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Biologically relevant physical studies of insulin-enhancing vanadium complexes Liboiron, Barry D.

Abstract

Investigations of the in vivo transport and accumulation of insulin-enhancing vanadium complexes are presented. Detailed spectroscopic studies of bis(maltolato)oxovanadium(IV) (BMOV), bis(ethylmaltolato)oxovanadium(IV) (BEOV) and the inorganic salt vanadyl sulfate (VOSO4) were carried out on in vitro solutions of serum proteins, and in vivo tissue samples from animals previously treated with a vanadium complex. Serum proteins apo-transferrin and albumin are both capable of effecting the decomposition of BMOV and BEOV under physiological conditions (pH 7.4, 0.16 M NaCl) to form vanadyl-protein adducts. Interactions of these complexes with the proteins were studied by continuous wave electron paramagnetic resonance (EPR) and difference ultraviolet spectroscopies. Apo-transferrin can bind up to two equivalents of BMOV at the Fe(III) binding sites, but (bi)carbonate (or another suitable synergistic anion) must be present for vanadyl binding to take place. The inability of maltolate to act in this role is demonstrated. Chelated vanadyl sources show no preference for either the N - or C-terminus binding site. Albumin binds BMOV only at the strong Cu(II) binding site; the presence of maltol imparts a site selectivity to the system in that BMOV will not bind at exposed carboxylates. Through consideration of the active equilbria in solution, formation of a ternary maltol-vanadyl-albumin complex is proposed and discussed in terms of reactivity differences between BMOV and VOS04 and transport of chelated vanadyl sources in the bloodstream. Pulsed EPR methods - electron spin echo envelope modulation (ESEEM) and hyperfine sublevel correlation (HYSCORE) - were used to study the in vivo coordination of vanadyl ions in rat kidney, liver and bone samples, which had been previously taken from animals chronically administered BEOV via drinking water. The chelated vanadyl source becomes ligated by amines in the kidney and liver, and by as many as three different phosphate groups in bone mineral. Model studies of the vanadyl-triphosphate and vanadylhydroxyapatite systems were also studied to gain structural insights into the in vivo coordination state of the vanadyl ions in bone. Both systems proved to be very good models of the in vivo complex. Based on the number and relative magnitudes of the isotropic and anisotropic ³¹P and ¹H coupling constants, a proposed solution structure, consistent with all spectroscopic data, is presented.

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