Interactions of Bismuth with Human Lactoferrin and Recognition of the BiIII−Lactoferrin Complex by Intestinal Cells

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Abstract
Several bismuth compounds are currently used as antiulcer drugs, but the mechanism of action still remains unclear. The antimicrobial activity of Bi III complexes toward Gram-negative bacteria is reported to be dependent on the iron uptake system [Domenico, P., et al. (1996) J. Antimicrob. Chemother. 38, 1031-1040]. Electronic absorption and 13C NMR spectroscopic data show that Bi III binds to human lactoferrin at the specific Fe III sites along with either carbonate or oxalate as the synergistic anion. The uptake of Bi III by apo-hLF was rapid [minutes in 10 mM Hepes buffer and 5 mM bicarbonate (pH 7.4)], and almost equal in both lobes. The presence of ATP facilitates the release of Bi III from the Bi 2-hLF complex when the pH is lowered. The Bi 2-hLF complex blocked the uptake of the radiolabeled 59Fe-hLF complex into rat IEC-6 cells. Surprisingly, apo-hLF (but not apotransferrin) was almost as effective in blocking 59Fe uptake as bismuth-loaded lactoferrin. These results suggest that Bi III-loaded hLF might be recognized by the lactoferrin receptor and be taken up into cells.link_to_subscribed_fulltex