New Insights into the Interactions of Serum Proteins with Bis(maltolato)oxovanadium(IV):  Transport and Biotransformation of Insulin-Enhancing Vanadium Pharmaceuticals

Abstract

Significant new insights into the interactions of the potent insulin-enhancing compound bis(maltolato)oxovanadium(IV) (BMOV) with the serum proteins, apo-transferrin and albumin, are presented. Identical reaction products are observed by electron paramagnetic resonance (EPR) with either BMOV or vanadyl sulfate (VOSO4) in solutions of human serum apo-transferrin. Further detailed study rules out the presence of a ternary ligand-vanadyl-transferrin complex proposed previously. By contrast, differences in reaction products are observed for the interactions of BMOV and VOSO4 with human serum albumin (HSA), wherein adduct formation between albumin and BMOV is detected. In BMOV-albumin solutions, vanadyl ions are bound in a unique manner not observed in comparable solutions of VOSO4 and albumin. Presentation of chelated vanadyl ions precludes binding at the numerous nonspecific sites and produces a unique EPR spectrum which is assigned to a BMOV-HSA adduct. The adduct species cannot be produced, however, from a solution of VOSO4 and HSA titrated with maltol. Addition of maltol to a VOSO4-HSA solution instead results in formation of a different end product which has been assigned as a ternary complex, VO(ma)(HSA). Furthermore, analysis of solution equilibria using a model system of BMOV with 1-methylimidazole (formation constant log K1 = 4.5(1), by difference electronic absorption spectroscopy) lends support to an adduct binding mode (VO(ma)2-HSA) proposed herein for BMOV and HSA. This detailed report of an in vitro reactivity difference between VOSO4 and BMOV may have bearing on the form of active vanadium metabolites delivered to target tissues. Albumin binding of vanadium chelates is seen to have a potentially dramatic effect on pharmacokinetics, transport, and efficacy of these antidiabetic chelates.

Chemistry and Biochemistry of Insulin-Mimetic Vanadium and Zinc Complexes. Trial for Treatment of Diabetes Mellitus

“…16 The sensitively of the EPR parameters reflects the coordination environment around vanadyl ion. Therefore, the interaction of vanadyl complexes with blood serum components, such as oxalic acid, 19 lactic acid, 19 citric acid, 19 phosphoric acid, 30 saccharic acid, 18 mucic acid, 18 catecholamines, 31 apo-transferin, 32 and albumin, 32 has been extensively investigated by means of EPR spectroscopy. EPR spectra of various freshly isolated organs, such as liver and kidney, were also measured to estimate the coordination environment around the detected vanadyl species in the organs.…”

A novel VIVO–pyrimidinone complex: synthesis, solution speciation and human serum protein binding

“…11,[18][19][20] Several vanadium complexes have been found to have higher insulin enhancing activities than inorganic oxovanadium(V) or oxovanadium(IV) salts, but probably this improved efficacy probably relates to the increased bioavailability of the metal ion when involved in a complex rather than to increased potency at the phosphatase enzyme active sites. [19][20][21][22][23] Among the several complexes exhibiting insulin enhancing properties, V IV O(maltolato) 2 (BMOV) and V IV O(ethylmaltolato) 2 (BEOV) have been extensively studied from the chemical and pharmacological points of view. 8,[21][22][23][24][25][26] Complexes with 3-hydroxy-4-pyrones (3,4-HP) have also been extensively studied.…”

“…[19][20][21][22][23] Among the several complexes exhibiting insulin enhancing properties, V IV O(maltolato) 2 (BMOV) and V IV O(ethylmaltolato) 2 (BEOV) have been extensively studied from the chemical and pharmacological points of view. 8,[21][22][23][24][25][26] Complexes with 3-hydroxy-4-pyrones (3,4-HP) have also been extensively studied. 19,[24][25][26][27][28][29] Replacement of the O atom of the pyrone ring by a N or N-R group yields pyridinone derivatives, and both families of compounds maintain the (O − , O − ) binding set, forming quite stable complexes with many metal ions.…”

“…22,23,40,[43][44][45][46][47][48][49][50] Transferrin (hTF) is a single-chain glycoprotein containing around 630 amino acids which are arranged in two similar lobes, and is important for iron transportation. It is present in human blood plasma in about 37 μM concentration.…”

“…Strong evidence has been provided to support that most of the vanadium in the serum is bound to hTF, even in the absence of HCO 3 − . 22,23,40,43,[48][49][50][51][52][53][54][55][56][57] The results indicate that two vanadium ions are bound to the metal-ion-free apo-hTF, at the usual specific Fe III binding sites. Under the physiological conditions, particularly in the hypothetical situation where the vanadium concentration is higher than ca.…”