Interaction of antidiabetic vanadium compounds with hemoglobin and red blood cells and their distribution between plasma and erythrocytes.
The interaction of V(IV)O(2+) 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 V(IV)O(2+) in vitro was proved, and three unspecific sites (named α, β, and γ) were characterized, with the probable coordination of His-N, Asp-O(-), and Glu-O(-) donors. The value of log β for (VO)Hb is 10.4, significantly lower than for human serum apo-transferrin (hTf). In the systems with V(IV)O 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 V(IV)O complexes with formulation VO(L(1),L(2)) and VO(L(3),L(4)), where L(1), L(2), L(3), and L(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.
Istituto CNR di Chimica Biomolecolare , Trav. La Crucca 3, I-07040 Sassari, Italy.
Daniele
D
Sanna
Maria
M
Serra
Giovanni
G
Micera
Eugenio
E
Garribba
D000328:Adult; D004578:Electron Spin Resonance Spectroscopy; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D008958:Models, Molecular; D011485:Protein Binding; D014168:Transferrin / Q000378:metabolism; D017968:Vanadium Compounds / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics
D006454:Hemoglobins; D007004:Hypoglycemic Agents; D014168:Transferrin; D017968:Vanadium Compounds