{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T06:27:26Z","timestamp":1769236046204,"version":"3.49.0"},"reference-count":57,"publisher":"American Society of Hematology","issue":"13","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2001,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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 \u201cshuttle\u201d 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.<\/jats:p>","DOI":"10.1182\/blood.v98.13.3831","type":"journal-article","created":{"date-parts":[[2002,10,28]],"date-time":"2002-10-28T20:44:12Z","timestamp":1035837852000},"page":"3831-3839","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":45,"title":["Cellular zinc content is a major determinant of iron chelator\u2013induced apoptosis of thymocytes"],"prefix":"10.1182","volume":"98","author":[{"given":"Kirsteen H.","family":"Maclean","sequence":"first","affiliation":[{"name":"From the Department of Biochemistry, St Jude Children's Research Hospital, Memphis, Tennessee; and Department of Haematology, University College London, England."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John L.","family":"Cleveland","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, St Jude Children's Research Hospital, Memphis, Tennessee; and Department of Haematology, University College London, England."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John B.","family":"Porter","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry, St Jude Children's Research Hospital, Memphis, Tennessee; and Department of Haematology, University College London, England."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"234","reference":[{"key":"2020021219080912400_B1","doi-asserted-by":"crossref","first-page":"20291","DOI":"10.1074\/jbc.271.34.20291","article-title":"The relationship of intracellular iron chelation to the inhibition and regeneration of human ribonucleotide reductase.","volume":"71","author":"Cooper","year":"1996","journal-title":"J Biol Chem."},{"key":"2020021219080912400_B2","doi-asserted-by":"crossref","first-page":"2727","DOI":"10.1182\/blood.V78.10.2727.2727","article-title":"Comparison of the subacute toxicity and efficacy of 3-hydroxypyridin-4-one iron chelators in overloaded and nonoverloaded mice.","volume":"78","author":"Porter","year":"1991","journal-title":"Blood."},{"key":"2020021219080912400_B3","first-page":"86","article-title":"In vivo and in vitro effects of 3-hydroxypyridin-4-one chelators on murine hemopoiesis.","volume":"21","author":"Hoyes","year":"1993","journal-title":"Exp Hematol."},{"issue":"8660","key":"2020021219080912400_B4","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/S0140-6736(89)90641-7","article-title":"Agranulocytosis and thromobocytopenia in patient with Blackfan-Diamond anaemia during oral chelator trial.","volume":"2","author":"Hoffbrand","year":"1989","journal-title":"Lancet."},{"key":"2020021219080912400_B5","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1046\/j.1365-2141.2000.01866.x","article-title":"Safety profile of the oral iron chelator deferiprone: a multicentre study.","volume":"108","author":"Cohen","year":"2000","journal-title":"Br J Haematol."},{"key":"2020021219080912400_B6","first-page":"73","article-title":"Evidence of toxicity due to 1,2-dimethyl-3-hydroxypyridid-4-one (L1) in normal rats.","volume":"28","author":"Grady","year":"1992","journal-title":"Drugs Today Suppl A."},{"key":"2020021219080912400_B7","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1111\/j.1365-2141.1993.tb08660.x","article-title":"Contrasting interspecies efficacy and toxicology of 1,2-diethyl-hydroxypyridin-4-one, CP94, relates to differing metabolism of iron chelating site.","volume":"85","author":"Porter","year":"1993","journal-title":"Br J Haematol."},{"key":"2020021219080912400_B8","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1016\/0140-6736(93)92443-W","article-title":"Toxicity of oral iron chelator L1.","volume":"341","author":"Berdoukas","year":"1993","journal-title":"Lancet."},{"key":"2020021219080912400_B9","first-page":"371","article-title":"Thymocyte apoptosis: a rapid model for comparative screening of iron chelators: implications for treatment of iron overload in thalassaemia. 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