Iron Mobilization From Myocardial Cells by 3-Hydroxypyridin-4-One Chelators: Studies in Rat Heart Cells in Culture

The ability of 3-hydroxypyridin-4-ones (CP), a family of bidentate orally effective iron chelators, to remove iron and to prevent iron-induced lipid peroxidation was studied in beating rat myocardial cells in culture. The iron (III) binding constant (log β3) of all CP compounds is 36, but their lipo...

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Bibliographic Details
Published in:Blood 1991-05, Vol.77 (9), p.2049-2053
Main Authors: Hershko, C., Link, G., Pinson, A., Peter, H.H., Dobbin, P., Hider, R.C.
Format: Article
Language:English
Subjects:
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Animals
Biological and medical sciences
Cell Membrane - metabolism
Cells, Cultured
Deferoxamine - metabolism
Intensive care medicine
Iron - isolation & purification
Iron - metabolism
Iron Chelating Agents - metabolism
Iron Chelating Agents - pharmacology
Kinetics
Lipid Peroxidation - drug effects
Malondialdehyde - metabolism
Medical sciences
Myocardium - chemistry
Pyridones - metabolism
Pyridones - pharmacology
Rats
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Summary:The ability of 3-hydroxypyridin-4-ones (CP), a family of bidentate orally effective iron chelators, to remove iron and to prevent iron-induced lipid peroxidation was studied in beating rat myocardial cells in culture. The iron (III) binding constant (log β3) of all CP compounds is 36, but their lipophilicity may be modified by altering the length of the R2 substituent on the ring nitrogen. There was a direct relation between lipid solubility and chelating efficiency. Although at high concentrations all CP compounds were more effective in iron mobilization than deferoxamine, the opposite was true for low concentrations. Further studies with 1,2-diethyl-3-hydroxypyridin-4-one (CP94), the most effective CP compound, have shown that iron mobilization is completed within 6 hours, that effective mobilization requires a drug: iron molar ratio exceeding 3:1 permitting the formation of a hexadentate complex, and that the beneficial effects of iron mobilization are manifested in a marked reduction in membrane lipid peroxidation as indicated by cellular malonaldehyde content. Our study represents the first demonstration of a direct interaction between myocardial cells and an orally effective iron chelator, and underlines the need for high molar concentrations for achieving an optimal therapeutic effect.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.V77.9.2049.2049