title: Reactivity and Speciation of Anti-Diabetic Vanadium Complexes in Whole Blood and Its Components: The Important Role of Red Blood Cells.
abstract: Reactions with blood components are crucial for controlling the antidiabetic, anticancer, and other biological activities of V(V) and V(IV) complexes. Despite extensive studies of V(V) and V(IV) reactions with the major blood proteins (albumin and transferrin), reactions with whole blood and red blood cells (RBC) have been studied rarely. A detailed speciation study of Na3[V(V)O4] (A), K4[V(IV)2O2(citr)2]·6H2O (B; citr = citrato(4-)); [V(IV)O(ma)2] (C; ma = maltolato(-)), and (NH4)[V(V)(O)2(dipic)] (D; dipic = pyridine-2,6-dicarboxylato(2-)) in whole rat blood, freshly isolated rat plasma, and commercial bovine serum using X-ray absorption near-edge structure (XANES) spectroscopy is reported. The latter two compounds are potential oral antidiabetic drugs, and the former two are likely to represent their typical decomposition products in gastrointestinal media. XANES spectral speciation was performed by principal component analysis and multiple linear regression techniques, and the distribution of V between RBC and plasma fractions was measured by electrothermal atomic absorption spectroscopy. Reactions of A, C, or D with whole blood (1.0 mM V, 1-6 h at 310 K) led to accumulation of ∼50% of total V in the RBC fraction (∼10% in the case of B), which indicated that RBC act as V carriers to peripheral organs. The spectra of V products in RBC were independent of the initial V complex, and were best fitted by a combination of V(IV)-carbohydrate (2-hydroxyacid moieties) and/or citrate (65-85%) and V(V)-protein (15-35%) models. The presence of RBC created a more reducing environment in the plasma fraction of whole blood compared with those in isolated plasma or serum, as shown by the differences in distribution of V(IV) and V(V) species in the reaction products of A-D in these media. At physiologically relevant V concentrations (<50 μM), this role of RBC may promote the formation of V(III)-transferrin as a major V carrier in the blood plasma. The results reported herein have broad implications for the roles of RBC in the transport and speciation of metal pro-drugs that have broad applications across medicine.
authors.affiliation: †School of Chemistry, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: Aviva
authors.initials: A
authors.lastname: Levina
authors.affiliation: †School of Chemistry, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: McLeod
authors.affiliation: †School of Chemistry, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: Sylvia J
authors.initials: SJ
authors.lastname: Gasparini
authors.affiliation: †School of Chemistry, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: Annie
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: †School of Chemistry, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: W G Manori
authors.initials: WG
authors.lastname: De Silva
authors.affiliation: †School of Chemistry, The University of Sydney, Sydney NSW 2006, Australia.|‡Australian Synchrotron, 800 Blackburn Rd., Clayton VIC 3168, Australia.
authors.forename: Jade B
authors.initials: JB
authors.lastname: Aitken
authors.affiliation: †School of Chemistry, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: Hugh H
authors.initials: HH
authors.lastname: Harris
authors.affiliation: ‡Australian Synchrotron, 800 Blackburn Rd., Clayton VIC 3168, Australia.
authors.forename: Chris
authors.initials: C
authors.lastname: Glover
authors.affiliation: ‡Australian Synchrotron, 800 Blackburn Rd., Clayton VIC 3168, Australia.
authors.forename: Bernt
authors.initials: B
authors.lastname: Johannessen
authors.affiliation: †School of Chemistry, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Lay
mesh_terms: D000818:Animals; D001692:Biological Transport; D001798:Blood Proteins / Q000378:metabolism; D002417:Cattle; D004912:Erythrocytes / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000378:metabolism*; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D014639:Vanadium / Q000737:chemistry*; D056928:X-Ray Absorption Spectroscopy
chemical_list: D001798:Blood Proteins; D007004:Hypoglycemic Agents; D009942:Organometallic Compounds; D014639:Vanadium