In vivo coordination structural changes of a potent insulin-mimetic agent, bis(picolinato)oxovanadium(IV), studied by electron spin-echo envelope modulation spectroscopy

Abstract

Bis(picolinato)oxovanadium(IV) [VO(pic) 2] is one of the most potent insulin-mimetic vanadium complexes. To probe coordination structural changes of this complex in vivo and provide insights into the origin of its high potency, an electron spin-echo envelope modulation (ESEEM) study was performed on organs (kidney, liver and bone) of VO(pic) 2- and VOSO 4-treated rats. Kidney and liver samples from both types of rats exhibited a 14N ESEEM signal that could be attributed to equatorially coordinating amine nitrogen. The relative intensity of the amine signal was larger for the organs of the rat treated with the less potent VOSO 4, suggesting that this amine coordination inhibits the insulin-mimetic activity. The spectra of kidney and liver from the VO(pic) 2-treated rat contained a weak signal due to the picolinate imine nitrogen. This suggests that some picolinato species (including both the bispicolinato and a partially decomposed monopicolinato species) still exist in the organs as a minor species, where the proportions of the picolinato species to the total amount of the EPR-detectable V IVO species are estimated as 8–16% in the kidney and 12–24% in the liver. The picolinate ligand presumably serves to prevent VO 2+ from being converted into the inactive amine-coordinated species. Bone samples from both types of rats exhibited an ESEEM signal due to 31P nuclei. The VO 2+ in bone is therefore most likely incorporated into the hydroxyapatite Ca 10(PO 4) 6(OH) 2 matrix, which is consistent with the hypothesis that the bone-accumulated VO 2+ is gradually released and transported to other organs as is Ca 2+. No 14N signals were observed, even in the bone samples of the VO(pic) 2-treated rats, indicating that vanadium uptake by bone requires complete decomposition of the complex.