title: 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.
authors.affiliation: Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, Canada, V6T 1Z1.
authors.forename: Barry D
authors.initials: BD
authors.lastname: Liboiron
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Thompson
authors.forename: Graeme R
authors.initials: GR
authors.lastname: Hanson
authors.forename: Edmond
authors.initials: E
authors.lastname: Lam
authors.forename: Nicolas
authors.initials: N
authors.lastname: Aebischer
authors.forename: Chris
authors.initials: C
authors.lastname: Orvig
mesh_terms: D001059:Apoproteins / Q000737:chemistry* / Q000378:metabolism*; D001711:Biotransformation; D004357:Drug Synergism; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D007700:Kinetics; D008970:Molecular Weight; D011753:Pyrones / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism*; D014168:Transferrin / Q000737:chemistry* / Q000378:metabolism*; D014638:Vanadates / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D017968:Vanadium Compounds / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D001059:Apoproteins; D007093:Imidazoles; D007328:Insulin; D011753:Pyrones; D012709:Serum Albumin; D014168:Transferrin; D017968:Vanadium Compounds; C028284:apotransferrin; C074212:bis(maltolato)oxovanadium(IV); D014638:Vanadates; C034028:vanadyl sulfate; C018100:1-methylimidazole