The
therapeutic effect of
iron (Fe)
chelators on the potentially toxic plasma pool of nontransferrin-bound
iron (NTBI), often present in Fe overload diseases and in some
cancer patients during
chemotherapy, is of considerable interest. In the present investigation, several multidentate
pyridinones were synthesized and compared with their bidentate analogue,
deferiprone (
DFP; L1, orally active) and
desferrioxamine (DFO; hexadentate; orally inactive) for their effect on the metabolism of NTBI in the rat hepatocyte and a
hepatoma cell line (McArdle 7777, Q7).
Hepatoma cells took up much less NTBI than the hepatocytes (< 10%). All the
chelators inhibited NTBI uptake (80-98%) much more than they increased mobilization of Fe from cells prelabelled with NTBI (5-20%). The hexadentate pyridinone, N,N,N-tris(3-hydroxy-1-methyl-2(1H)-pyridinone-4-carboxaminoethyl)amine showed comparable activity to DFO and
DFP. There was no apparent correlation between Fe status, Fe uptake and
chelator activity in hepatocytes, suggesting that NTBI transport is not regulated by cellular Fe levels. The intracellular distribution of
iron taken up as NTBI changed in the presence of
chelators suggesting that the
chelators may act intracellularly as well as at the cell membrane. In conclusion (a) rat hepatocytes have a much greater capacity to take up NTBI than the rat
hepatoma cell line (Q7), (b) all
chelators bind NTBI much more effectively during the uptake phase than in the mobilization of Fe which has been stored from NTBI and (c) while
DFP is the most active
chelator, other multidentate
pyridinones have potential in the treatment of Fe overload, particularly at lower, more readily clinically available concentrations, and during
cancer chemotherapy, by removing plasma NTBI.