bis(maltolato)oxovanadium(iv) and vanadyl-sulfate

Vanadyl sulfate (VOSO(4)) was given orally to 16 subjects with type 2 diabetes mellitus for 6 weeks at a dose of 25, 50, or 100 mg vanadium (V) daily [Goldfine et al., Metabolism 49 (2000) 1-12]. Elemental V was determined by graphite furnace atomic absorption spectrometry (GFAAS). There was no correlation of V in serum with clinical response, determined by reduction of mean fasting blood glucose or increased insulin sensitivity during euglycemic clamp. To investigate the effect of administering a coordinated V, plasma glucose levels were determined in streptozotocin (STZ)-induced diabetic rats treated with the salt (VOSO(4)) or the coordinated V compound bis(maltolato)oxovandium(IV) (abbreviated as VO(malto)(2)) administered by intraperitoneal (i.p.) injection. There was no relationship of blood V concentration with plasma glucose levels in the animals treated with VOSO(4), similar to our human diabetic patients. However, with VO(malto)(2) treatment, animals with low plasma glucose tended to have high blood V. To determine if V binding to serum proteins could diminish biologically active serum V, binding of both VOSO(4) and VO(malto)(2) to human serum albumin (HSA), human apoTransferrin (apoHTf) and pig immunoglobulin (IgG) was studied with EPR spectroscopy. Both VOSO(4) and VO(malto)(2) bound to HSA and apoHTf forming different V-protein complexes, while neither V compound bound to the IgG. VOSO(4) and VO(malto)(2) showed differences when levels of plasma glucose and blood V in diabetic rodents were compared, and in the formation of V-protein complexes with abundant serum proteins. These data suggest that binding of V compounds to ligands in blood, such as proteins, may affect the available pool of V for biological effects.

Topics: Animals; Apoproteins; Biological Availability; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Electron Spin Resonance Spectroscopy; Fasting; Humans; Hypoglycemic Agents; Immunoglobulin G; Male; Pyrones; Rats; Rats, Wistar; Serum Albumin; Streptozocin; Transferrin; Treatment Outcome; Vanadates; Vanadium; Vanadium Compounds

Rhabdomyosarcoma (RMS) cells were incubated with four vanadium compounds: cations BMOV and vanadyl sulphate, and anions ortho- and metavanadate. Growth inhibition of RMS cells in the culture was determined by two staining methods: with N-hexamethylpararosaniline (crystal violet = CV) or bromide 3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium (MTT). After 48 h incubation with 10-40 μM for NaVO3 or 20-40 μM for the other three vanadium salts, the results were statistically significantly lower (0.001 < p < 0.01) as compared to the controls (without vanadium in the medium). A vanadium concentration higher than 40 μM resulted in cell destruction or death in all cells. A comparison with our previously obtained results showed the greatest sensitivity of rat hepatoma H 35-19 cells in comparison to four human cancer cell lines (A549, DU145, HTB, RMS). Investigations of human cancer cells demonstrated that the highest resistance to orthovanadate was characteristic of RMS (c.40 μM) and HTB (c. 20 μM). Electron microscopic examination showed pleomorphic nuclei with visible amounts of heterochromatin and large nucleoli, characteristic of RMS cells. Cells at various stages of differentiation were observed.

Topics: Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Cell Survival; Cytoplasm; Drug Screening Assays, Antitumor; Humans; Pyrones; Rhabdomyosarcoma; Vanadates; Vanadium Compounds

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.

Topics: Apoproteins; Biotransformation; Drug Synergism; Electron Spin Resonance Spectroscopy; Humans; Imidazoles; Insulin; Kinetics; Molecular Weight; Pyrones; Serum Albumin; Transferrin; Vanadates; Vanadium Compounds

Today, vanadium compounds are frequently included in nutritional supplements and are also being developed for therapeutic use in diabetes mellitus. Previously, tissue uptake of vanadium from bis(maltolato)oxovanadium(IV) (BMOV) was shown to be increased compared to its uptake from vanadyl sulfate (VS). Our primary objective was to test the hypothesis that complexation increases vanadium uptake and that this effect is independent of oxidation state. A secondary objective was to compare the effects of vanadium complexation and oxidation state on tissue iron, copper, and zinc. Wistar rats were fed either ammonium metavanadate (AMV), VS, or BMOV (1.2 mM each in the drinking water). Tissue uptake of V following 12 wk of BMOV or AMV was higher than that from VS (p < 0.05). BMOV led to decreased tissue Zn and increased bone Fe content. The same three compounds were compared in a cellular model of absorption (Caco-2 cells). Vanadium uptake from VS was higher than that from BMOV or AMV at 10 min, but from BMOV (250 microM only, 60 min), uptake was far greater than from AMV or VS. These results show that neither complexation nor oxidation state alone are adequate predictors of relative absorption, tissue accumulation, or trace element interactions.

Topics: Animals; Biological Availability; Bone and Bones; Caco-2 Cells; Copper; Humans; Iron; Kidney; Male; Oxidation-Reduction; Pyrones; Rats; Rats, Wistar; Vanadates; Vanadium; Vanadium Compounds; Zinc

1. Vanadium compounds can mimic actions of insulin through alternative signalling pathways. The effects of three organic vanadium compounds were studied in non-ketotic, streptozotocin-diabetic rats: vanadyl acetylacetonate (VAc), vanadyl 3-ethylacetylacetonate (VEt), and bis(maltolato)oxovanadium (VM). A simple inorganic vanadium salt, vanadyl sulphate (VS) was also studied. 2. Oral administration of the three organic vanadium compounds (125 mg vanadium element 1(-1) in drinking fluids) for up to 3 months induced a faster and larger fall in glycemia (VAc being the most potent) than VS. Glucosuria and tolerance to a glucose load were improved accordingly. 3. Activities and mRNA levels of key glycolytic enzymes (glucokinase and L-type pyruvate kinase) which are suppressed in the diabetic liver, were restored by vanadium treatment. The organic forms showed greater efficacy than VS, especially VAc. 4. VAc rats exhibited the highest levels of plasma or tissue vanadium, most likely due to a greater intestinal absorption. However, VAc retained its potency when given as a single i.p. injection to diabetic rats. Moreover, there was no relationship between plasma or tissue vanadium levels and any parameters of glucose homeostasis and hepatic glucose metabolism. Thus, these data suggest that differences in potency between compounds are due to differences in their insulin-like properties. 5. There was no marked toxicity observed on hepatic or renal function. However, diarrhoea occurred in 50% of rats chronically treated with VS, but not in those receiving the organic compounds. 6. In conclusion, organic vanadium compounds, in particular VAc, correct the hyperglycemia and impaired hepatic glycolysis of diabetic rats more safely and potently than VS. This is not simply due to improved intestinal absorption, indicating more potent insulin-like properties.

Topics: Administration, Oral; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Disinfectants; Glucokinase; Glucose; Hydroxybutyrates; Hypoglycemic Agents; Injections, Intraperitoneal; Insulin; Islets of Langerhans; Ligands; Liver; Liver Glycogen; Male; Muscles; Organometallic Compounds; Pentanones; Phosphoenolpyruvate Carboxykinase (GTP); Pyrones; Pyruvate Kinase; Rats; Rats, Wistar; RNA, Messenger; Time Factors; Vanadates; Vanadium Compounds

Vanadium has been found to be orally active in lowering plasma glucose levels; thus it provides a potential treatment for diabetes mellitus. Bis(maltolato)oxovanadium(IV) (BMOV) is a well-characterized organovanadium compound that has been shown in preliminary studies to have a potentially useful absorption profile. Tissue distributions of BMOV compared with those of vanadyl sulfate (VS) were studied in Wistar rats by using 48V as a tracer. In this study, the compounds were administered in carrier-added forms by either oral gavage or intraperitoneal injection. Data analyzed by a compartmental model, by using simulation, analysis, and modeling (i.e., SAAM II) software, showed a pattern of increased tissue uptake with use of 48V-BMOV compared with 48VS. The highest 48V concentrations at 24 h after gavage were in bone, followed by kidney and liver. Most ingested 48V was eliminated unabsorbed by fecal excretion. On average, 48V concentrations in bone, kidney, and liver 24 h after oral administration of 48V-BMOV were two to three times higher than those of 48VS, which is consistent with the increased glucose-lowering potency of BMOV in acute glucose lowering compared with VS.

Topics: Animals; Computer Simulation; Hypoglycemic Agents; Male; Models, Biological; Pyrones; Rats; Rats, Wistar; Tissue Distribution; Vanadates; Vanadium Compounds

Controversial reports on the efficacy and possible toxicity of vanadium obtained from various studies may be attributed to differences in the method of diabetes induction and (or) to differences in animal strains. The objective of this study was to evaluate the contribution of these two factors to the effects of vanadium in the treatment of experimental diabetes. Two methods of streptozotocin induction of diabetes in rats have been used for studying the antidiabetic effects of vanadium. One involves a single intravenous injection of 60 mg/kg streptozotocin, and the other uses two subcutaneous injections of 40 mg/kg streptozotocin, to either Wistar or Sprague-Dawley rats. In a 7-week chronic study, Sprague-Dawley rats appeared to develop a more severe diabetes (indicated by higher plasma cholesterol and higher fasting plasma glucose levels) following the single intravenous injection of streptozotocin than rats made diabetic by two subcutaneous injections of streptozotocin. Irrespective of the method of diabetes induction, the responses of all the diabetic animals to chronic vanadyl sulphate treatment were similar. In an acute study, Wistar diabetic rats were more responsive than Sprague-Dawley diabetic rats to vanadyl sulphate and to lower doses (0.6 and 0.8 mmol/kg) of a new organic vanadium compound, bis(maltolato)oxovanadium(i.v.).

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Fatty Acids, Nonesterified; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Pyrones; Rats; Rats, Sprague-Dawley; Rats, Wistar; Streptozocin; Triglycerides; Vanadates; Vanadium Compounds

The mitogen-activated protein (MAP) kinases and ribosomal S6 protein kinases in the skeletal muscle of insulin-resistant long-term (2 and 6 months' duration) diabetic rats were investigated to understand further the changes in insulin intracellular signaling pathways that accompany diabetes. The effects of insulin-mimetic vanadium compounds on the activity of these kinases were also examined. In the insulin-resistant 2-month diabetic rats, the basal activities of MAP kinases were relatively unchanged, while the basal activities of S6 kinases were significantly increased. Intravenous injection of insulin moderately activated both the 42-kDa MAP kinase (p42mapk) and a 44-kDa MAP kinase (p44erk1) in the 2-month control rats but not in the 2-month diabetic rats. Insulin treatment markedly stimulated the activity of a novel 31-kDa S6 kinase and the previously described 90-kDa ribosomal S6 kinase encoded by one of the rsk genes (p90rsk) in the 2-month control rats, while the effect was substantially reduced in the diabetic rats. In the 6-month diabetic rats, the basal phosphotransferase activities of both MAP kinases were depressed threefold or greater. This correlated with reductions in the amount of immunoreactive p42mapk and p44erk1 proteins in extracts from the diabetic rats. The basal activity of the 31-kDa S6 kinase activity was also reduced fourfold in the 6-month diabetic rats. Treatment of the 2-month diabetic rats with vanadyl sulfate resulted in euglycemia, prevented the increase in the basal activity of S6 kinase, and improved the activation of S6 kinase by insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinases; Chromatography, Ion Exchange; Diabetes Mellitus, Experimental; Hypoglycemic Agents; Insulin; Insulin Resistance; Kinetics; Muscle, Skeletal; Protein Serine-Threonine Kinases; Pyrones; Rats; Rats, Wistar; Reference Values; Ribosomal Protein S6 Kinases; Ribosomes; Time Factors; Vanadates; Vanadium; Vanadium Compounds

Numerous studies, both in vitro and in vivo, have demonstrated the insulin-mimetic properties of vanadium. Chronic oral administration of inorganic and organic compounds of both vanadium(IV) and vanadium(V) reduced plasma glucose levels and restored plasma lipid levels in streptozotocin-diabetic rats. We investigated the acute effects of both vanadyl sulfate and bis(maltolato)oxovanadium(IV) (BMOV), an organic vanadium compound, on plasma glucose levels by several routes of administration. Previous studies have shown that chronic administration of vanadyl sulfate has resulted in a sustained euglycemia following withdrawal of the drug. This effect was not observed following the chronic administration of BMOV; therefore, we investigated the effect of increasing the concentration of BMOV on the production of a sustained euglycemic response. An acute plasma glucose lowering effect was obtained with both vanadyl sulfate and BMOV when administered as a single dose by either oral gavage or intraperitoneal injection. In those animals that responded to vanadium treatment, plasma glucose levels were within the normal range within 2 to 6 h when given by i.p. injection or within 4 to 8 h when given by oral gavage. BMOV-treated rats that responded to treatment maintained the euglycemic effect for extended periods, ranging from 1 to 14 weeks following administration. However, vanadyl sulfate treated rats reverted to hyperglycemia within 12 to 24 h, depending on the route of administration. Intravenous administration of BMOV was effective in lowering plasma glucose levels only when administered by continuous infusion. An oral dose-response curve showed that BMOV was 2 to 3 times as potent as vanadyl sulfate. This difference in potency was observed with both oral and intraperitoneal administration, which suggests that the increase in potency with BMOV cannot be totally attributed to increased gastrointestinal absorption. Organic chelation of vanadium may facilitate uptake into vanadium-sensitive tissues. Chronic oral administration of higher concentrations of BMOV did not result in a sustained reduction in plasma glucose following withdrawal of the drug. All diabetic rats eventually responded to increased concentrations of BMOV with a restoration of plasma glucose levels to normal values; however, reversion to the hyperglycemic state occurred within 2 days of withdrawal of treatment. Chronic oral administration of BMOV did not produce a sustained euglycemic effect follow

Topics: Administration, Oral; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Hypoglycemic Agents; Injections, Intraperitoneal; Injections, Intravenous; Male; Pyrones; Rats; Rats, Wistar; Time Factors; Vanadates; Vanadium Compounds