Iron mobilization from myocardial cells by 3-hydroxypyridin-4-one chelators: studies in rat heart cells in culture.
Iron mobilization from myocardial cells by 3-hydroxypyridin-4-one chelators: studies in rat heart cells in culture.
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DOI：
10.1182/blood.v77.9.2049.2049
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发表时间：
1991-05
期刊：
影响因子：
20.3
通讯作者：
C. Hershko;G. Link;A. Pinson;H. Peter;P. Dobbin;R. Hider
中科院分区：
文献类型：
--
作者：
C. Hershko;G. Link;A. Pinson;H. Peter;P. Dobbin;R. Hider
本文研究了口服双齿铁螯合剂3-羟基吡啶-4-酮（CP）清除铁和防止铁诱导的心肌细胞脂质过氧化的能力。所有CP化合物的铁（III）结合常数（log β 3）为36，但它们的亲脂性可以通过改变环氮上R2取代基的长度来改变。脂溶性和螯合效率之间有直接关系。虽然在高浓度下，所有CP化合物在铁动员方面比去铁胺更有效，但在低浓度下则相反。对最有效的CP化合物1，2-二乙基-3-羟基吡啶-4-酮（CP 94）的进一步研究表明，铁动员在6小时内完成，有效的动员需要药物：铁摩尔比超过3：1，允许形成六齿复合物，铁动员的有益作用表现为膜脂质过氧化的显著减少，如细胞丙二醛含量所示。我们的研究首次证明了心肌细胞与口服有效的铁螯合剂之间的直接相互作用，并强调了需要高摩尔浓度才能达到最佳治疗效果。
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 beta 3) 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.