The structural basis of action of vanadyl (VO2+) chelates in cells

Abstract Much emphasis has been given to vanadium compounds as potential therapeutic reagents for the treatment of diabetes mellitus. Thus far, no vanadium compound has proven efficacious for long-term treatment of this disease in humans. Therefore, in review of the research literature, our goal has been to identify properties of vanadium compounds that are likely to favor physiological and biochemical compatibility for further development as therapeutic reagents. We have, therefore, limited our review to those vanadium compounds that have been used in both in vivo experiments with small, laboratory animals and in in vitro studies with primary or cultured cell systems and for which pharmacokinetic and pharmacodynamics results have been reported, including vanadium tissue content, vanadium and ligand lifetime in the bloodstream, structure in solution, and interaction with serum transport proteins. Only vanadyl (VO2+) chelates fulfill these requirements despite the large variety of vanadium compounds of different oxidation states, ligand structure, and coordination geometry synthesized as potential therapeutic agents. Extensive review of research results obtained with use of organic VO2+-chelates shows that the vanadyl chelate bis(acetylacetonato)oxidovanadium(IV) [VO(acac)2], exhibits the greatest capacity to enhance insulin receptor kinase activity in cells compared to other organic VO2+-chelates, is associated with a dose-dependent capacity to lower plasma glucose in diabetic laboratory animals, and exhibits a sufficiently long lifetime in the blood stream to allow correlation of its dose-dependent action with blood vanadium content. The properties underlying this behavior appear to be its high stability and capacity to remain intact upon binding to serum albumin. We relate the capacity to remain intact upon binding to serum albumin to the requirement to undergo transcytosis through the vascular endothelium to gain access to target tissues in the extravascular space. Serum albumin, as the most abundant transport protein in the blood stream, serves commonly as the carrier protein for small molecules, and transcytosis of albumin through capillary endothelium is regulated by a Src protein tyrosine kinase system. In this respect it is of interest to note that inorganic VO2+ has the capacity to enhance insulin receptor kinase activity of intact 3T3-L1 adipocytes in the presence of albumin, albeit weak; however, in the presence of transferrin no activation is observed. In addition to facilitating glucose uptake, the capacity of VO2+-chelates for insulin-like, antilipolytic action in primary adipocytes has also been reviewed. We conclude that measurement of inhibition of release of only free fatty acids from adipocytes stimulated by epinephrine is not a sufficient basis to ascribe the observations to purely insulin-mimetic, antilipolytic action. Adipocytes are known to contain both phosphodiesterase-3 and phosphodiesterase-4 (PDE3 and PDE4) isozymes, of which insulin antagonizes lipolysis only through PDE3B. It is not known whether the other isozyme in adipocytes is influenced directly by VO2+-chelates. In efforts to promote improved development of VO2+-chelates for therapeutic purposes, we propose synergism of a reagent with insulin as a criterion for evaluating physiological and biochemical specificity of action. We highlight two organic compounds that exhibit synergism with insulin in cellular assays. Interestingly, the only VO2+-chelate for which this property has been demonstrated, thus far, is VO(acac)2.