an iron-specific pathway. In conclusion, the findings of the present study provide several lines of evidence against the commonly accepted view that the intestinal absorption of Al occurs via iron-specific pathways. Most likely, this is related to the fact, that neither the absorption of Fe nor the absorption of Al are mediated via transferrin receptors. In addition, the enhanced intestinal absorption of Al observed in uremic rats does also not occur via iron-specific pathways, but seems to due to increased paracellular permeability of the intestine.