Levina Aviva, McLeod Andrew I, Pulte Anna, Aitken Jade B, Lay Peter A
School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.
Inorg Chem. 2015 Jul 20;54(14):6707-18. doi: 10.1021/ic5028948. Epub 2015 Apr 23.
The antidiabetic activities of vanadium(V) and -(IV) prodrugs are determined by their ability to release active species upon interactions with components of biological media. The first X-ray absorption spectroscopic study of the reactivity of typical vanadium (V) antidiabetics, vanadate (V(V)O4, A) and a vanadium(IV) bis(maltolato) complex (B), with mammalian cell cultures has been performed using HepG2 (human hepatoma), A549 (human lung carcinoma), and 3T3-L1 (mouse adipocytes and preadipocytes) cell lines, as well as the corresponding cell culture media. X-ray absorption near-edge structure data were analyzed using empirical correlations with a library of model vanadium(V), -(IV), and -(III) complexes. Both A and B ([V] = 1.0 mM) gradually converged into similar mixtures of predominantly five- and six-coordinate V(V) species (∼75% total V) in a cell culture medium within 24 h at 310 K. Speciation of V in intact HepG2 cells also changed with the incubation time (from ∼20% to ∼70% V(IV) of total V), but it was largely independent of the prodrug used (A or B) or of the predominant V oxidation state in the medium. Subcellular fractionation of A549 cells suggested that V(V) reduction to V(IV) occurred predominantly in the cytoplasm, while accumulation of V(V) in the nucleus was likely to have been facilitated by noncovalent bonding to histone proteins. The nuclear V(V) is likely to modulate the transcription process and to be ultimately related to cell death at high concentrations of V, which may be important in anticancer activities. Mature 3T3-L1 adipocytes (unlike for preadipocytes) showed a higher propensity to form V(IV) species, despite the prevalence of V(V) in the medium. The distinct V biochemistry in these cells is consistent with their crucial role in insulin-dependent glucose and fat metabolism and may also point to an endogenous role of V in adipocytes.
钒（V）和钒（IV）前药的抗糖尿病活性取决于它们与生物介质成分相互作用时释放活性物种的能力。使用HepG2（人肝癌细胞）、A549（人肺癌细胞）和3T3-L1（小鼠脂肪细胞和前脂肪细胞）细胞系以及相应的细胞培养基，对典型的钒（V）抗糖尿病药物钒酸盐（[V（V）O4]（3-），A）和钒（IV）双（麦芽酚）配合物（B）与哺乳动物细胞培养物的反应性进行了首次X射线吸收光谱研究。利用与钒（V）、钒（IV）和钒（III）模型配合物库的经验相关性分析了X射线吸收近边结构数据。在310K下，A和B（[V]=1.0 mM）在细胞培养基中24小时内逐渐收敛为主要是五配位和六配位V（V）物种的相似混合物（占总V的75%）。完整HepG2细胞中V的形态也随孵育时间而变化（从总V的20%到~70%的V（IV）），但很大程度上与所用前药（A或B）或培养基中主要的V氧化态无关。A549细胞的亚细胞分级分离表明，V（V）还原为V（IV）主要发生在细胞质中，而V（V）在细胞核中的积累可能是通过与组蛋白的非共价结合促进的。核V（V）可能调节转录过程，并最终与高浓度V时的细胞死亡有关，这在抗癌活性中可能很重要。成熟的3T3-L1脂肪细胞（与前脂肪细胞不同）显示出形成V（IV）物种的倾向更高，尽管培养基中V（V）占优势。这些细胞中独特的V生物化学与其在胰岛素依赖性葡萄糖和脂肪代谢中的关键作用一致，也可能表明V在脂肪细胞中的内源性作用。
