Interactions of bismuth with human lactoferrin and recognition of the Bi-III-lactoferrin complex by intestinal cells

Several bismuth compounds are currently used as antiulcer drugs, but the me chanism of action still remains unclear. The antimicrobial activity of Bi-I II complexes toward Gram-negative bacteria is reported to be dependent on t he iron uptake system [Domenico, P., et al. (1996) J. Antimicrob. Chemother . 38, 1031-1040]. Electronic absorption and C-13 NMR spectroscopic data sho w 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 B i-III by apo-hLF was rapid [minutes in 10 mM Hepes buffer and 5 mM bicarbon ate (pH 7.4)], and almost equal in both lobes. The presence of ATP facilita tes 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 Fe-59-hLF comp lex into rat IEC-6 cells. Surprisingly, apo-hLF (but not apotransferrin) wa s almost as effective in blocking Fe-59 uptake as bismuth-loaded lactoferri n. These results suggest that Bi-III-loaded hLF might be recognized by the lactoferrin receptor and be taken up into cells.