Pulmonary Immunotoxic Potentials of Metals Are Governed by Select Physicochemical Properties: Vanadium Agents

Abstract

The in situ reactions of metal ions/complexes are important in understanding the mechanisms by which environmental and occupational metal particles alter lung immune responses. A better understanding of these reactions in situ will also allow for the improved specificity and controlled toxicity of novel metallocompounds to be used as inhaled diagnostics or therapeutics. Our previous work showed that inhalation of metals (e.g., chromium, vanadium, nickel) caused altered lung immune cell function and host resistance. The data also suggested that the degree of immunomodulation induced depended not only on the amount of metal deposited, but also the compound used. If specificity governs pulmonary immunomodulatory potential, it follows that physicochemical properties inherent to the metal have a role in the elicited effects. We hypothe-size that major determinants of any metal compound's potential are its redox behavior, valency (generally referred to as oxidation state and considered speciation in chemical literature), and/or solubility. In accord with the extensive work carried out with vanadium (chemical symbol V) compounds showing the importance of form used, differences in potential for a range of V agents (pentavalent [V(V)] insoluble vanadium pentoxide and soluble sodium metavanadate, tetravalent [V(IV)] vanadyl dipicolinate, and trivalent [V(III)] bis(dipicolinato)vanadium) were quantified based on induced changes in local bacterial resistance after host inhalation of each agent at 100 mu g V/m(3) (5 hr/d for 5 d). Differences in effect between V(V) forms indicated that solubility was a critical property in in situ pulmonary immunotoxicity. Among the soluble forms, oxidizing vanadate had the greatest impact on resistance; reducing V(III) altered resistance to a lesser extent. Both the V(IV) and insoluble V(V) had no effect. When data was analyzed in the context of pre-infection lung V burdens, soluble V agents with different oxidation states induced varying responses, supporting the hypothesis that differences in immunomodulatory potential might be attributed to redox behavior or valency. Our findings both provide a basis for understanding why some metals could be a greater health risk than others (when encountered in equal amounts) and will assist in the design of inhalable metallopharmaceuticals by allowing researchers to preempt selection of certain metal ions or complexes for use in such products.

Decavanadate (V10O286-) and oxovanadates: Oxometalates with many biological activities

“…Recently in vivo vanadium toxicological studies using decavanadate showed that in hepatic and cardiac muscle cells, the degree of vanadate toxicity depends on the nature of the compounds and whether they are administered by intraperitoneal or intravenous methods [31]. This conclusion is in agreement with other vanadium compounds [16,46,47]. The response to decavanadate in vanadium accumulation, lipid peroxidation and oxidative stress markers [48] and yeast growth responses [26,27,49], is significantly different than that observed for the simple monomeric vanadate.…”

Vanadium compounds induced mitochondria permeability transition pore (PTP) opening related to oxidative stress

“…Vanadium induced apoptosis of cells associated with elevated ROS levels and ROS-related signal transduction [23,24], while antioxidants, either as complex ligands [25] or co-administration [26,27], significantly reduced vanadium toxicity. Stimulation of ROS production by vanadium varied depending on redox activity of vanadium species [9,28]. Vanadium compounds with various ligands and oxidative number may act on mitochondria differently.…”

Effects of decavanadate and insulin enhancing vanadium compounds on glucose uptake in isolated rat adipocytes

“…Indeed, recently the effects of V5 dipic was found to be different than the corresponding vanadium(IV) and (III) dipicolinate complexes in lowering the elevated blood glucose and lipid levels in Wistar rats with STZ induced diabetic rats [29]. In addition, the toxicity of the V5 dipic complex was found to be different than that of the vanadium(IV) and (III) dipicolinate complexes [35].…”

“…A larger fraction of BMOV is likely to remain intact during the assays and the amavadine analog is expected to remain intact during the duration of these experiments [19,33,34]. These predictions are based on chemical studies that the V5 dipic complex hydrolyze and reduce at neutral pH, and that BMOV oxidize in the presence of air [30,31] as well as studies in biological in which these compounds were found to provoke different responses [18,29,33,35]. The structures of the above vanadium complexes, as well of the vanadate oligomers are described elsewhere [15,19].…”