Deferoxamine: stimulation of hematin polymerization and antagonism of its inhibition by chloroquine.
Deferoxamine: stimulation of hematin polymerization and antagonism of its inhibition by chloroquine.
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去铁胺：刺激血红素聚合并拮抗氯喹对其的抑制作用。
DOI：
10.1016/s0006-2952(99)00161-6
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发表时间：
1999
影响因子：
5.8
通讯作者：
Vennerstrom,JL
中科院分区：
文献类型：
--
作者：
Vippagunta,SR;Dorn,A;Bubendorf,A;Ridley,RG;Vennerstrom,JL
铁络合剂去铁胺增强了对恶性疟原虫寄生虫病的清除，并可能在治疗脑型疟疾的药物组合中有用。然而，去铁胺-氯喹药物组合在体外对恶性疟原虫具有拮抗作用，或最好的相加作用。由于氯喹被认为是通过与寄生虫食物液泡中血红蛋白降解释放的血红素相互作用而发挥抗疟疾活性，我们假设去铁胺可能干扰氯喹抑制血红素聚合的能力，因为有报道去铁胺与血红素相互作用。因此，我们更详细地评估了去铁胺与血红素的结合，并研究了去铁胺在氯喹存在和不存在的情况下对血红素聚合的影响。恒温滴定实验表明，在pH 6.5时，去铁胺与血红素μ-氧代二聚体结合，结合常数为2.8×10~4M−1，结合亲和力比氯喹低14倍。去铁胺的三个异羟肟酸官能团中至少必须有两个官能团被联合起来才能有效结合。我们还发现去铁胺拮抗氯喹对血红素聚合的抑制作用。出乎意料的是，去铁胺增加了血红素的可溶性形式的浓度，并加快了血红素聚合的速度。去铁胺也能引发血红素聚合。相反，氯喹降低了可溶形式的血红素浓度，并抑制了血红素聚合。这项工作支持了这样的假设，即启动血红素聚合需要比聚合的延伸阶段更高浓度的可溶性血红素单体，并为观察到去铁胺和氯喹在培养中对寄生虫的拮抗作用提供了一种可能的解释。
The iron chelator deferoxamine enhances the clearance of Plasmodium falciparum parasitemia and may be useful in drug combinations for the treatment of cerebral malaria. However, the deferoxamine–chloroquine drug combination is antagonistic, or at best additive, against P. falciparum in vitro. As chloroquine is thought to exert its antimalarial activity by interacting with hematin released from the proteolytic degradation of hemoglobin in the parasite food vacuole, we hypothesized that deferoxamine might interfere with the ability of chloroquine to inhibit hematin polymerization, since it was reported that deferoxamine interacts with hematin. Therefore, we assessed deferoxamine–hematin binding in more detail and investigated the effect of deferoxamine on hematin polymerization in the presence and absence of chloroquine. Isothermal titration calorimetry (ITC) experiments demonstrated an enthalpy-driven deferoxamine:hematin μ-oxo dimer binding with an association constant of 2.8 × 104M−1at pH 6.5, a binding affinity 14-fold lower than that measured for chloroquine. At least two of the three hydroxamic acid functional groups of deferoxamine must be unionized for effective binding. We also discovered that deferoxamine antagonized chloroquine-mediated inhibition of hematin polymerization. Unexpectedly, deferoxamine increased the concentration of soluble forms of hematin and enhanced the rate of hematin polymerization. Deferoxamine also could initiate hematin polymerization. In contrast, chloroquine decreased the concentration of soluble forms of hematin and inhibited hematin polymerization. This work supports the postulate that initiation of hematin polymerization requires a higher concentration of soluble hematin monomer than does the elongation phase of polymerization and provides one possible explanation for the observed antagonism between deferoxamine and chloroquine against parasites in culture.