New Developments in the Comprehension of the Biotransformation and Transport of Insulin-Enhancing Vanadium Compounds in the Blood Serum

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Abstract

The possible biotransformations in the blood serum of four representative insulin-enhancing vanadium compounds, [VO(6-mepic)(2)], cis-[VO(pic)(2)(H(2)O)], [VO(acac)(2)], and [VO(dhp)(2)], where 6-mepic, pic, acac, and dhp indicate the deprotonated forms of 6-methylpicolinic and picolinic acids, acetylacetone, and 1,2-dimethyl-3-hydroxy-4(1H)-pyridinone, were examined. In particular, the behavior of the quinary systems formed by the insulin-enhancing species, human serum apo-transferrin (hTf), human serum albumin (HSA), and lactate (lact) or citrate (citr) at physiological pH and conditions was studied. The results indicate that, besides the case in which the ligand is very weak like 6-mepic, the carrier can interact in some form with VO(2+) ion until its intake into the cell. In fact with stronger ligands like pic, acac, and dhp, VO(2+) is transported not only by transferrin but also as [VO(carrier)(2)] and as mixed species VO(2+)-hTF-carrier. There are two ways in which the undissociated form of a bis-chelated complex can interact with transferrin, one "specific" when the carrier possesses a carboxylate group and behaves like a synergistic anion, and another "non-specific" when an imidazole nitrogen of a histidine residue from hTf replaces an equatorially coordinated water molecule giving rise to a ternary species with cis-octahedral geometry and cis-VO(carrier)(2)(hTf) stoichiometry. It is found that also albumin can participate in the transport of an insulin-enhancing compound forming a mixed species cis-VO(carrier)(2)(HSA), when the carrier stabilizes in aqueous solution the cis-octahedral form, or the dinuclear compound (VO)(2)(d)HSA, when the carrier forms unstable complexes. These insights were confirmed through density functional theory (DFT) calculations.

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