Internal dose of vanadium in rats following repeated exposure to vanadyl sulfate and sodium orthovanadate via drinking water.

Vanadium is a ubiquitous environmental contaminant that exists in multiple oxidation states. Humans are exposed to vanadyl (V4+) and vanadate (V5+) from dietary supplements, food, and drinking water and hence there is a concern for adverse human health. The current investigation is aimed at identifying vanadium oxidation states in vitro and in vivo and internal concentrations following exposure of rats to vanadyl sulfate (V4+) or sodium metavanadate (V5+) via drinking water for 14 d. Investigations in simulated gastric and intestinal fluids showed that V4+ was stable in gastric fluid while V5+ was stable in intestinal fluid. Analysis of rodent plasma showed that the only vanadium present was V4+, regardless of the exposed compound suggesting conversion of V5+ to V4+ in vivo and/or instability of V5+ species in biological matrices. Plasma, blood, and liver concentrations of total vanadium, after normalizing for vanadium dose consumed, were higher in male and female rats following exposure to V5+ than to V4+. Following exposure to either V4+ or V5+, the total vanadium concentration in plasma was 2- to 3-fold higher than in blood suggesting plasma as a better matrix than blood for measuring vanadium in future work. Liver to blood ratios were 4-7 demonstrating significant tissue retention following exposure to both compounds. In conclusion, these data point to potential differences in absorption and disposition properties of V4+ and V5+ salts and may explain the higher sensitivity in rats following drinking water exposure to V5+ than V4+ and highlights the importance of internal dose determination in toxicology studies.

Response to vanadate exposure in Ochrobactrum tritici strains.

Vanadium is a transition metal that has been added recently to the EU list of Raw Critical Metals. The growing needs of vanadium primarily in the steel industry justify its increasing economic value. However, because mining of vanadium sources (i. e. ores, concentrates and vanadiferous slags) is expanding, so is vanadium environmental contamination. Bioleaching comes forth as smart strategy to deal with supply demand and environmental contamination. It requires organisms that are able to mobilize the metal and at the same time are resistant to the leachate generated. Here, we investigated the molecular mechanisms underlying vanadium resistance in Ochrobactrum tritici strains. The highly resistant strain 5bvl1 was able to grow at concentrations > 30 mM vanadate, while the O. tritici type strain only tolerated < 3 mM vanadate concentrations. Screening of O. tritici single mutants (chrA, chrC, chrF and recA) growth during vanadate exposure revealed that vanadate resistance was associated with chromate resistance mechanisms (in particular ChrA, an efflux pump and ChrC, a superoxide dismutase). We also showed that sensitivity to vanadate was correlated with increased accumulation of vanadate intracellularly, while in resistant cells this was not found. Other up-regulated proteins found during vanadate exposure were ABC transporters for methionine and iron, suggesting that cellular responses to vanadate toxicity may also induce changes in unspecific transport and chelation of vanadate.

Vanadium ionic species from degradation of Ti-6Al-4V metallic implants: In vitro cytotoxicity and speciation evaluation.

Among the metallic materials used in biomedical industry, the most common choice for orthopedics and dental implants is titanium (Ti) and its alloys, mainly due to their superior corrosion and tribocorrosion resistance and biocompatibility. Under different conditions in vivo, such as different pH levels, composition of body fluid and mechanical loads, metallic materials may suffer from degradation, resulting in the release of undesired wear particles and ions. In particular, the Ti-6Al-4V system represents almost half of the production of Ti as a biomaterial and many concerns have been raised about titanium, aluminum and vanadium ions releasing. This work evaluates the cytotoxic effects of vanadium ionic species generated from Ti-6Al-4V surfaces regarding mouse pre-osteoblasts and fibroblasts. In our cell viability tests, we noticed a significant decrease in the fibroblasts' cell viability with vanadium concentrations (23 µM) close to those previously reported to be observed in vivo in patients with poor functioning of their medical devices based on Ti-6Al-4V (30 µM). Speciation modelling was carried-out, for the first time, to this system. Results of the modelling reveal that vanadates(V), namely H2VO4- and HVO42-, are the main species present in cell culture media. Otherwise, in synovial fluids of individuals with poorly functioning implants, wherein the concentration of vanadium may go up to ca. 30 µM, the tentative theoretical speciation data indicates a high occurrence probability for VV- and VIV-species bound to albumin and hyaluronic acid. In conclusion, even though relatively low concentrations of vanadium may be released from Ti-6Al-4V implants in vivo, the continuous contact with peri-implant cells for long periods of time may represent a potentially hazardous situation.

Inhibition and stimulation of the human breast cancer resistance protein as in vitro predictor of drug-drug interactions of drugs of abuse.

Transporter-mediated drug-drug interactions (DDI) may induce adverse clinical events. As drugs of abuse (DOA) are marketed without preclinical safety studies, only very limited information about interplay with membrane transporters are available. Therefore, 13 DOA of various classes were tested for their in vitro affinity to the human breast cancer resistance protein (hBCRP), an important efflux transporter. As adenosine 5'-triphosphate (ATP) hydrolysis is crucial for hBCRP activity, adenosine 5'-diphosphate (ADP) formation was measured and used as in vitro marker for hBCRP ATPase activity. ADP quantification was performed by hydrophilic interaction liquid chromatography coupled to high-resolution tandem mass spectrometry and its amount in test compound incubations was compared to that in reference incubations using the hBCRP substrate sulfasalazine or the hBCRP inhibitor orthovanadate. If DOA caused stimulation or inhibition, further investigations such as Michaelis-Menten kinetic modeling or IC50 value determination were conducted. Among the tested DOA, seven compounds showed statistically significant hBCRP ATPase stimulation. The entactogen 3,4-BDB and the plant alkaloid mitragynine were identified as strongest stimulators. Their affinity to the hBCRP ATPase was lower than that of sulfasalazine but comparable to that of rosuvastatin, another hBCRP model substrate. Five DOA showed statistically significant hBCRP ATPase inhibition. Determination of IC50 values identified the synthetic cannabinoid receptor agonists JWH-200 and WIN 55,212-2 as the strongest inhibitors comparable to orthovanadate. The present study clearly demonstrated that tested DOA show in part high affinities to the hBCRP within the range of model substrates or inhibitors. Thus, there is a risk of hBCRP-mediated DDI, which needs to be considered in clinical settings.

Evaluation of cellular uptake, cytotoxicity and cellular ultrastructural effects of heteroleptic oxidovanadium(IV) complexes of salicylaldimines and polypyridyl ligands.

Searching for prospective vanadium-based drugs for cancer treatment, a new series of structurally related [VIVO(L-2H)(NN)] compounds (1-8) was developed. They include a double deprotonated salicylaldimine Schiff base ligand (L-2H) and different NN-polypyridyl co-ligands having DNA intercalating capacity. Compounds were characterized in solid state and in solution. EPR spectroscopy suggests that the NN ligands act as bidentate and bind through both nitrogen donor atoms in an axial-equatorial mode. The cytotoxicity was evaluated in human tumoral cells (ovarian A2780, breast MCF7, prostate PC3). The cytotoxic activity was dependent on type of cell and incubation time. At 24h PC3 cells presented low sensitivity, but at 72h all complexes showed high cytotoxic activity in all cells. Human kidney HEK293 and ovarian cisplatin resistant A2780cisR cells were also included to evaluate selectivity towards cancer cells and potency to overcome cisplatin resistance, respectively. Most complexes showed no detectable interaction with plasmid DNA, except 2 and 7 which depicted low ability to induce single strand breaks in supercoiled DNA. Based on the overall cytotoxic profile, complexes with 2,2´-bipyridine and 1,10-phenanthroline ligands (1 and 2) were selected for further studies, which consisted on cellular distribution and ultrastructural analyses. In the A2780 cells both depicted different distribution profiles; the former accumulates mostly at the membrane and the latter in the cytoskeleton. Morphology of treated cells showed nuclear atypia and membrane alterations, more severe for 1. Complexes induce different cell death pathways, predominantly necrosis for 1 and apoptosis for 2. Complexes alternative mode of cell death motivates the possibility for further developments.

Vanadium bioavailability in soils amended with blast furnace slag.

Blast furnace (BF) slags are commonly applied as soil amendments and in road fill material. In Sweden they are also naturally high in vanadium. The aim of this study was to assess the vanadium bioavailability in BF slags when applied to soil. Two soils were amended with up to 29% BF slag (containing 800 mg V kg(-1)) and equilibrated outdoors for 10 months before conducting a barley shoot growth assay. Additional soil samples were spiked with dissolved vanadate(V) for which assays were conducted two weeks (freshly spiked) and 10 months (aged) after spiking. The BF slag vanadium was dominated by vanadium(III) as shown by V K-edge XANES spectroscopy. In contrast, results obtained by HPLC-ICP-MS showed that vanadium(V), the most toxic vanadium species, was predominant in the soil solution. Barley shoot growth was not affected by the BF slag additions. This was likely due to limited dissolution of vanadium from the BF slag, preventing an increase of dissolved vanadium above toxic thresholds. The difference in vanadium bioavailability among treatments was explained by the vanadium concentration in the soil solution. It was concluded that the vanadium in BF slag is sparingly available. These findings should be of importance in environmental risk assessment.

Hypoglycemic, lipid-lowering and metabolic regulation activities of metforminium decavanadate (H2Metf)3 [V10O28]·8H2O using hypercaloric-induced carbohydrate and lipid deregulation in Wistar rats as biological model.

Because of the increasing global spread of type 2 diabetes mellitus, there is a need to develop new antidiabetic agents. Recently we have synthesized new decavanadates using metformin as counterion. In particular, the compound containing three metforminium dications has been obtained in high yield and has been completely characterized. Biological studies using Wistar rats that have been fed with a high caloric diet inducing insulin resistance and metabolic syndrome were carried out. Results of the impact on key biochemical parameters mediated by metformin alone and the new compound are here presented. The metforminium decavanadate (H2Metf)3[V10O28]·8H2O, abbreviated as Metf-V10O28, was shown to have pharmacological potential as a hypoglycemic, lipid-lowering and metabolic regulator, since the resulting compound made of the two components with antidiabetic activities, reduces both dosage and time of administration (twice a week). Hence, due to the beneficial effects induced by the metforminium decavanadate we recommend to continue the exploration into the mechanism and toxicology of this new compound.

Astrogliosis and HSP 70 activation in neonate rats' brain exposed to sodium metavanadate through lactation.

The effect of sodium metavanadate (NaVO3) exposure on lipid oxidative damage in the CNS of suckling rats was studied. Using histological markers of cellular injury, we also studied the morphological alterations of neurons and astroglial cells in different regions of neonate rats CNS after NaVO3 exposure. Dams of treated litters were intraperitoneally injected with 3mgNaVO3/kgbody weight/day during 12days starting on post-natal day (PND) 10. On the 21st PND, four pups of each litter were sacrificed by decapitation and six brain areas were removed for lipid peroxidation assay by the thiobarbituric acid (TBA) reaction, the other four were transcardially perfused-fixed and their brains were removed and cut with a cryostat. Brain sections were processed for: NADPHd histochemistry and anti-HSP70, anti-GFAP and anti-S100 immunohistochemistry. The relative optical density of the NADPHd stained layers and of S100 (+) astrocytes and the GFAP (+) astrocyte surface area in Cer and Hc were measured. Although MDA levels, S100 immunostaining and NADPHd activity didn't show differences between experimental and control groups, both astrogliosis and HSP70 activation were detected in Cer, while only the former was detected in Hc of V-exposed pups.

Transport of the anti-diabetic VO2+ complexes formed by pyrone derivatives in the blood serum.

The biotransformation in the blood serum of the two anti-diabetic agents [VO(ema)(2)] - or BEOV - and [VO(koj)(2)] formed by ethylmaltol (Hema) and kojic acid (Hkoj) was studied with EPR spectroscopy, pH-potentiometry and DFT calculations. For comparison, the behavior of the systems with tropolone (Htrop) was also analyzed. The interaction of [VO(ema)(2)] and [VO(koj)(2)] with the most important bioligands of the serum, lactic (Hlact) and citric acid (H(3)citr), human serum transferrin (hTf), human serum albumin (HSA) and immunoglobulin G (IgG) was examined and discussed. Among the several mixed species observed, cis-VO(carrier)(2)(hTf), cis-VO(carrier)(2)(HSA) and cis-VO(carrier)(2)(IgG), where carrier is ethylmaltolate or kojate, with a His-N of the protein coordinated in the equatorial position, are plausible candidates for the transport processes of the drug toward the target organs. The values of the logß are in the range 19.6-19.8 for the species formed by ethylmaltol and 17.4-17.6 for those formed by kojic acid. The formation of such species was confirmed through pH-titrations of the model systems VO(2+)/carrier/1-MeIm and VO(2+)/carrier/Ac-his, where 1-MeIm and Ac-his are 1-methylimidazole and N-acetylhistamine, and DFT calculations of (51)V A(z) of the model species cis-[VO(carrier)(2)(1-MeIm)] and cis-[VO(carrier)(2)(Ac-his)]. The values of the stability constants for the mixed species observed were used to predict the biodistribution of VO(2+) ion between the blood serum components for concentrations of 1, 10 and 50 µM.

Effect of 12-week vanadate and magnesium co-administration on chosen haematological parameters as well as on some indices of iron and copper metabolism and biomarkers of oxidative stress in rats.

Changes in some blood parameters after 12-week administration of sodium metavanadate (SMV; 0.125mgV/ml) or/and magnesium sulphate (MS; 0.06mgMg/ml) in drinking water were studied in outbred male Wistar rats (16 rats/each group) to explore the probable mechanism(s) underlying SMV toxicity and check whether Mg at the level selected during SMV co-administration can protect, at least in part, from a possible deleterious action of SMV. Exposure to SMV alone and in combination with MS (a) led to a decrease in fluid and food intake and body weight gain; (b) predisposed the animals to the development of microcytic-hypochromic anaemia (with excessive liver and spleen Fe deposition, unaltered plasma Fe level and enhanced Zn concentration in the erythrocytes (RBCs) characterized by a reduced haematocrit (Ht) index and haemoglobin (Hb) level, unchanged erythrocyte and reticulocyte count, anisocytosis, lowered total iron binding capacity (TIBC) and elevated transferrin saturation (TS); (c) disturbed Cu homeostasis, but (d) did not influence the leukocyte count and the plasma total antioxidant status (TAS). We suggest that abnormal metabolism and accumulation of Fe as well as an altered Cu status and the RBC Zn level might lead to defective Fe utilization and be a factor promoting the development of Fe-utilization anaemia. The disturbances in the antioxidative capacity reported previously in rats' RBCs after SMV intoxication (Scibior, Zaporowska, Environ. Toxicol. Pharmacol. 30 (2010) 153-161) may suggest that oxidative stress (OS) could also be, in part, involved in the mechanism responsible for the development of anaemia. The Mg dose ingested in combination with V under SMV-MS co-administration (a) was able to decrease, to some extent, the V concentration in the blood, (b) normalized the RBC Mg and Fe levels and (c) restored the values of some parameters of the Fe status near the control values. These results allow a supposition that a higher Mg dose consumed during SMV exposure could have better protective potential and be more effective in limiting the SMV toxicity observed.

Absorption, transport and insulin-mimetic properties of bis(maltolato)oxovanadium (IV) in streptozotocin-induced hyperglycemic rats by integrated mass spectrometric techniques.

The use of V(IV) complexes as insulin-enhancing agents has been increasing during the last decade. Among them, 3-hydroxy-2-methyl-4-pyrone and 2-ethyl-3-hydroxy-4-pyrone (maltol and ethyl maltol, respectively) have proven to be especially suitable as ligands for vanadyl ions. In fact, they have passed phase I and phase II clinical trials, respectively. However, the mechanism through which those drugs exert their insulin-mimetic properties is still not fully understood. Thus, the aim of this study is to obtain an integrated picture of the absorption, biodistribution and insulin-mimetic properties of the bis(maltolato)oxovanadium (IV) (BMOV) in streptozotocin-induced hyperglycaemic rats. For this purpose, BMOV hypoglycaemic properties were evaluated by monitoring both the circulating glucose and the glycohemoglobin, biomarkers of diabetes mellitus. In both cases, the results were drug concentration dependent. Using doses of vanadium at 3 mg/day, it was possible to reduce the glycaemia of the diabetic rats to almost control levels. BMOV absorption experiments have been conducted by intestinal perfusion revealing that approximately 35% of V is absorbed by the intestinal cells. Additionally, the transport of the absorbed vanadium (IV) by serum proteins was studied. For this purpose, a speciation strategy using high-performance liquid chromatography (HPLC) for separation and inductively coupled serum mass spectrometry, ICP-MS, for detection has been employed. The obtained HPLC-ICP-MS results, confirmed by MALDI-MS data, showed evidence that V, administered orally, is uniquely bound to transferrin in rat serum.

Protection against vanadium-induced testicular toxicity by testosterone propionate in rats.

Vanadium is a well recognized industrial hazard known to adversely affect male reproductive functions. The intricate mechanistic aspects of this metal and the role of oxidative stress in the deterioration of testicular functions are investigated in the current study. The experiment also focused on the effects of testosterone propionate in testicular and sperm functions in the rat intoxicated with vanadate. Vanadium exposure resulted in a more prominent spermatogenic arrest and consistently abolished the conversion of round to mature spermatids along with decreased epididymal sperm number and increased percentage of abnormal sperm. This is followed by a precipitous decline in the level of serum testosterone and gonadotropins and consequently the testicular steroidogenic and antioxidant enzymes were inhibited. Vanadium induces degeneration in the genital organs of rats and exhibits high indices of lipid oxidative damage. In response to exogenous testosterone propionate (TP) administration, spermatogonial cell populations remained suppressed, while the spermatogenesis was restored quantitatively. In contrast, the hormone treatment had no effect on the dramatically decreased serum FSH level after vanadate treatment. Moreover, TP could ameliorate the toxicity, as indicated by decreased testicular lipid peroxidation with marginal but significant increase in the activities of all the measured enzymes following vanadate-treatment. Taken together all these studies establish that vanadium is a testicular toxicant that perturbs the male reproductive system adversely. However, hormone replacement therapy by testosterone propionate may provide partial protection. The results suggest the feasibility of using endocrine regimens to impede deleterious effects of vanadium on the male reproductive system.

Insulin-enhancing activity of a dinuclear vanadium complex: 5-chloro-salicylaldhyde ethylenediamine oxovanadium(V) and its permeability and cytotoxicity.

A new insulin-enhancing oxovanadium complex 5-chloro-salicylaldhyde ethylenediamine oxovanadium (V) ([V(2)O(2)(mu-O)(2)L(2)]) has been synthesized. The complex was characterized by a variety of physical methods, including X-ray crystallography. The X-ray diffraction analysis show a dinuclear complex of two six-coordinate vanadium centers doubly bridged by the oxygen atoms of the Schiff base ligand with a V(2)O(2) diamond core. The complex was administered intragastrically to STZ-diabetic rats for 2 weeks. The biological activity results show that the complex at the dose of 10.0 and 20.0 mg V kg(-1), could significantly decrease the blood glucose level and ameliorate impaired glucose tolerance in STZ-diabetic rats. That results suggested that the complex exerts an antidiabetic effect in STZ-diabetic rats. Furthermore, the complex ([V(2)O(2)(mu-O)(2)L(2)]) had permeability above 10(-5)cm/s. The experimental results suggested that the vanadium complex permeates via a passive diffusion mechanism. It was also suggested the complex with salen-type ligands has good lipophilic properties and better oral administration. The cytotoxicity of the complex ([V(2)O(2)(mu-O)(2)L(2)]) on Caco-2 cells was measured by a decrease of cell viability using the MTT assay suggesting that the chlorine atom at C4 of complex [V(2)O(2)(mu-O)(2)L(2)] increased cytotoxicity for vanadium complexes.

The anti-diabetic effects and pharmacokinetic profiles of bis(maltolato)oxovanadium in non-diabetic and diabetic rats.

The purpose of this study was to evaluate the anti-diabetic effects and pharmacokinetics of bis(maltolato)oxovanadium (BMOV) in rats. The anti-diabetic study was carried out in non-diabetic and diabetic rats by single-dose subcutaneous and intragastric administration. Pharmacokinetic investigation was performed using non-diabetic rats. Results showed that BMOV significantly decreased plasma glucose levels in diabetic rats at all given doses, and restored hyperglycaemic values to normal values after subcutaneous injections at doses of 4 and 8 mg vanadium (V)/kg or after intragastric administration at doses of 14 and 28 mgV/kg, respectively, but did not affect the plasma glucose level in non-diabetic rats. BMOV could be rapidly absorbed, slowly eliminated from plasma, widely distributed in various tissues and accumulated to a greater extent in the femur tissue. The average absolute bioavailability for intragastric administration at a single dose of 3, 6 and 12 mgV/kg was 28.1%, 33.7% and 21.4%, respectively. The presence of the peak vanadium level in the plasma was not coincident with that of the maximum effect of lowering plasma glucose levels. In conclusion, at the present dosing levels and administration routes, BMOV was effective in lowering plasma glucose levels in diabetic rats. BMOV has a promising outlook as an oral glucose-lowering drug.

Spectroscopic characterization of a VO2+ complex of oxodiacetic acid and its bioactivity on osteoblast-like cells in culture.

The oxovanadium(IV) complex of oxodiacetic acid (H2oda) of stoichiometry [VO(oda)(H2O)2], which presents an unprecedented tridentate OOO coordination, was thoroughly characterized by infrared, Raman, electronic, and electron paramagnetic resonance spectroscopies. The biological activity of the complex on the cell proliferation and differentiation was tested on osteoblast-like cells (MC3T3E1 osteoblastic mouse calvaria-derived cells and UMR106 rat osteosarcoma-derived cells) in culture. The complex caused inhibition of cellular proliferation in both osteoblast-like cells in culture, but the cytotoxicity was stronger in the normal (MC3T3E1) than in the tumoral (UMR106) osteoblasts. The effect of the complex in cell differentiation was tested through the specific activity of alkaline phosphatase of the UMR106 cells because they expressed a high activity of this enzyme. What occurs with other vanadium compounds [VO(oda)(H2O)2] is an inhibitory agent of osteoblast differentiation.

Metallokinetic characteristics of antidiabetic bis(allixinato)oxovanadium(IV)-related complexes in the blood of rat.

The antidiabetic effect of vanadium is a widely accepted phenomenon; some oxovanadium(IV) complexes have been found to normalize high blood glucose levels in both type 1 and type 2 diabetic animals. In light of the future clinical use of these complexes, the relationship among their chemical structures, physicochemical properties, metallokinetics, and antidiabetic activities must be closely investigated. Recently, we found that among bis(3-hydroxypyronato)oxovanadium(IV) [VO(3hp)(2)] related complexes, bis(allixinato)oxovanadium(IV) [VO(alx)(2)] exhibits a relatively strong hypoglycemic effect in diabetic animals. Next, we examined its metallokinetics in the blood of rats that received five VO(3hp)(2)-related complexes by the blood circulation monitoring-electron paramagnetic resonance method. The metallokinetic parameters were obtained from the blood clearance curves based on a two-compartment model; most parameters, such as area under the concentration curve and mean residence time, correlated significantly with the in vitro insulinomimetic activity in terms of 1/IC(50) (IC(50) is the 50% inhibitory concentration of the complex required for the release of free fatty acids in adipocytes) and the lipophilicity of the complex (log P (com)). The oxovanadium(IV) concentration was significantly higher and the species resided longer in the blood of rats that received VO(alx)(2) than in the blood of rats that received VO(3hp)(2) or bis(kojato)oxovanadium(IV); VO(alx)(2) also exhibited higher log P (com) and 1/IC(50) values. On the basis of these results, we propose that the introduction of lipophilic groups at the C2 and C6 positions of the 3hp ligand is an effective method to enhance the hypoglycemic effect of the complexes, as supported by the observed in vivo exposure and residence in the blood.

Vanadium distribution, lipid peroxidation and oxidative stress markers upon decavanadate in vivo administration.

The contribution of decameric vanadate species to vanadate toxic effects in cardiac muscle was studied following an intravenous administration of a decavanadate solution (1mM total vanadium) in Sparus aurata. Although decameric vanadate is unstable in the assay medium, it decomposes with a half-life time of 16 allowing studying its effects not only in vitro but also in vivo. After 1, 6 and 12h upon decavanadate administration the increase of vanadium in blood plasma, red blood cells and in cardiac mitochondria and cytosol is not affected in comparison to the administration of a metavanadate solution containing labile oxovanadates. Cardiac tissue lipid peroxidation increases up to 20%, 1, 6 and 12h after metavanadate administration, whilst for decavanadate no effects were observed except 1h after treatment (+20%). Metavanadate administration clearly differs from decavanadate by enhancing, 12h after exposure, mitochondrial superoxide dismutase (SOD) activity (+115%) and not affecting catalase (CAT) activity whereas decavanadate increases SOD activity by 20% and decreases (-55%) mitochondrial CAT activity. At early times of exposure, 1 and 6h, the only effect observed upon decavanadate administration was the increase by 20% of SOD activity. In conclusion, decavanadate has a different response pattern of lipid peroxidation and oxidative stress markers, in spite of the same vanadium distribution in cardiac cells observed after decavanadate and metavanadate administration. It is suggested that once formed decameric vanadate species has a different reactivity than vanadate, thus, pointing out that the differential contribution of vanadium oligomers should be taken into account to rationalize in vivo vanadate toxicity.

2-Acetyl-1,3-cyclopentanedione-oxovanadium(IV) complexes. Acidity and implications for gastrointestinal absorption.

Since vanadyl sulphate has demonstrated insulin-like effects on glucose metabolism in animal and human trials, and organic vanadium complexes are better absorbed by the intestinal tract than vanadyl species, in this work the complexation of oxovanadium(IV) with 2-acetyl-1,3-cyclopentanedione is studied. Kinetic and equilibria in aqueous 1:1 chelation are investigated spectrophotometrically in aqueous solution at 25 degrees C. The mechanism proposed to account for the kinetic data involves a reversible pathway where VO(+2) reacts with the enolate ion of the ligand. From calculated kinetic and thermodynamic parameters, it can be expected that the rates between final and initial monocharged complex concentration could help a better control of the absorption through the lipophilic membranes in the intestinal tract.

Short-term bioaccumulation of vanadium when ingested with a tea decoction in streptozotocin-induced diabetic rats.

Sodium orthovanadate suspended in a lichee black tea decoction effectively regulates blood glucose levels in rats with insulin-dependent, streptozotocin (STZ)-induced diabetes. The primary advantage of vanadate delivery with the tea decoction over conventional systems that use water suspensions of vanadate is a significant reduction in the toxic side effects of vanadate. It is unknown if the tea alters the bioavailability of vanadate. Male Sprague-Dawley rats were administered an intravenous injection of STZ to induce diabetes. Four days later, the diabetic rats were treated by oral gavage with 40 mg of Na-orthovanadate suspended in double-distilled, deionized water (V/H2O), tea/vanadate (TV) decoction, or were treated with the tea decoction alone. Vanadium concentrations were measured in blood and various tissues at 1 to 24 hours posttreatment using graphite furnace atomic absorption spectrophotometry. With the exception of bone, maximal vanadium concentration in plasma and tissue samples were observed 2 hours after ingestion, but steadily decreased after that. Plasma vanadium levels continued to decrease until 16 hours. In contrast, vanadium steadily accumulated in bone over the 24-hour period. Overall, rats treated with V/H2O contained similar or significantly higher concentrations of vanadium in all tissues compared with TV treatment. The pattern of vanadium accumulation was also similar over time in both treatment groups. Vanadium levels were highest in bone > kidney > liver > pancreas > lung > heart > muscle > brain in both TV- and V/H2O-treated animals. This study demonstrates that the accumulation of vanadium in diabetic rats is reduced when coadministered with a black tea decoction in comparison to administration of vanadium in water. However, this effect is unlikely to be of a magnitude to explain the full capacity of TV to reduce the toxic side effects of vanadate.

The effects of vanadium treatment on bone in diabetic and non-diabetic rats.

Vanadium-based drugs lower glucose by enhancing the effects of insulin. Oral vanadium drugs are being tested for the treatment of diabetes. Vanadium accumulates in bone, though it is not known if incorporated vanadium affects bone quality. Nine- to 12-month-old control and streptozotocin-induced diabetic female Wistar rats were given bis(ethylmaltolato)oxovanadium(IV) (BEOV), a vanadium-based anti-diabetic drug, in drinking water for 12 weeks. Non-diabetic rats received 0, 0.25 or 0.75 mg/ml BEOV. Groups of diabetic rats were either untreated or treated with 0.25-0.75 mg/ml BEOV as necessary to lower blood glucose in each rat. In diabetic rats, this resulted in a Controlled Glucose group, simulating relatively well-managed diabetes, and an Uncontrolled Glucose group, simulating poorly managed diabetes. Plasma insulin, glucose and triglyceride assays assessed the diabetic state. Bone mineral density (BMD), mechanical testing, mineral assessment and histomorphometry measured the effects of diabetes on bone and the effects of BEOV on non-diabetic and diabetic bone. Diabetes decreased plasma insulin and increased plasma glucose and triglycerides. In bone, diabetes decreased BMD, strength, mineralization, bone crystal length, and bone volume and connectivity. Treatment was effective in incorporating vanadium into bone. In all treated groups, BEOV increased osteoid volume. In non-diabetic bone, BEOV increased cortical bone toughness, mineralization and bone formation. In controlled glucose rats, BEOV lowered plasma glucose and improved BMD, mechanical strength, mineralization, bone crystal length and bone formation rate. In poorly controlled rats, BEOV treatment slightly lowered plasma glucose but did not improve bone properties. These results suggest that BEOV improves diabetes-related bone dysfunction primarily by improving the diabetic state. BEOV also appeared to increase bone formation. Our study found no negative effects of vanadium accumulation in bone in either diabetic or non-diabetic rats at the dose given.