Vanadium, transferrin binding

Vanadium in the plasma can exist in a bound or unbound form (Bruech et al. 1984). Vanadium as vanadyl (Patterson et al. 1986) or vanadate (Harris and Carrano 1984) reversibly binds to human serum transferrin at two metalbinding sites on the protein. With intravenous administration of vanadate or vanadyl, there is a short lag time for vanadate binding to transferrin, but, at 30 hours, the association is identical for the two vanadium forms (Harris et al. 1984). The vanadium-transferrin binding is most likely to occur with the vanadyl form as this complex is more stable (Harris et al. 

Vanadium can bind to transferrins in three different oxidation states. V(III) has been reported (131) as giving an air-stable complex with transferrin, probably as the simple cation V3+ the corresponding lactoferrin complex of V(III) is, however, extremely air sensitive, being oxidized in minutes (156), and the transferrin result has been questioned (133). V(IV) forms a colorless complex with transferrins, shown by EPR spectroscopy to incorporate the vanadyl (V02+) ion (155). Displacement studies show that the V02+ ions occupy the specific Fe3+ sites... 

Vanadate transport in the erythrocyte was shown to occur via facilitated diffusion in erythrocyte membranes and was inhibited by 4,4 -diisothiocyanostilbene-2,2 -disulfonic acid (DIDS), a specific inhibitor of the band 3 anion transport protein [23], Vanadium is also believed to enter cells as the vanadyl ion, presumably through cationic facilitated diffusion systems. The divalent metal transporter 1 protein (called DMT1, and also known as Nramp2), which carries iron into cells in the gastrointestinal system and out of endosomes in the transferrin cycle [24], has been proposed to also transport the vanadyl cation. In animal systems, specific transport protein systems facilitate the transport of vanadium across membranes into the cell and between cellular compartments, whereas the transport of vanadium through fluids in the organism occurs via binding to proteins that may not be specific to vanadium. 

There is further evidence that V(V) may be converted to V02+ in serum, which then binds to the iron transport protein transferrin. This hypothesis is supported by the observation of Hopkins that vanadium, a few hours after injection, becomes associated with transferring. Sabbioni and Marafante176 have also observed a small amount of vanadium bound to serum transferrin. However, in their experiments, and those of Hopkins, no precautions appear to have been taken to protect the vanadium from oxidation during the protein separation steps. Under these conditions, most VOz+ associated with transferrin may be lost from the protein. The possibility that vanadate(V) binds to transferrin has not been investigated. If, in fact, most of the vanadium is bound to transferrin after a few hours, this could explain the failure of red cells to acquire much of the metal. These cells have relatively few receptor sites for the protein. 

There is circumstantial evidence for a link between vanadium and iron metabolism (see Ref. 8). For example, in addition to the data discussed above, rats and chicks on low vanadium diets show elevated blood and bone iron levels and increased hematocrits, respectively. Sabbioni and coworkers186 have shown that some vanadium introduced as V02+ into bovine milk becomes associated with lactoferrin and that vanadium bound to transferrin can exchange with ferritin when cellular components are present187. However, precautions against air oxidation of V02+ were also not taken in these experiments. Very low levels of vanadium were found associated with these proteins relative to their binding capacity. 

Vanadium is an element, and as such, is not metabolized. However, in the body, there is an interconversion of two oxidation states of vanadium, the tetravalent form, vanadyl (V+4), and the pentavalent form, vanadate (V+5). Vanadium can reversibly bind to transferrin protein in the blood and then be taken up into erythrocytes. These two factors may affect the biphasic clearance of vanadium that occurs in the blood. Vanadate is considered more toxic than vanadyl, because vanadate is reactive with a number of enzymes and is a potent inhibitor of the Na+K+-ATPase of plasma membranes (Harris et al. 1984 Patterson et al. 1986). There is a slower uptake of vanadyl into erythrocytes compared to the vanadate form. Five minutes after an intravenous administration of radiolabeled vanadate or vandadyl in dogs, 30% of the vanadate dose and 12% of the vanadyl dose is found in erythrocytes (Harris et al. 1984). It is suggested that this difference in uptake is due to the time required for the vanadyl form to be oxidized to vanadate. When V+4 or V+5 is administered intravenously, a balance is reached in which vanadium moves in and out of the cells at a rate that is comparable to the rate of vanadium removal from the blood (Harris et al. 1984). Initially, vanadyl leaves the blood more rapidly than vandate, possibly due to the slower uptake of vanadyl into cells (Harris et al. 1984). Five hours after administration, blood clearance is essentially identical for the two forms. A decrease in glutathione, NADPH, and NADH occurs within an hour after intraperitoneal injection of sodium vanadate in mice (Bruech et al. 1984). It is believed that vanadate requires these cytochrome P-450 components for oxidation to the vanadyl form. A consequence of this action is the diversion of electrons from the monooxygenase system resulting in the inhibition of drug dealkylation (Bruech et al. 1984). 

Nagaoka MH, Yamazaki T and Maitani T (2002) Binding patterns of vanadium ions with different valence states to human serum transferrin studied by HPLC/high-resolution ICP-MS. Biochem Biophys Res Commun 296 1207-1214. 

A likely difference in the metabolism of free and chelated sources lies in post-absorptive processes, particularly transport in the bloodstream. The study of the interactions of insulin-enhancing compounds with serum proteins has been almost exclusively studied by EPR. Apo-transferrin and albumin have been implicated in the transport of vanadyl ions in the blood, and these proteins represent a significant metal-binding capability in the blood. Considerable interest in the role of these proteins in the transport and biotransformation of administered vanadium compounds has been evident in the recent literature. 

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