Interaction of Antidiabetic Vanadium Compounds with Hemoglobin and Red Blood Cells and Their Distribution between Plasma and Erythrocytes

The interaction of VIVO2+ ion with hemoglobin (Hb) was studied with the combined application of spectroscopic (EPR), spectrophotometric (UV-vis), and computational (DFT methods) techniques. Binding of Hb to VIVO2+ in vitro was proved, and three unspecific sites (named alpha, beta, and gamma) were characterized, with the probable coordination of His-N, Asp-O-, and Glu-O- donors. The value of log beta for (VO)Hb is 10.4, significantly lower than for human serum apo-transferrin (hTf). In the systems with VIVO potential antidiabetic compounds, mixed species cis-VOL2(Hb) (L = maltolate (ma), 1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate (dhp)) are observed with equatorial binding of an accessible His residue, whereas no ternary complexes are observed with acetylacetonate (acac). The experiments of uptake of [VO(ma)2], [VO(dhp)2], and [VO(acac)2] by red blood cells indicate that the neutral compounds penetrate the erythrocyte membrane through passive diffusion, and percent amounts higher than 50% are found in the intracellular medium. The biotransformation of [VO(ma)2], [VO(dhp)2], and [VO(acac)2] inside the red blood cells was proved. [VO(dhp)2] transforms quantitatively in cis-VO(dhp)2(Hb), [VO(ma)2] in cis-VO(ma)2(Hb), and cis-VO(ma)2(Cys-S-), with the equatorial coordination of a thiolate-S- of GSH or of a membrane protein, and [VO(acac)2] in the binary species (VO)xHb and two VIVO complexes with formulation VO(L1,L2) and VO(L3,L4), where L1, L2, L3, and L4 are red blood cell bioligands. The results indicate that, in the studies on the transport of a potential pharmacologically active V species, the interaction with red blood cells and Hb cannot be neglected, that a distribution between the erythrocytes and plasma is achieved, and that these processes can significantly influence the effectiveness of a V drug.