Iron mobilization from hepatocyte monolayer cultures by chelators: the importance of membrane permeability and the iron-binding constant.
Iron mobilization from hepatocyte monolayer cultures by chelators: the importance of membrane permeability and the iron-binding constant.
复制标题
螯合剂从肝细胞单层培养物中动员铁：膜通透性和铁结合常数的重要性。
作者：
JB Porter;M. Gyparaki;LC Burke;E. Huehns;P. Sarpong;V. Saez;R. Hider
一系列具有治疗潜力的双齿羟基吡啶酮铁络合剂已被系统地研究，以确定哪些性质对动员肝细胞铁最关键。研究了各络合剂游离态和络合态的脂溶性与肝细胞铁释放的关系，以及铁结合常数的贡献。羟基吡啶-4-酮在脂相和水相中的溶解度大致相同，是最具活性的化合物，游离络合剂的分配系数似乎比络合形式的分配系数对决定铁的释放更为关键。高亲水性的螯合剂不能动员细胞内的铁库，而高亲脂性的化合物对肝细胞有毒性。通过比较具有相似分配系数的羟基吡啶-4-酮(对数β3=36)和羟基吡啶-2-酮(对数β3=32)来评估铁(III)结合常数对细胞铁释放的贡献。结果表明，在低浓度(小于100mumol/L)的条件下，铁的结合作用尤为重要，而在较高浓度(大于500mumol/L)时，铁的活化受到可用的螯合池的限制。用其他螯合剂测定铁的释放，证实了脂类溶解度和铁(III)结合常数对铁动员的重要性。在等摩尔浓度下，最活跃的羟基吡啶-4-酮比去铁胺释放更多的肝细胞铁。结果表明，铁络合剂进入细胞的能力是有效动员铁的关键，一旦进入细胞，螯合剂与铁(III)的结合常数就成为主导因素。
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.
转铁蛋白与分离的肝细胞的相互作用。
DOI：
10.1016/0304-4165(80)90400-6
发表时间：
1980
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Young,SP;Aisen,P
通讯作者：
Aisen,P