Chelator-facilitated removal of iron from transferrin: relevance to combined chelation therapy
Chelator-facilitated removal of iron from transferrin: relevance to combined chelation therapy
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DOI：
10.1042/bj20070823
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发表时间：
2008-01-15
影响因子：
4.1
通讯作者：
Hider, Robert C.
中科院分区：
文献类型：
--
作者：
Devanur, Lakshmi D.;Evans, Robert W.;Hider, Robert C.
目前的铁螯合疗法主要包括DFO（去铁胺），其必须通过静脉输注与去铁酮和地拉罗司一起施用，其是口服活性螯合剂。这些螯合剂，虽然有效地减少铁负荷，但与许多副作用有关。Grady认为，较小的二齿螯合剂和较大的六齿螯合剂（如DFO）的联合给药将导致比单独使用任一种螯合剂更大的铁去除[Grady，Bardoukas和Giardina（1998）Blood 92，16 b]。这反过来可能导致所需螯合剂剂量的减少。为了检验这一假设，监测铁从一系列双齿HPO（羟基吡啶-4-酮）螯合剂转移到DFO的速率。利用光谱方法监测Fe-HPO络合物浓度的降低。已经确定铁从双齿螯合剂到DFO的穿梭在临床相关浓度的螯合剂下确实发生，进行研究以评估这种转移机制是否适用于从转铁蛋白中去除铁。再次，发现双齿螯合剂和DFO两者的同时存在提高了在临床相关螯合剂水平下从转铁蛋白螯合铁的速率。去铁酮被发现是特别有效的“穿梭”铁从转铁蛋白DFO，可能是由于它的小尺寸和相对较低的亲和力铁相比，其他类似的HPO螯合剂。
Current iron chelation therapy consists primarily of DFO (desferrioxamine), which has to be administered via intravenous infusion, together with deferiprone and deferasirox, which are orally-active chelators. These chelators, although effective at decreasing the iron load, are associated with a number of side effects. Grady suggested that the combined administration of a smaller bidentate chelator and a larger hexadentate chelator, such as DFO, would result in greater iron removal than either chelator alone [Grady, Bardoukas and Giardina (1998) Blood 92, 16b]. This in turn could lead to a decrease in the chelator dose required. To test this hypothesis, the rate of iron transfer from a range of bidentate HPO (hydroxypyridin-4-one) chelators to DFO was monitored. Spectroscopic methods were utilized to monitor the decrease in the concentration of the Fe-HPO complex. Having established that the shuttling of iron from the bidentate chelator to DFO does occur under clinically relevant concentrations of chelator, studies were undertaken to evaluate whether this mechanism of transfer would apply to iron removal from transferrin. Again, the simultaneous presence of both a bidentate chelator and DFO was found to enhance the rate of iron chelation from transferrin at clinically relevant chelator levels. Deferiprone was found to be particularly effective at 'shuttling' iron from transferrin to DFO, probably as a result of its small size and relative low affinity for iron compared with other analogous HPO chelators.