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Blood, 15 December 2001, Vol. 98, No. 13, pp. 3831-3839
RED CELLS
Cellular zinc content is a major determinant of iron
chelator-induced apoptosis of thymocytes
Kirsteen H. Maclean,
John
L. Cleveland, and
John B. Porter
From the Department of Biochemistry, St Jude
Children's Research Hospital, Memphis, Tennessee; and Department of
Haematology, University College London, England.
Desferrioxamine (DFO) and the hydroxypiridinone (HPO) deferiprone
(CP20) chelate iron as well as other metals. These chelators are used
clinically to treat iron overload, but they induce apoptosis in
thymocytes. Thymocyte apoptosis is potentiated by zinc deficiency, suggesting that these iron chelators may induce
apoptosis by depleting stores of zinc. Exposure of murine
thymocytes to either DFO or deferiprone resulted in significant
reductions in the labile intracellular zinc pool. Moreover, increasing
intracellular zinc levels, by chronic zinc dietary supplementation to
mice or in vitro loading with zinc, abrogated deferiprone-induced
murine thymocyte apoptosis. Bidentate hydroxypyridinones such as
deferiprone interact with intracellular zinc pools in a manner distinct
from that of DFO, which is a hexadentate iron chelator. Whereas
deferiprone acts synergistically with the zinc chelator
NNNN-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) to induce
apoptosis, DFO does not. This difference is most likely due to the
ability of HPOs but not DFO to "shuttle" zinc onto acceptors such
as metallothioneins. By nature of its structure, DFO is larger than
deferiprone and is thus less able to access some intracellular zinc
pools. Additionally, metal complexes of DFO are more stable than those
of HPOs and thus are less likely to donate zinc to other acceptors. The
ability of deferiprone to preferentially access zinc pools was also
demonstrated by inhibition of a zinc-containing enzyme phospholipase C,
particularly when combined with TPEN. These findings suggest that
bidentate iron chelators access intracellular zinc pools not available
to DFO and that zinc chelation is a mechanism of apoptotic induction by
such chelators in thymocytes.
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