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

The interaction of (VO2+)-O-IV 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 (VO2+)-O-IV 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 (VO)-O-IV 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) Hb and two (VO)-O-IV complexes with formulation VO(L-1,L-2) and VO(L-3,L-4), where L-1, L-2, L-3, and 1,4 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.