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Review
. 2020 Sep:61:126508.
doi: 10.1016/j.jtemb.2020.126508. Epub 2020 Apr 12.

Vanadium: Risks and possible benefits in the light of a comprehensive overview of its pharmacotoxicological mechanisms and multi-applications with a summary of further research trends

Agnieszka Ścibior  1 , Łukasz Pietrzyk  1   2 , Zbigniew Plewa  3 , Andrzej Skiba  4
Affiliations
Review

Vanadium: Risks and possible benefits in the light of a comprehensive overview of its pharmacotoxicological mechanisms and multi-applications with a summary of further research trends

Agnieszka Ścibior et al. J Trace Elem Med Biol. 2020 Sep.

Abstract

Background: Vanadium (V) is an element with a wide range of effects on the mammalian organism. The ability of this metal to form organometallic compounds has contributed to the increase in the number of studies on the multidirectional biological activity of its various organic complexes in view of their application in medicine.

Objective: This review aims at summarizing the current state of knowledge of the pharmacological potential of V and the mechanisms underlying its anti-viral, anti-bacterial, anti-parasitic, anti-fungal, anti-cancer, anti-diabetic, anti-hypercholesterolemic, cardioprotective, and neuroprotective activity as well as the mechanisms of appetite regulation related to the possibility of using this element in the treatment of obesity. The toxicological potential of V and the mechanisms of its toxic action, which have not been sufficiently recognized yet, as well as key information about the essentiality of this metal, its physiological role, and metabolism with certain aspects on the timeline is collected as well. The report also aims to review the use of V in the implantology and industrial sectors emphasizing the human health hazard as well as collect data on the directions of further research on V and its interactions with Mg along with their character.

Results and conclusions: Multidirectional studies on V have shown that further analyses are still required for this element to be used as a metallodrug in the fight against certain life-threatening diseases. Studies on interactions of V with Mg, which showed that both elements are able to modulate the response in an interactive manner are needed as well, as the results of such investigations may help not only in recognizing new markers of V toxicity and clarify the underlying interactive mechanism between them, thus improving the medical application of the metals against modern-age diseases, but also they may help in development of principles of effective protection of humans against environmental/occupational V exposure.

Keywords: 3-HMG-CoA, 3-hydroxy-3-methyl-glutaryl-CoA; AIDS, acquired immune deficiency syndrome; ALB, albumin; ALP, alkaline phosphatase; AS, antioxidant status; Akt, protein kinase B (PKB); AmD, Assoc American Dietetic Association; Anti-B, anti-bacterial; Anti-C, anti-cancer; Anti-D, anti-diabetic; Anti-F, anti-fungal; Anti-O, anti-obesity; Anti-P, anti-parasitic; Anti-V, anti-viral; Anti−HC, anti-hypercholesterolemic; ApoA-I, apolipoprotein A; ApoB, apolipoprotein B; B, bone; BCOV, bis(curcumino)oxavanadyl; BEOV, bis(ethylmaltolato)oxovanadium; BMOV, bis(maltolato)oxavanadium(IV); Bim, Blc-2 interacting mediator of cell death; Biological role; BrOP, bromoperoxidase; C, cholesterol; C/EBPα, CCAAT-enhancer-binding protein α; CD4, CD4 receptor; CH, cerebral hemisphere; CHO-K1, Chinese hamster ovary cells; CXCR-4, CXCR-4 chemokine co-receptor; Cardio-P, cardioprotective; Citrate-T, citrate transporter; CoA, coenzyme A; Cyt c, cytochrome c; DM, diabetes mellitus; ELI, extra low interstitial; ERK, extracellular regulated kinase; FHR, fructose hypertensive rats; FKHR/FKHR1/AFX, class O members of the forkhead transcription factor family; FLIP, FLICE-inhibitory protein; FOXOs, forkhead box class O family member proteins; FPP, farnesyl-pyrophosphate; FasL, Fas ligand, FER: ferritin; GI, gastrointestinal; GLU, glucose; GLUT-4, glucose transporter type 4; GPP, geranyl-pyrophosphate; GPT, glutamate-pyruvate transaminase; GR, glutathione reductase; GSH, reduced glutathione; GSSG, disulfide glutathione; HDL, high-density lipoproteins; HDL-C, HDL cholesterol; HIV, human immunodeficiency virus; HMMF, high molecular mass fraction; HOMA-IR, insulin resistance index; Hb, hemoglobin; HbF, hemoglobin fraction; Hyper-LEP, hyperleptynemia; IDDM, insulin-dependent diabetes mellitus; IGF-IR, insulin-like growth factor receptor; IL, interleukin; INS, insulin; INS-R, insulin resistance; INS-S, insulin sensitivity; IPP, isopentenyl-5-pyrophosphate; IRS, insulin receptor tyrosine kinase substrate; IgG, immunoglobulin G; Industrial importance; Interactions; JAK2, Janus kinase 2; K, kidney; L, liver; L-AA, L-ascorbic acid; LDL, low-density lipoproteins; LDL-C, LDL cholesterol; LEP, leptin; LEP-R, leptin resistance; LEP-S, leptin sensitivity; LEPS, the concentration of leptin in the serum; LMMF, low molecular mass fraction; LPL, lipoprotein lipase; LPO, lipid peroxidation; Lactate-T, lactate transporter; M, mitochondrion; MEK, ERK kinase activator; MRC, mitochondrial respiratory chain; NAC, N-acetylcysteine; NEP, neutral endopeptidase; NIDDM, noninsulin-dependent diabetes mellitus; NO, nitric oxide; NPY, neuropeptide Y; NaVO3, sodium metavanadate; Neuro-P, neuroprotective; OXPHOS, oxidative phosphorylation; Organic-AT, organic anion transporter; Over-W, over-weight; P, plasma; PANC-1, pancreatic ductal adenocarcinoma cells; PARP, poly (ADP-ribose) polymerase; PLGA, (Poly)Lactide-co-Glycolide copolymer; PO43−, phosphate ion; PPARγ, peroxisome-activated receptor γ; PTK, tyrosine protein kinase; PTP, protein tyrosine phosphatase; PTP-1B, protein tyrosine phosphatase 1B; Pharmacological activity; Pi3K, phosphoinositide 3-kinase (phosphatidylinositol 3-kinase); RBC, erythrocytes; ROS, reactive oxygen species; RT, reverse transcriptase; SARS, severe acute respiratory syndrome; SAcP, acid phosphatase secreted by Leshmania; SC-Ti-6Al-4V, surface-coated Ti-6Al-4V; SHR, spontaneously hypertensive rats; SOD, superoxide dismutase; STAT3, signal transducer/activator of transcription 3; Sa, mean roughness; Sq, root mean square roughness; Sz, ten-point height; TC, total cholesterol; TG, triglycerides; TS, transferrin saturation; Tf, transferrin; TfF, transferrin fraction; TiO2, nHA:Ag-Ti-6Al-4V: titanium oxide-based coating containing hydroxyapatite nanoparticle and silver particles; Top-IB, IB type topoisomerase; Toxicological potential; V, vanadium; V-BrPO, vanadium bromoperoxidase; V-DLC, diamond-like layer with vanadium; V5+/V4+, pentavalent/tetravalent vanadium; VO2+, vanadyl cation; VO2+-FER, vanadyl-ferritin complex; VO4-/VO3-, vanadate anion; VO43-, vanadate ion; VS, vanadyl sulfate; Vanadium; WB, whole blood; ZDF rats, Zucker diabetic fatty rats; ZF rats, Zucker fatty rats; breakD, breakdown; eNOS, endothelial nitric oxide synthase; mo, months; n-HA, nano-hydroxyapatite; pRb, retinoblastoma protein; wk, weeks.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

None
Graphical abstract
Fig. 1
Fig. 1
Vanadium and its most common forms. Based on available literature data cited in section 1.1.
Fig. 2
Fig. 2
Historical outline of vanadium discovery. V: vanadium. Based on available literature data cited in section 1.2.
Fig. 3
Fig. 3
Industrial, biological, and pharmacological importance of vanadium. V: vanadium, NI: normal intake.
Fig. 4
Fig. 4
Role of vanadium in the mammalian organism. Based on available literature data cited in section 4.
Fig. 5
Fig. 5
Summary of positive and negative aspects of vanadium. AmDAssoc: American Dietetic Association. Based on available literature data cited in section 5.1 and other reports [[30], [31], [32], [33], [34]].
Fig. 6
Fig. 6
Summary of selected aspects of vanadium toxicity/essentiality on the timeline. V: vanadium, N: nitrogen, V-BrPO: vanadium bromoperoxidase. Based on available literature data cited in section 5.1 and other reports; †after [33], **after [38], ††after [39], *after [40], ##after [41].
Fig. 7
Fig. 7
Summary of the mechanisms and factors of vanadium toxicity: vanadium; LPO: lipid peroxidation; ROS: reactive oxygen species; MRC: mitochondrial respiratory chain; OXPHOS: oxidative phosphorylation; M: mitochondrion; Cyt c: cytochrome c; PARP: poly (ADP-ribose) polymerase. Based on available literature data cited in section 5.2.
Fig. 8
Fig. 8
Major symptoms of vanadium poisoning via ingestion and inhalation. Based on available literature data cited in section 6.2.
Fig. 9
Fig. 9
Summary of metabolism of vanadium and species of this metal in physiological fluids and tissues. V: vanadium, V5+: pentavalent vanadium, V4+: tetravalent vanadium, VO4−/VO3−: vanadate anion, VO2+: vanadyl cation, V*: exchangeable vanadium (‘free’), VO(OH)2: insoluble vanadyl hydroxide, GSH: reduced glutathione, Hb: hemoglobin, RBC: erythrocytes, ALB: albumin, Tf: transferrin, IgG: immunoglobulin G, FER: ferritin, Citrate-T: citrate transporter, Lactate-T: lactate transporter, Organic-AT: organic anion transporter, LMMF: low molecular mass fraction, HMMF: high molecular mass fraction, TfF: transferrin fraction, HbF: hemoglobin fraction. Based on available literature data cited in section 7 and other reports [60,90,91].
Fig. 10
Fig. 10
Vanadium against certain viruses, bacteria, parasites, and fungi. Based on available literature data [26,33,39,45,[124], [125], [126], [127], [128], [129], [130], [131], [132], [133], [134], [135], [136], [137]].
Fig. 11
Fig. 11
Summary of the mechanisms of the pharmacological activity of vanadium. Anti-V, Anti-B, Anti-P, Anti-F, Anti-C, Anti-D, Cardio-P, Neuro-P, Anti−HC, and Anti-O: anti-viral, anti-bacterial, anti-parasitic, anti-fungal, anti-cancer, anti-diabetic, cardioprotective, neuroprotective, anti-hypercholesterolemic, and anti-obesity, respectively, CD4: CD4 receptor, CXCR-4: CXCR-4 chemokine co-receptor, RT: reverse transcriptase, Na+/K+-ATPase: sodium-potassium pump, ROS: reactive oxygen species, ERK: extracellular regulated kinase, MEK: ERK kinase activator, SAcP: acid phosphatase secreted by Leshmania, pRb: retinoblastoma protein, AS: antioxidant status, GSH: reduced glutathione, GSSG: disulfide glutathione, Top-IB: IB type topoisomerase, NEP: neutral endopeptidase, VO43−: vanadate ion, PO43−: phosphate ion, PTP: protein tyrosine phosphatase, Pi3K: phosphoinositide 3-kinase (phosphatidylinositol 3-kinase), Akt: protein kinase B (PKB), GLUT-4: glucose transporter type 4, PTK: tyrosine protein kinase, eNOS: endothelial nitric oxide synthase, NO: nitric oxide, FLIP: FLICE-inhibitory protein; Bim: Blc-2 interacting mediator of cell death; FasL: Fas ligand; breakD: breakdown; Ca: calcium; K: potassium, FKHR/FKHR1/AFX: class O members of the forkhead transcription factor family, PTP-1B: protein tyrosine phosphatase 1B; JAK2: Janus kinase 2; STAT3: signal transducer/activator of transcription 3; NPY: neuropeptide Y; PPARγ: peroxisome-activated receptor γ; C/EBPα: CCAAT-enhancer-binding protein α; LPL: lipoprotein lipase. ↓: decrease, ↑: increase, ↓: inhibition/inactivation, ↑: activation, ↑↑: hyperactivation, ⊣ blockade of expression,→: modulation. Based on available literature data cited in section 8.2 and other reports [[139], [140], [141], [142]].
Fig. 12
Fig. 12
Summary of the most important aspects related to vanadium anti-diabetic effects on the timeline. V: vanadium, DM: diabetes mellitus, GLU: glucose, INS: insulin, BEOV: bis(ethylmaltolato)oxovanadium(IV). ↓: decrease. Based on available literature data cited in section 8.2.2.6 and other reports; **after [34], #after [174].
Fig. 13
Fig. 13
Summary of trials with inorganic vanadium compounds used in diabetic patients on the timeline. V: vanadium, VS: vanadyl sulfate, SMV: sodium metavanadate, NIDDM: noninsulin-dependent diabetes mellitus, IDDM: insulin-dependent diabetes mellitus, Over-W: over-weight, wk: weeks, mo: months. Based on available literature data cited in section 8.2.2.6.
Fig. 14
Fig. 14
Vanadium doses in normalization of glucose in rodents and humans. V: vanadium, GLU: glucose. Based on available literature data cited in section 8.2.2.6.
Fig. 15
Fig. 15
Mechanism of vanadium-induced weight loss – in vivo studies. V: vanadium, LEP: leptin, LEPS: the concentration of leptin in the serum, LEP-R: leptin resistance, Hyper-LEP: hyperleptynemia, LEP-S: leptin sensitivity, INS: insulin, INS-R: insulin resistance, INS-S: insulin sensitivity, NPY: neuropeptide Y, PTP-1B: protein tyrosine phosphatase 1B, JAK2: Janus kinase 2, STAT3: signal transducer/transcription factor, IRS: insulin receptor tyrosine kinase substrate ↓: decrease, ↑: increase, ↓: activity/pathway blockade, ↑: activation, ↓: signal blockade. Based on available literature data cited in section 8.2.2.8.
Fig. 16
Fig. 16
Cholesterol biosynthesis pathway with probable sites of vanadium action (I) along with changes in the lipid profile in humans occupationally exposed to vanadium (II) and in diabetic patients receiving inorganic vanadium salts (III). CoA: coenzyme A, 3-HMG-CoA: 3-hydroxy-3-methyl-glutaryl-CoA, IPP: isopentenyl-5-pyrophosphate, GPP: geranyl-pyrophosphate, FPP: farnesyl-pyrophosphate, C: cholesterol, HDL: high-density lipoproteins, LDL: low-density lipoproteins, HDL-C: HDL cholesterol, ApoA-I: apolipoprotein A, TC: total cholesterol, LDL-C: LDL cholesterol, ApoB: apolipoprotein B, VOSO4: vanadyl sulfate, NaVO3: sodium metavanadate. Based on available literature data cited in section 8.2.2.9.
Fig. 17
Fig. 17
Vanadium-associated issues – deserving more in-depth investigations.
Fig. 18
Fig. 18
Summary of vanadium-magnesium interactions – in vivo model: our studies (I) and studies of other authors (II). V: vanadium; Mg: magnesium, Fe: iron, Cu: copper: P: phosphorus, RBC: erythrocytes, GR: glutathione reductase, LPO: lipid peroxidation, CH: cerebral hemisphere, B: bone, WB: whole blood, L: liver, K: kidney, P: plasma, TS: transferrin saturation, L-AA: L-ascorbic acid, ALP: alkaline phosphatase, SOD: superoxide dismutase, Sa: mean roughness, Sq: root mean square roughness, Sz: ten-point height, Ins: insulin, HOMA-IR: insulin resistance index. Based on available literature cited in section 9.2.
Fig. 19
Fig. 19
Historical outline of certain issues linked to mineral interactions and studies on the effects of combined administration of vanadium and elements with antioxidant properties to animals (mainly to rats). Mg: magnesium, Zn: zinc, Se: selenium, Cr: chromium. *after [265].
Fig. 20
Fig. 20
Key factors affecting the mode of V action.
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