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PubMed1999

Vanadium and diabetes.

Vanadium is an ultratrace element, widely distributed in nature, yet with no presently known specific physiological function in mammals. The apparent role of vanadium in regulation of intracellular signaling, as a cofactor of enzymes essential in energy metabolism, and as a possible therapeutic agent in diabetes is of increasing interest as more and more research reports present evidence of vanadium's potentially unique biological function. In this mini-review, the author summarizes current knowledge of the bioinorganic chemistry of vanadium, the basic features of diabetes mellitus and its metabolic sequelae, and the in vitro and in vivo effects of both inorganic and organically-chelated vanadium compounds. Results of clinical trials to date, as well as kinetic studies of tissue uptake are covered. Examples of ways to enhance the positive effects of vanadium as an oral therapeutic adjunct in diabetic control, while minimizing potential toxicity, are compared with regard to desirable features and possible drawbacks.

Animals↗
PubMed1993

Non-insulin-like action of sodium orthovanadate in the isolated perfused liver of fed, non-diabetic rats.

Vanadium compounds exert insulin-like effects on isolated rat adipocytes and skeletal muscle and improve glucose homeostasis in diabetic rats and mice. However, reports on metabolic actions of vanadium in the liver are still contradictory. Thus, the acute effect of sodium orthovanadate infusion on net glucose production was measured in isolated perfused livers of non-fasting, non-diabetic rats. Continuous infusion (0.2 ml/min; 90 min) of vanadate (10-500 mumol/l) rapidly increased hepatic glucose (p < 0.001), but not cyclic AMP output, reaching peak values after 20 min. The cumulative glucose release displayed concentration dependence with a maximal net effect of 394.3 mumol/100 g body weight and an apparent half-maximal effective vanadate concentration of 19.6 mumol/l. The glycogenolytic response to vanadate was almost completely blocked by 100 mU/l insulin (p < 0.005), by 0.1 mmol/l indomethacin (p < 0.05) and in the absence of Ca2+ (p < 0.001). These results indicate that sodium orthovanadate stimulates glycogenolysis in livers of fed, non-diabetic rats by a Ca(2+)-dependent mechanism, which may involve the release of prostaglandins.

Animals↗
PubMed1989

Importance of hydroxyl radical in the vanadium-stimulated oxidation of NADH.

Vanadium compounds are known to stimulate the oxidation of NAD(P)H, but the mechanism remains unclear. This reaction was studied spectrophotometrically and by electron spin resonance spectroscopy (ESR) using vanadium in the reduced state (+4, vanadyl) and the oxidized state (+5, vanadate). In 25 mM sodium phosphate buffer at pH 7.4, vanadyl was slightly more effective in stimulating NADH oxidation than was vanadate. Addition of a superoxide generating system, xanthine/xanthine oxidase, resulted in a marked increase in NADH oxidation by vanadyl, and to a lesser extent, by vanadate. Decreasing the pH with superoxide present increased NADH oxidation for both vanadate and vanadyl. Addition of hydrogen peroxide to the reaction mixture did not change the NADH oxidation by vanadate, regardless of concentration or pH. With vanadyl however, addition of hydrogen peroxide greatly enhanced NADH oxidation which further increased with lower pH. Use of the spin trap DMPO in reaction mixtures containing vanadyl and hydrogen peroxide or a superoxide generating system resulted in the detection by ESR of hydroxyl. In each case, the hydroxyl radical signal intensity increased with vanadium concentration. Catalase was able to inhibit the formation of the DMPO--OH adduct formed by vanadate plus superoxide. These results show that the ability of vanadium to act in a Fenton-type reaction is an important process in the vanadium-stimulated oxidation of NADH.

Cyclic N-Oxides↗
PubMed2002

Structural basis for inhibition of protein tyrosine phosphatases by Keggin compounds phosphomolybdate and phosphotungstate.

Protein-tyrosine phosphatases (PTPs) constitute a family of receptor-like, and cytoplasmic enzymes, which catalyze the dephosphorylation of phosphotyrosine residues in a variety of receptors and signaling molecules. Together with protein tyrosine kinases (PTKs), PTPs are critically involved in regulating many cellular signaling processes. In this study, diverse compounds were screened for PTP inhibition and selectively screened for inhibitors with the end product inhibition properties. Among phosphate analogues and their derivatives for PTP inhibition, Keggin compounds phosphomolybdate (PM) and phosphotungstate (PT) strongly inhibited both PTP-1B and SHP-1, with K(i) values of 0.06-1.2 micromM in the presence of EDTA. Unlike the vanadium compounds, inhibition potencies of PM and PT were not significantly affected by EDTA. PM and PT were potent, competitive inhibitors for PTPs, but relatively poor inhibitors of Ser/Thr phosphatase. Interestingly, PM and PT did not inhibit alkaline phosphatase at all. The crystal structure of PTP-1B in complex with PM, at 2.0 A resolution, reveals that MoO(3), derived from PM by hydrolysis, binds at the active site. The molybdenium atom of the inhibitor is coordinated with six ligands: three oxo-ligands, two apical water molecules and a S atom of the catalytic cysteine residue. In support of the crystallographic finding, we observed that molybdenium oxides (MoO(3), MoO(2), and MoO(2)Cl(2)) inhibited PTP-1B with IC(50) in the range 5-15 micromM.

Binding, Competitive↗
PubMed2005

Assessment of the in vivo genotoxicity of vanadate: analysis of micronuclei and DNA damage induced in mice by oral exposure.

Vanadium compounds are able to interact with living cells exerting a variety of biological effects. The pentavalent form is the most stable and toxic form of the element. In systems in vitro pentavalent vanadium is an effective genotoxic agent, inducing DNA damage and chromosome malsegregation at low doses. On the other hand, no adequate in vivo data are available for the characterization of the genotoxic hazard following oral intake, the most relevant route of human exposure. In this study, the genotoxic effects produced by the oral intake of sodium ortho-vanadate (Na(3)VO(4)) were investigated. Male CD-1 mice were treated for 5 weeks with a range of concentrations of Na(3)VO(4) in drinking water (0.75-1500 mg/l). Both micronuclei and primary DNA lesions as detected by comet assay were assessed in several tissues. Statistically significant increases of micronuclei in bone marrow were observed in mice receiving the two highest concentrations of Na(3)VO(4) (750 and 1500 mg/l). A significant increase of comet tail length was observed in splenocytes of mice receiving Na(3)VO(4) at 1500 mg/l, whereas no effect was observed in bone marrow and testis cells. No treatment-related effect on sperm chromatin structure or on testis cell population was observed. The determination of vanadium content in mouse tissues at the end of treatment highlighted a very low internal exposure, especially in soft tissues. Overall, the results obtained indicate that the genotoxic activity of pentavalent vanadium is expressed in vivo only following high dose exposure, possibly as a consequence of the poor bioavailability of the element.

Administration, Oral↗
PubMedDate not supplied

In vitro and in vivo antineoplastic effects of orthovanadate.

In the present study we have demonstrated that orthovanadate at concentrations of 5-10 uM is cytotoxic to proliferating cells including primary cultures and tumour cell lines. However, concentrations of up to 50 uM did not affect the viability of non-proliferating cells. The cytotoxicity appears to be dependent on the vanadium concentration rather than on the oxidation state of vanadium or the vanadium compound. Furthermore, tumour cell lines with different proliferative rates were equally sensitive to orthovanadate cytotoxicity. Although the mechanisms responsible for the cytotoxicity are not known, addition of H2O2 potentiated orthovanadate cytotoxicity suggesting that hydroxyl or vanadium radicals may be involved. In vivo subcutaneous injections of orthovanadate into mice containing MDAY-D2 tumours resulted in the inhibition of tumour growth by 85-100%. These data indicated that orthovanadate at concentrations greater than 5 uM has antineoplastic properties and may be useful as a chemotherapeutic agent.

Animals↗
PubMed1997

Influence of vanadate on glycolysis, intracellular sodium, and pH in perfused rat hearts.

Vanadium compounds have been shown to cause a variety of biological and metabolic effects including inhibition of certain enzymes, alteration of contractile function, and as an insulin like regulator of glucose metabolism. However, the influence of vanadium on metabolic and ionic changes in hearts remains to be understood. In this study we have examined the influence of vanadate on glucose metabolism and sodium transport in isolated perfused rat hearts. Hearts were perfused with 10 mM glucose and varying vanadate concentrations (0.7-100 microM) while changes in high energy phosphates (ATP and phosphocreatine (PCr)), intracellular pH, and intracellular sodium were monitored using 31P and 23Na NMR spectroscopy. Tissue lactate, glycogen, and (Na+, K+)-ATPase activity were also measured using biochemical assays. Under baseline conditions, vanadate increased tissue glycogen levels two fold and reduced (Na+, K+)-ATPase activity. Significant decreases in ATP and PCr were observed in the presence of vanadate, with little change in intracellular pH. These changes under baseline conditions were less severe when the hearts were perfused with glucose, palmitate and beta-hydroxybutyrate. During ischemia vanadate did not limit the rise in intracellular sodium, but slowed sodium recovery on reperfusion. The presence of vanadate during ischemia resulted in attenuation of acidosis, and reduced lactate accumulation. Reperfusion in the presence of vanadate resulted in a slower ATP recovery, while intracellular pH and PCr recovery was not affected. These results indicate that vanadate alters glucose utilization and (Na+, K+)-ATPase activity and thereby influences the response of the myocardium to an ischemic insult.

3-Hydroxybutyric Acid↗
PubMed1983

[Effect of metavanadate on papillary water uptake].

It has been examined the influence of vanadium on the papillary osmotic water-salts uptake in order to differentiate it from water flow of other biological substrates as amphibia epithelia. Between the different vanadium compounds only the metavanadate is active and only after administration in the abdominal vein. The general influence of metavanadate is a facilitating one and concerns: electrical receptor afferent discharge, osmotic water uptake and ciliary motility. At the papillary level therefore vanadium is not at all an inhibitory agent as observed in many biological substrates. This observation rule out any analogy in the processes of water inflow operating respectively at the fungiform papillae and amphibia epithelia.

Animals↗
PubMed1999

Possible mechanism of action of vanadium ions as an antidiabetic agent.

Vanadium compounds, at much higher concentrations than they are typically ingested, are being considered for use in the treatment of diabetes mellitus. They exert an insulin-mimetic effect in an insulin-receptor-independent manner. In our study we obtained new data about the vanadium insulin-receptor-independent mechanism of action on cell membranes. When rat stomach smooth muscle samples are treated with NH4VO3 (10(-7) divided by 10(-5) this action is possibly exhibited with increased influx of Ca2+ through VDCa2+C.

Animals↗
PubMed2005

The first enantioselective synthesis of the amavadin ligand and its complexation to vanadium.

The ligand of the naturally occurring vanadium compound amavadin found in Amanita muscaria, (2S, 2'S)-N-hydroxyimino-2,2'-dipropionic acid (1), was synthesized stereoselectively in two steps with 43% overall yield. After complexation of this ligand to vanadyl acetate, amavadin was isolated in quantitative yield. Due to the chirality at vanadium amavadin consists of a mixture of delta and lambda diastereoisomers. Directly after its synthesis, the delta to lambda ratio of amavadin is 2.27 and it decreases to 0.80 after equilibrium has been reached. During this epimerization the optical rotation for V[(2S,2'S)-N-hydroxyimino-(2,2')-dipropionate]2 (=amavadin) changes from [alpha](D)25 = +36 degrees to +114.0 degrees (c = 0.5, H2O). For V[(2R,2'R)-N-hydroxyimino-(2,2')-dipropionate] the optical rotation changes from [alpha](D)25 = -36 degrees to -113.2 degrees (c = 0.5, H2O).

Alanine↗
PubMed1993

Oral vanadate and Tiron in treatment of diabetes mellitus in rats: improvement of glucose homeostasis and negative side-effects.

It has been shown that improvement of glucose homeostasis by oral vanadate or vanadyl treatment in streptozotocin-induced diabetic rats is accompanied by severe negative side effects (some deaths, decreased weight gain, alteration in renal function as well as tissue vanadium accumulation) which argue against the use of vanadium compounds in diabetes treatment. The present study was undertaken to assess the effectiveness in alleviating some signs of diabetes in streptozotocin-treated rats with oral therapy with sodium metavanadate (NaVO3) and sodium 4,5 dihydroxybenzene-1,3-disulfonate (Tiron), a chelating agent effective in mobilizing vanadium. In a preliminary experiment, diabetic rats were given aqueous solutions of 0.20 mg NaVO3/ml for 4 days. Vanadium-treated rats which showed blood glucose levels significantly lower (p < 0.001) than vanadate-untreated diabetic rats were selected for subsequent experiments. These animals were given 0.20 mg NaVO3/ml in drinking water and 0, 125.6, 314 or 628 mg Tiron/kg/d by gavage for 2 w. Although most of the animals did not become normoglycemic, several characteristic signs of diabetes (hyperglycemia, hyperphagia and polydipsia) were alleviated by the NaVO3 treatment. The administration of 314 mg Tiron/kg/d (approximately 1 NaVO3: 5 Tiron, mole ratio) did not diminish the ameliorative effects of NaVO3 with respect to diabetes, but significantly decreased the level of vanadium accumulation in target organs. These results show that some of the beneficial effects of NaVO3 are maintained in diabetic animals given Tiron, while the administration of the chelator results in a significant decrease in tissue vanadium accumulation. Accordingly, this would diminish the possibility of toxic side effects derived from prolonged oral vanadium administration.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed2006

Insulin signal mimicry as a mechanism for the insulin-like effects of vanadium.

Among several metals, vanadium has emerged as an extremely potent agent with insulin-like properties. These insulin-like properties have been demonstrated in isolated cells, tissues, different animal models of type I and type II diabetes as well as a limited number of human subjects. Vanadium treatment has been found to improve abnormalities of carbohydrate and lipid metabolism and of gene expression in rodent models of diabetes. In isolated cells, it enhances glucose transport, glycogen and lipid synthesis, and inhibits gluconeogenesis and lipolysis. The molecular mechanism responsible for the insulin-like effects of vanadium compounds have been shown to involve the activation of several key components of insulin-signaling pathways that include the mitogen-activated-protein kinases (MAPKs) extracellular signal-regulated kinase 1/2 (ERK1/2) and p38MAPK, and phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB). It is interesting that the vanadium effect on these signaling systems is independent of insulin receptor protein tyrosine kinase activity, but it is associated with enhanced tyrosine phosphorylation of insulin receptor substrate-1. These actions seem to be secondary to vanadium-induced inhibition of protein tyrosine phosphatases. Because MAPK and PI3-K/PKB pathways are implicated in mediating the mitogenic and metabolic effects of insulin, respectively, it is plausible that mimicry of these pathways by vanadium serves as a mechanism for its insulin-like responses.

Animals↗
PubMed1999

Effect of age on vanadium nephrotoxicity in rats.

The present study was designed to assess potential age dependent differences of vanadium nephrotoxicity in the rat following parenteral administration of vanadate. Young (22 days) and adult (62 days) male Sprague-Dawley rats received i.p. injections of sodium orthovanadate at 10 mg/kg/day for 8 consecutive days. Two additional groups of control rats received i.p. injections of 0.9% saline during the same period. Significant age-differences were found in most of the parameters used as indicators of nephrotoxicity in young and adult rats, with adverse renal effects being more severe with age. Vanadium-induced morphologic changes in the kidney were also more pronounced with age. These findings agree with a higher renal concentration of vanadium in the group of adult rats treated with vanadate than in the vanadate-untreated group. The current results can be of concern if in the future, vanadium compounds can be administered in the treatment of diabetic patients.

Aging↗
PubMed1997

Elevated blood pressure in spontaneously hypertensive rats consuming a high sucrose diet is associated with elevated angiotensin II and is reversed by vanadium.

OBJECTIVE: To determine the changes in serum angiotensin II (Ang II) and endothelin-1 levels induced by vanadium treatment of sugar-fed rats in order to investigate the relationship between changes in blood pressure and Ang II and endothelin-1 levels. METHODS: Male spontaneously hypertensive rats (SHR) were fed starch (control), sucrose, and sucrose plus vanadium compounds at various concentrations. The systolic blood pressure of the rats was estimated by tail-cuff plethysmography. Serum Ang II and endothelin-1 levels were measured by radioimmunoassay. RESULTS: There were increases in systolic blood pressure (by 8%) and in serum Ang II (by 20%) in sucrose-fed SHR compared with control. In sucrose plus vanadium-fed SHR, the lowering of the systolic blood pressure (by 11-16% of the sucrose-fed value) was accompanied by a significant decrease in Ang II levels (by 25-60% of the sucrose-fed value) and an increase in endothelin-1 level (by 61-76% of the sucrose-fed value). CONCLUSION: That Ang II levels are elevated in sucrose-induced hypertension and decreased after vanadium therapy suggests that the renin-angiotensin system plays a role in the induction of hypertension in this model. On the other hand, the elevation of endothelin-1 levels associated with a decreased systolic blood pressure might be secondary to vanadium stimulation of endothelial cells. The data suggest that endothelin-1 is not involved in sugar-induced elevations of the blood pressure.

Angiotensin II↗
PubMed1989

Contractile responses of the guinea-pig vas deferens to the combination of vanadium ions with ouabain.

1. Vanadate and vanadyl ions (10(-5)-10(-2) M) induced dose-dependent rhythmic contractions of the vas deferens of reserpine-treated guinea-pigs. The Na, K-ATPase blocker ouabain (10(-5)-10(-3) M) induced similar, though smaller, effects. Experiments were performed to verify if these effects are due to an interaction with the same receptor population. 2. Ouabain caused a striking potentiation of vanadium effects, which was also observed in denervated organs, indicating that a release of neuronal substances is not involved in potentiation. Similar potentiations were observed by combining vanadium with K-free solutions instead of ouabain, corroborating the involvement of the latter drug with Na, K, ATPase. 3. From the analysis of time-response and concentration-response curves, there are at least three indications that vanadium and ouabain interact with different sites: (a) the combined effect of both agonists was several times higher than the corresponding isolated effects; (b) the combined effect, expected to be independent of the order of addition of the agonist, was higher if vanadium was added before, than after ouabain; (c) the combined effect on the time elapsed between the addition of the two agonists, being higher if an interval of at least 10 min was allowed between vanadium and ouabain additions. 4. In conclusion, our results do not support the hypothesis that vanadium compounds and ouabain have a similar mechanism of action for the contraction induced in guinea-pig vas deferens.

Animals↗
PubMed2006

Synthesis and characterization of the octahydrotriborate complexes Cp*V(B3H8)2 and Cp*Cr(B3H8)2 and the unusual cobaltaborane cluster Cp*2Co2(B6H14).

The new compounds CpV(B(3)H(8))(2), CpCr(B(3)H(8))(2), and Cp(2)Co(2)(B(6)H(14)) have been synthesized by treating the pentamethylcyclopentadienyl complexes [CpVCl(2)](3), [CpCrCl(2)](2), and [CpCoCl](2) with NaB(3)H(8). X-ray crystallography shows that CpV(B(3)H(8))(2) and CpCr(B(3)H(8))(2) have the same ligand sets but different molecular structures: the vanadium compound contains two bidentate B(3)H(8) ligands (i.e., bound to the metal center via two vicinal hydrogen atoms), whereas the chromium compound has one bidentate B(3)H(8) ligand and one B(3)H(8) ligand bound in an unprecedented fashion via two geminal hydrogen atoms. The "gem-bound" B(3)H(8) group itself has an atypical structure consisting of a BH(2)-BH(2)-BH(3) triangle with one additional hydrogen atom bridging the unique BH(2)-BH(2) edge. The B-B distances are nearly identical within experimental error at 1.790(5), 1.792(5), and 1.786(6) Angstrom. The relationship between the electronic and molecular structures of the V and Cr compounds is briefly discussed. The structure of Cp(2)Co(2)(B(6)H(14)) can be viewed in two different ways: as a dicobalt complex in which two CpCo units are each bound to four adjacent boron atoms of an S-shaped B(6)H(14) ligand, or as an eight-vertex hypho cluster compound. In the former case, the B(6)H(14) ligand is best regarded as a dianionic bi-borallyl group H(3)B(mu-H)BH(mu-H)BHBH(mu-H)BH(mu-H)BH(3) in which one hydrogen at each end of the chain is involved in an agostic interaction. From a cluster point of view, the structure of Cp(2)Co(2)(B(6)H(14)) can be generated by removing three adjacent high-connectivity vertices from the eleven-vertex closo polyhedron. The Co-B distances vary from 2.008(5) to 2.183(4) Angstrom, and the B-B distances within in the S-shaped chain range from 1.734(8) to 1.889(6) Angstrom. Finally, a new synthesis of the known molybdenum compound Cp(2)Mo(2)(B(5)H(9)) is described; its structure as established by X-ray crystallography closely resembles that of the previously described (C(5)H(4)Me) analogue.

Journal Article↗
PubMed1978

Similarity in metabolic patterns of different chemical species of vanadium in the rat.

To gain information about the influence of the oxidation state of vanadium on its metabolic behavior, different 48V-labeled vanadium compounds, such as cationic VO2+(V), VO2+(IV), V3+(III), and anionic V4O12(3-)(V), VS4(3-)(V) species were prepared and intravenously injected into rats. The 48V radioactivity was measured in whole tissues as well as in nuclei, mitochondria, lysosomes, microsomes, and cytosols from liver and kidney homogenates. The distribution of 48V radioactivity between the plasma components was investigated using gel filtration of the 48V-labeled plasma. The findings indicate that there are common pathways of the different chemical forms of vanadium in animals. The similarities are referred to the distribution in different tissues and their intracellular distribution as well as to the transport in the blood, in which 48V was always found in the plasma bound to transferrin. The results obtained tend to exclude a possible influence of the oxidation state of vanadium on its metabolism and support the existence in the body of two mechanisms of conversion of different chemical forms of vanadium ions to one with the same valence.

Animals↗
PubMed2004

Morphology and biochemical activity of rat liver golgi complexes after pretreatment with bis(kojato)oxovanadium(IV) or kojic acid alone.

The authors studied the effect of a short (2 days) oral treatment of rats with bis(kojato)oxovanadium (IV) [VO(ka)2] as 1.8 mmol liquid solution on the biochemical activity and morphology of liver Golgi complexes (Group pVC). Such a short treatment induced greater changes than a longer (1 week) application of the same vanadium compound, what had been observed previously. Especially the Golgi marker enzyme activity (GalT) was the highest among all the investigated groups, and additionally, the greatest dispersion of result was obtained in this group. This group of animals showed twisted Golgi complexes, which--apart from 2-3 narrow cisterns--often contained 1-2 grossly distended cisterns filled with clear, floccular contents. The fairly long cisterns were irregular in shape and were often bent, forming ring-like structures. In the second experiment, we studied the effect of the ligand alone (kojic acid) (Group C+ka2) employed in the same way as in the case of the previously used vanadium complex (time and concentration). The biochemical parameters (body and liver weight, liquid and food intake, blood sugar level and GalT activities) were the same as in the untreated control group (C). Contrary to the biochemical findings, the morphology of Golgi complexes changed in effect of 3.6 mmol kojic acid application (the same application, time and concentration as in the whole complex with vanadium) over a 1-week period, manifesting the stimulation of exocytosis (in the trans region and directed toward plasma membrane), with the cisterns of Golgi dictyosomes being rounded or oval in more than 85% of cases. In this group, electron microscopy revealed the presence of two types of Golgi complexes, namely 2-3 short, slightly arched cisterns grossly distended at both ends and filled with clear, floccular material, as well as vacuoles with the same contents, which were visible in the vicinity of the cisterns. The other type, which was observed less frequently, was represented by Golgi complexes formed by haphazardly twisted cisterns.

Administration, Oral↗