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Iron mobilization from hepatocyte monolayer cultures by chelators: the
importance of membrane permeability and the iron-binding constant
JB Porter, M Gyparaki, LC Burke, ER Huehns, P Sarpong, V Saez and RC Hider
Department of Clinical Haematology, University College London, England.
A series of bidentate hydroxypyridinone iron chelators that have
therapeutic potential as oral iron chelators, have been studied
systematically to determine which properties are the most critical for the
mobilization of hepatocyte iron. The relationship between lipid solubility
of the free and complexed forms of each chelator and hepatocyte iron
release has been investigated as well as the contribution of the binding
constant for iron (III). Hydroxypyridin-4- ones that were approximately
equally soluble in lipid and aqueous phases were the most active compounds,
the partition coefficient of the free chelator appearing to be more
critical in determining iron release than that of the iron-complexed form.
Highly hydrophilic chelators did not mobilize intracellular iron pools,
whereas highly lipophilic compounds were toxic to hepatocytes. The
contribution of the binding constant for iron (III) to cellular iron
release was assessed by comparing hydroxypyridin-4-ones (log beta 3 = 36)
and hydroxypyridin-2- ones (log beta 3 = 32), which possess similar
partition coefficients. The results show that the binding for iron (III) is
particularly important at low concentrations of chelator (less than 100
mumol/L) and that at higher concentrations (greater than 500 mumol/L) iron
mobilization is limited by the available chelatable pool. Measurement of
iron release with other chelators confirms the importance of both the lipid
solubilities and iron (III)-binding constants to iron mobilization. The
most active hydroxypyridin-4-ones released more hepatocyte iron than did
deferoxamine when compared at equimolar concentrations. The results suggest
that the ability of an iron chelator to enter the cell is crucial for
effective iron mobilization and that once within the cell the binding
constant of the chelator for iron (III) becomes a dominant factor.
Volume 72,
Issue 5,
pp. 1497-1503,
11/01/1988
Copyright © 1988 by The American Society of Hematology
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