Comparative studies on the biospeciation of antidiabetic VO(IV) and Zn(II) complexes Tamás Kiss a,b, * , Tamás Jakusch b , Dominik Hollender b , Éva Anna Enyedy a, * , László Horváth a a Department of Inorganic and Analytical Chemistry, University of Szeged, P.O. Box 440, Szeged H-6701, Hungary b Bioinorganic Chemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, P.O. Box 440, Szeged H-6701, Hungary article info Article history: Received 30 September 2008 Received in revised form 7 November 2008 Accepted 12 November 2008 Available online 27 November 2008 Keywords: VO(IV) complexes Zn(II) complexes Biospeciation Insulin-mimesis Ultrafiltration abstract The speciation of several insulin-mimetic/enhancing VO(IV) and Zn(II) complexes in human blood serum was studied and a comparison was made concerning the ability of the serum components to interact with the original metal complexes and the distribution of the metal ions between the low and the high molec- ular fractions of the serum. It was found that the low molecular mass components may play a larger role in transporting Zn(II) than in the case with VO(IV). Among the high molecular mass serum proteins, transferrin is the primary binder of VO(IV), and albumin is that of Zn(II). The results revealed that pro- tein–ligand interactions may influence the metal ion distribution in the serum. Ó 2008 Elsevier Inc. All rights reserved. 1. Introduction Diabetes mellitus is currently one of the most widespread dis- eases. The number of patients with diabetes is increasing year by year, and in 2006 it reached approximately 250 million worldwide. Over the last 25 years ions of metals such as Cr, Mn, Mo, W, V and Zn have been reported to exhibit insulin-like effects. Among these elements, V has proved to be one of the most efficient in this re- spect. Even simple inorganic V salts in oxidation state of +4 or +5 (e.g. vanadyl sulfate or sodium vanadate) have been shown to mi- mic most of the physiological effects of insulin, such as the stimu- lation of glucose uptake and metabolism in fat cells, the enhancement of glycogenesis in the muscles and liver, the inhibi- tion of gluconeogenesis from lipids or proteins, the stimulation of fatty acid formation in the adipocytes [1]. The main advantage of these V compounds over insulin is that they may be administered orally. Accordingly, one aim of the research in this field is to pre- pare V compounds which can reach the target cells with high effi- cacy. Large numbers of VO(IV) and V(V) complexes have been prepared and tested; one of them [VO(maltol) 2 ] has passed clinical phase 1 [2,3] and 2 [4] tests in Canada. The experimental conditions of preparation of metal complexes with potential biological activity usually differ considerably from the milieu in living systems where they exert their biological ef- fects. The solvent and the pH of the biological fluids, cells and tis- sues can differ significantly. Metal complexes with well-defined stoichiometry and structure in the solid state will decompose or dissociate after dissolution in biological fluids and tissues and sooner or later will attain the thermodynamic equilibrium state determined by the stability constants of the metal complex exist- ing at physiological pH. This thermodynamic equilibrium may re- quire merely seconds in the case of labile metal complexes (e.g. of Mn(II), V(IV) and Zn(II)), but it can take days or even weeks, as in the case of Cr(III) or the isopolyacids or heteropolyacids of W(VI)). Accordingly, complexes of the former metal ions will be present in thermodynamic equilibrium shortly after their adminis- tration; whereas the latter complexes may not change during the time they spend in the body and will leave it without undergoing any significant change. These equilibrium speciations can be repre- sented by the concentration distribution curves of the complexes formed in the metal–ligand systems and calculated by the stability constants determined in the usual solution speciation studies for the given experimental conditions (e.g. a metal ion to ligand ratio of 1:2 when the solid complex is a bis complex, and pH around neutral for physiological conditions). The same solution composi- tion can be achieved simply by making a sample containing the metal ion and the ligand in the given composition and adjusting the pH to the desired value. As an illustration, the decomposi- tion/dissociation processes of the VO(IV)–maltolate system [5–7] 0162-0134/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.jinorgbio.2008.11.006 * Corresponding authors. Address: Department of Inorganic and Analytical Chemistry, University of Szeged, P.O. Box 440, Szeged H-6701, Hungary (T. Kiss), Tel.: +36 62 544337; fax: +36 62 420505. E-mail addresses: tkiss@chem.u-szeged.hu (T. Kiss), enyedy@chem.u-szeged.hu (É.A. Enyedy). Journal of Inorganic Biochemistry 103 (2009) 527–535 Contents lists available at ScienceDirect Journal of Inorganic Biochemistry journal homepage: www.elsevier.com/locate/jinorgbio brought to you by CORE View metadata, citation and similar papers at core.ac.uk provided by SZTE Publicatio Repozitórium - SZTE - Repository of Publications