Interaction of vanadium complexes with red blood cells

Vanadium complexes have been studied as potential insulin-enhancing agents for the treatment of type 2 diabetes [1] and, more recently, as potential anti-tumor agents [2]. After oral or parenteral administration, the V complexes interact with red blood cells in the bloodstream. Therefore, this interaction has a crucial importance in determining the amount of complex which reaches the target organs. Once inside the red blood cells the metal species can: i) survive in an inactivated form, ii) exert its effects or iii) be excreted. The interaction of V(V) and V(IV) complexes with erythrocytes was studied by EPR spectroscopy in order to understand the mechanism of transport across the erythrocyte membrane and the speciation inside the red blood cells. When starting with V(V) complexes the metal ion is reduced inside the red blood cells and EPR active V(IV)O2+ complexes are found, confirming data already known in the literature [3]. The speciation and the mechanism of transport across the membrane depends on the stability of the V(V) complex under examination: stable V(V) complexes at physiological pH, like those formed by 1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate (dhp), [VO2(dhp)2]-, do not cross the membrane using the AE1 (anion exchanger 1) channel and their transport is not hindered by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), while the transport of unstable V(V) complexes, like those formed by picolinate (pic), takes place through AE1 channels and is inhibited by DIDS. The experimental results show that, when the V(V)-pic system is considered, the ligand picolinate and vanadate(V) cross independently the erythrocyte membrane and inside the red blood cells the V(IV)O2+ complexes of picolinate are found. The complex [V(IV)O(pic)2(H2O)] forms inside the red blood cells mixed complexes with proteins after the replacement of the equatorial water molecule by imidazole nitrogen of histidine and thiolate of cysteine side chain donors. The V(V) complex of dhp is reduced inside the red blood cells and the same species are found inside the erythrocytes as those detected when starting with [V(IV)O(dhp)2]. These results demonstrate that: i) when two oxidation states are available for a specific metal ion, unstable complexes in the extracellular medium could became stable species inside the erythrocytes, ii) metals and ligands could cross the erythrocyte membrane independently and form stable complexes inside the red blood cells.