New insights into the interactions of serum proteins with bis(maltolato)oxovanadium(IV): Transport and biotransformation of insulin-enhancing vanadium pharmaceuticals
New insights into the interactions of serum proteins with bis(maltolato)oxovanadium(IV): Transport and biotransformation of insulin-enhancing vanadium pharmaceuticals
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DOI：
10.1021/ja043944n
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发表时间：
2005-04-13
影响因子：
15
通讯作者：
Orvig, C
中科院分区：
文献类型：
--
作者：
Liboiron, BD;Thompson, KH;Orvig, C
有效的胰岛素增强化合物二（麦芽）oxovanadium（IV）（BMOV）与血清蛋白，脱铁转铁蛋白和白蛋白的相互作用的重要新见解，提出。通过电子顺磁共振（EPR）与BMOV或硫酸氧钒（VOSO 4）在人血清脱铁转铁蛋白溶液中观察到相同的反应产物。进一步的详细研究排除了存在的三元配体-钒酰-转铁蛋白复合物先前提出的。相比之下，对于BMOV和VOSO 4与人血清白蛋白（HSA）的相互作用，观察到反应产物的差异，其中检测到白蛋白和BMOV之间的加合物形成。在BMOV-白蛋白溶液中，钒基离子以独特的方式结合，在VOSO 4和白蛋白的可比溶液中未观察到。螯合钒离子的存在排除了在许多非特异性位点的结合，并产生了独特的EPR谱，这是分配给BMOV-HSA加合物。然而，加合物不能从VOSO 4和HSA的溶液中产生，用麦芽酚滴定。相反，向VOSO 4-HSA溶液中添加麦芽酚导致形成不同的终产物，其被指定为三元复合物VO（ma）（HSA）。此外，使用BMOV与1-甲基咪唑的模型系统（形成常数log K = 4.5（1），通过差示电子吸收光谱法）分析溶液平衡为本文提出的BMOV和HSA的加合物结合模式（VO（ma）（2）-HSA）提供支持。VOSO 4和BMOV之间的体外反应性差异的详细报告可能与递送至靶组织的活性钒代谢物的形式有关。钒螯合物的白蛋白结合被认为对这些抗糖尿病螯合物的药代动力学、转运和功效具有潜在的显著影响。
Significant new insights into the interactions of the potent insulin-enhancing compound bis(maltolato)oxovanadium(IV) (BMOV) with the serum proteins, apo-transferrin and albumin, are presented. Identical reaction products are observed by electron paramagnetic resonance (EPR) with either BMOV or vanadyl sulfate (VOSO4) in solutions of human serum apo-transferrin. Further detailed study rules out the presence of a ternary ligand-vanadyl-transferrin complex proposed previously. By contrast, differences in reaction products are observed for the interactions of BMOV and VOSO4 with human serum albumin (HSA), wherein adduct formation between albumin and BMOV is detected. In BMOV-albumin solutions, vanadyl ions are bound in a unique manner not observed in comparable solutions Of VOSO4 and albumin. Presentation of chelated vanadyl ions precludes binding at the numerous nonspecific sites and produces a unique EPR spectrum which is assigned to a BMOV-HSA adduct. The adduct species cannot be produced, however, from a solution Of VOSO4 and HSA titrated with maltol. Addition of maltol to a VOSO4-HSA solution instead results in formation of a different end product which has been assigned as a ternary complex, VO(ma)(HSA). Furthermore, analysis of solution equilibria using a model system of BMOV with 1-methylimidazole (formation constant log K = 4.5(1), by difference electronic absorption spectroscopy) lends support to an adduct binding mode (VO(ma)(2)-HSA) proposed herein for BMOV and HSA. This detailed report of an in vitro reactivity difference between VOSO4 and BMOV may have bearing on the form of active vanadium metabolites delivered to target tissues. Albumin binding of vanadium chelates is seen to have a potentially dramatic effect on pharmacokinetics, transport, and efficacy of these antidiabetic chelates.