http://academic.oup.com/milmed/article-pdf/146/7/506/24126715/milmed-146-7-506.pdf

Goodman and Gilman's The Pharmacological Basis of Therapeutics

6.1.2. Aqueous V(III) Chemistry 877 6.1.3. Oxidation State of Vanadium in Tunicates 878 6.1.4. Uptake of Vanadate into Tunicates 879 6.1.5. Vanadium Binding Proteins: Vanabins 879 6.1.6. Model Complexes and Their Chemistry 880 6.1.7. Catechol-Based Model Chemistry 880 6.1.8. Vanadium Sulfate Complexes 881 6.2. Fan Worm Pseudopotamilla occelata 883 7. Vanadium Nitrogenase 883 7.1. Nitrogenases 883 7.2. Biochemistry of Nitrogenase 884 7.3. Clusters in Nitrogenase and Model Systems: Structure and Reactivity 885

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The chemistry and biochemistry of vanadium and the biological activities exerted by vanadium compounds.

Trichothecene mycotoxins are a group of structurally similar fungal metabolites that are capable of producing a wide range of toxic effects. Deoxynivalenol (DON, vomitoxin), a trichothecene, is prevalent worldwide in crops used for food and feed production, including in Canada and the United States. Although DON is one of the least acutely toxic trichothecenes, it should be treated as an important food safety issue because it is a very common contaminant of grain. This review focuses on the ability of DON to induce toxicologic and immunotoxic effects in a variety of cell systems and animal species. At the cellular level, the main toxic effect is inhibition of protein synthesis via binding to the ribosome. In animals, moderate to low ingestion of toxin can cause a number of as yet poorly defined effects associated with reduced performance and immune function. The main overt effect at low dietary concentrations appears to be a reduction in food consumption (anorexia), while higher doses induce vomiting (emesis). DON is known to alter brain neurochemicals. The serotoninergic system appears to play a role in mediation of the feeding behavior and emetic response. Animals fed low to moderate doses are able to recover from initial weight losses, while higher doses induce more long-term changes in feeding behavior. At low dosages of DON, hematological, clinical, and immunological changes are also transitory and decrease as compensatory/adaptation mechanisms are established. Swine are more sensitive to DON than mice, poultry, and ruminants, in part because of differences in metabolism of DON, with males being more sensitive than females. The capacity of DON to alter normal immune function has been of particular interest. There is extensive evidence that DON can be immunosuppressive or immunostimulatory, depending upon the dose and duration of exposure. While immunosuppression can be explained by the inhibition of translation, immunostimulation can be related to interference with normal regulatory mechanisms. In vivo, DON suppresses normal immune response to pathogens and simultaneously induces autoimmune-like effects which are similar to human immunoglobulin A (IgA) nephropathy. Other effects include superinduction of cytokine production by T helper cells (in vitro) and activation of macrophages and T cells to produce a proinflammatory cytokine wave that is analogous to that found in lipopolysaccharide-induced shock (in vivo). To what extent the elevation of cytokines contributes to metabolic effects such as decreased feed intake remains to be established. Although these effects have been largely characterized in the mouse, several investigations with DON suggest that immunotoxic effects are also likely in domestic animals. Further toxicology studies and an assessment of the potential of DON to be an etiologic agent in human disease are warranted.

Toxicology of deoxynivalenol (vomitoxin).

Deoxynivalenol (DON) is a mycotoxin that commonly contaminates cereal-based foods worldwide. At the molecular level, DON disrupts normal cell function by inhibiting protein synthesis via binding to the ribosome and by activating critical cellular kinases involved in signal transduction related to proliferation, differentiation, and apoptosis. Relative to toxicity, there are marked species differences, with the pig being most sensitive to DON, followed by rodent > dog > cat > poultry > ruminants. The physiologic parameter that is most sensitive to low-level DON exposure is the emetic response, with as little as 0.05 to 0.1 mg/kg body weight (bw) inducing vomiting in swine and dogs. Chinese epidemiological studies suggest that DON may also produce emetic effects in humans. With respect to chronic effects, growth (anorexia and decreased nutritional efficiency), immune function, (enhancement and suppression), and reproduction (reduced litter size) are also adversely affected by DON in animals, whereas incidence of neoplasia is not affected. When hazard evaluations were conducted using existing chronic toxicity data and standard safety factors employed for anthropogenic additives/contaminants in foods, tolerable daily intakes (TDIs) ranging from 1 to 5 microg/kg bw have been generated. Given that critical data gaps still exist regarding the potential health effects of DON, additional research is needed to improve capacity for assessing adverse health effects of this mycotoxin. Critical areas for future DON research include molecular mechanisms underlying toxicity, sensitivity of human cells/tissues relative to other species, emetic effects in primates, epidemiological association with gastroenteritis and chronic disease in humans, and surveillance in cereal crops worldwide.

Deoxynivalenol: Toxicology and Potential Effects on Humans

The trichothecene mycotoxin deoxynivalenol (DON) is produced in wheat, barley and corn following infestation by the fungus Fusarium in the field and during storage. Colloquially known as “vomitoxin” because of its emetic effects in pigs, DON has been associated with human gastroenteritis. Since DON is commonly detected in cereal foods, there are significant questions regarding the risks of acute poisoning and chronic effects posed to persons ingesting this trichothecene. A further challenge is how to best manage perceived risks without rendering critical food staples unavailable to an ever-expanding world population. In experimental animal models, acute DON poisoning causes emesis, whereas chronic low-dose exposure elicits anorexia, growth retardation, immunotoxicity as well as impaired reproduction and development resulting from maternal toxicity. Pathophysiologic effects associated with DON include altered neuroendocrine signaling, proinflammatory gene induction, disruption of the growth hormone axis, and altered gut integrity. At the cellular level, DON induces ribotoxic stress thereby disrupting macromolecule synthesis, cell signaling, differentiation, proliferation, and death. There is a need to better understand the mechanistic linkages between these early dose-dependent molecular effects and relevant pathological sequelae. Epidemiological studies are needed to determine if relationships exist between consumption of high DON levels and incidence of both gastroenteritis and potential chronic diseases. From the perspective of human health translation, a particularly exciting development is the availability of biomarkers of exposure (e.g. DON glucuronide) and effect (e.g. IGF1) now make it possible to study the relationship between DON consumption and growth retardation in susceptible human populations such as children and vegetarians. Ultimately, a fusion of basic and translational research is needed to validate or refine existing risk assessments and regulatory standards for this common mycotoxin.

Deoxynivalenol: mechanisms of action, human exposure, and toxicological relevance.

Tissue Binding versus Plasma Binding of Drugs: General Principles and Pharmacokinetic Consequences

Influence of subchronic exposure to low dietary deoxynivalenol, a trichothecene mycotoxin, on intestinal absorption of nutrients in mice☆

1 Dimercaprol (BAL), 2,3-dimercaptopropanesulpho nate sodium (DMPS) and meso-2,3-dimercaptosucci nic acid (DMSA) are effective arsenic antidotes, but the question which one is preferable for optimal therapy of arsenic poisoning is still open to discussion. Major drawbacks of BAL include (a) its low therapeutic index, (b) its tendency to redistribute arsenic to brain and testes, for example, (c) the need for (painful) intramuscular injection and (d) its unpleasant odour.2 The newer antidotes DMPS and DMSA feature low toxicity and high therapeutic index. They can be given orally or intravenously due to their high water solubility. While these advantages make it likely that DMPS and DMSA will replace BAL for the treatment of chronic arsenic poisoning, acute intoxication - espe cially with lipophilic organoarsenicals - may pose a problem for the hydrophilic antidotes, because their ionic nature can adversely affect intracellular avail ability.3 This article focuses on aspects dealing with the power of BAL, DM...

Are we ready to replace dimercaprol (BAL) as an arsenic antidote

Aims Vanadium is currently undergoing clinical trials as an oral drug in patients with noninsulin-dependent diabetes mellitus. Furthermore, vanadium occurs in elevated concentrations in the blood of patients receiving intravenous albumin solutions containing large amounts of the metal ion as an impurity. The present study was performed to examine the pharmacokinetics of vanadium in humans following a single intravenous (i.v.) dose of a commercial albumin solution containing a high amount of vanadium.



Methods  The study was conducted in five healthy volunteer subjects who received intravenously 90 ml of a commercial 20% albumin infusion solution containing 47.6 µg vanadium as an impurity. Vanadium concentrations in serum and urine were determined by electrothermal atomic absorption spectrometry.



Results Vanadium serum concentrations after i.v. administration were measured for 31 days. The data could be fitted by a triexponential function corresponding formally to a three-compartment model. There was an initial rapid decrease in serum concentrations with half-lives of 1.2 and 26 h. This was followed by a long-terminal half-life time of 10 days. The terminal phase accounted for about 80% of the total area under the serum concentration-time curve (AUC). The mean apparent volume of distribution of the central compartment was found to be 10 l. The volume of distribution at steady state was 54 l, and total clearance was 0.15 l h−1. Vanadium was mainly excreted by the kidneys. About 52% of the dose was recovered in the urine after 12 days.



Conclusions This study provides data on vanadium pharmacokinetics in healthy humans.

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Pharmacokinetics of vanadium in humans after intravenous administration of a vanadium containing albumin solution.

The efficacy ofdl-dimercaptopropanol (British Anti-Lewisite, BAL),dl-dimercaptopropanesulfonate (DMPS), and meso-dimercaptosuccinic acid (DMS A) was compared in reducing the acute As2O3 toxicity in mice. Mice were treated with a single equimolar dose of a dithiol compound (0.7 mmol/kg i.p.) 0.5 or 30 min after the s.c. injection of various doses of As2O3. Both DMPS and DMSA were significantly (p<0.05) more effective in mice treated 0.5 min after the poisoning if compared to BAL on an equimolar level. The highest potency ratio (PR) (LD50 with treatment/LD5o without treatment) was found in animals injected with DMSA (PR=8.6). The corresponding value for DMPS was 4.2, and for BAL 2.1, respectively. In animals treated 30 min after poisoning the efficacy of DMPS (PR = 2.6) was similar to the efficacy of DMSA 2.4, both being only slightly superior to BAL 2.O. DMPS and DMSA were found to be much less toxic than BAL. The LD50 of arsenic was 0.057 mmol/kg. The efficacy of BAL, DMPS, and DMSA in reducing the tissue content of arsenic following acute As2O3 poisoning was investigated in mice (n=6/group) and guinea pigs (n=3-4/group). The animals were injected s.c. with 0.043 mmol/kg As2O3 (containing a tracer dose of74As(III)). Thirty minutes later the antidotes were administered A were more effective in reducing the arsenic content of tissues than BAL. Moreover, BAL caused accumulation of the toxicant in the brain. It is concluded that the recommendation of BAL as drug of choice in acute arsenic poisoning needs to be carefully re-evaluated.

B. Fichtl

Papers

Tissue Binding versus Plasma Binding of Drugs: General Principles and Pharmacokinetic Consequences

Influence of subchronic exposure to low dietary deoxynivalenol, a trichothecene mycotoxin, on intestinal absorption of nutrients in mice☆

Are we ready to replace dimercaprol (BAL) as an arsenic antidote

Pharmacokinetics of vanadium in humans after intravenous administration of a vanadium containing albumin solution.

Efficacy of various dithiol compounds in acute As2O3 poisoning in mice.