ICL670A: a new synthetic oral chelator: evaluation in hypertransfused rats with selective radioiron probes of hepatocellular and reticuloendothelial iron stores and in iron-loaded rat heart cells in culture
ICL670A: a new synthetic oral chelator: evaluation in hypertransfused rats with selective radioiron probes of hepatocellular and reticuloendothelial iron stores and in iron-loaded rat heart cells in culture
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DOI：
10.1182/blood.v97.4.1115
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发表时间：
2001-02-15
期刊：
影响因子：
20.3
通讯作者：
Link, G
中科院分区：
文献类型：
--
作者：
Hershko, C;Konijn, AM;Link, G
ICL 670 A（以前称为CGP 72 670）或4-[3，5-双-（羟基苯基）-1，2，4-三唑-1-基]-苯甲酸是双-羟基苯基-三唑类化合物的三齿铁选择性合成螯合剂。目前的研究使用选择性放射性铁探针的肝细胞和网状内皮（RE）的铁存储在高输血大鼠和铁负载的心脏细胞，以确定在体内的ICL 670 A螯合铁的来源及其排泄模式，检查其能力，直接从铁负载的心肌细胞中去除铁，并检查其与其他螯合剂通过可能的添加剂或协同效应相互作用的能力。结果表明，ICL 670 A口服给药在促进肝细胞铁库中可螯合铁的排泄方面比胃肠外去铁胺（DFO）有效4至5倍。ICL 670 A产生的铁排泄模式与DFO的铁排泄模式完全不同，并且所有铁排泄都限于胆汁，无论其是否来自RE或肝细胞铁储存。在心脏细胞培养物中的研究已经显示出DFO和ICL 670 A之间的有利相互作用，表现为ICL 670 A的螯合效率提高，这最有可能通过ICL 670 A和DFO之间螯合铁的交换来解释。ICL 670 A的这些独特的螯合特性可能对目前设计更好的治疗策略以管理输血铁过载的努力具有实际意义。
ICL670A(formerly CGP 72 670) or 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid is a tridentate iron-selective synthetic chelator of the bis-hydroxyphenyl-triazole class of compounds. The present studies used selective radioiron probes of hepatocellular and reticuloendothelial (RE) iron stores in hypertransfused rats and iron-loaded heart cells to define the source of iron chelated in vivo by ICL670A and its mode of excretion, to examine its ability to remove iron directly from iron-loaded myocardial cells, and to examine its ability to interact with other chelators through a possible additive or synergistic effect. Results indicate that ICL670A given orally is 4 to 5 times more effective than parenteral deferoxamine (DFO) in promoting the excretion of chelatable iron from hepatocellular iron stores. The pattern of iron excretion produced by ICL670A is quite different from that of DFO and all iron excretion is restricted to the bile regardless of whether it is derived from RE or hepatocellular iron stores. Studies in heart cell cultures have shown a favorable interaction between DFO and ICL670A manifested in improved chelating efficiency of ICL670A, which is most probably explained by an exchange of chelated iron between ICL670A and DFO. These unique chelating properties of ICL670A may have practical implications for current efforts to design better therapeutic strategies for the management of transfusional iron overload.