Open access peer-reviewed chapter

The Role of Vitamin C in the Protection and Modulation of Genotoxic Damage Induced by Metals Associated with Oxidative Stress

Written By

María del Carmen García-Rodríguez, Alejandro Gordillo-García and Mario Altamirano-Lozano

Submitted: November 23rd, 2016 Reviewed: March 21st, 2017 Published: August 2nd, 2017

DOI: 10.5772/intechopen.68686

Chapter metrics overview

1,572 Chapter Downloads

View Full Metrics

Abstract

This chapter reviews the effects of vitamin C on metal-induced genotoxicity. By focusing on cutting-edge studies, including our own results in experiments with vanadium(V) and chromium(VI), the suggestion that vitamin C can be used effectively to protect against or reduce the genotoxic effects induced by metal exposure by suppressing oxidative stress is particularly explored. After explaining the chemical mechanisms involved in oxidative stress associated with heavy metals, this chapter discusses the various proposals regarding the physiological processes of vitamin C at the molecular level, its relationship with oxidative stress, levels of 8-hydroxydeoxyguanosine (8-OH-dG, 7,8-dihy-dro-8-oxodeoxyguanosine) and apoptosis, and its role in the protection and modulation of DNA damage, as well as how they fit with our own results that showed an increase in apoptosis and 8-OH-dG when vitamin C was administered in addition to the metallic compounds. The relevant gaps in our understanding of the role of vitamin C with regard to these issues are highlighted, as well as the key importance of its clinical use, and ultimately, human health.

Keywords

  • vitamin C
  • antigenotoxic
  • genotoxic damage
  • antioxidant
  • heavy metals
  • oxidative stress

1. Introduction

Several studies have suggested that diets rich in fresh fruits and vegetables are associated with a lower risk of cardiovascular diseases and cancer because of the high levels of antioxidants such as vitamin C and polyphenols present in these foods [1]. The antioxidant effects of vitamin C have been observed both in vitroand in vivo. Ascorbic acid, which is a water-soluble bioactive form of vitamin C (Figure 1), can be found in all body fluids. At physiological pH, the 99% of vitamin C is present as AscH (Figure 1b), indicating that its chemical form confers its main antioxidant effects. The remaining percentage is covered by 0.05% of AscH2 (Figure 1a) and 0.004% of Asc2 (Figure 1c). The antioxidant activity of vitamin C develops in two ways: (a) directly, by scavenging oxygen free-radicals, more generally known as reactive oxygen species (ROS) and (b) indirectly, by regenerating other antioxidant systems [2, 3].

Figure 1.

Bioactive forms of vitamin C at physiological pH. a) Ascorbic acid with two ionisable hydroxyl groups, AscH2; b) Ascorbate anion, AscH-; and c) Ascorbate dianion, Asc2.

A significant number of studies have focused on metal-induced toxicity and carcinogenicity by emphasizing their role in the generation of ROS. Metal-mediated formation of free radicals may cause modifications to DNA bases, lipid peroxidation, and changes in calcium and sulfhydryl homeostasis [4, 5]. However, these effects can be influenced by the action of low molecular weight antioxidants such as vitamin C, which is capable of chelating metal ions, reducing their catalytic activity, and resulting ROS formation. Since the genotoxicity of heavy metals associated with oxidative stress is based on the oxidative mechanism during reduction [5], vitamin C can be used effectively to protect or reduce the induced genotoxic effects by suppressing oxidative stress caused by these metallic compounds [68]. However, paradoxically under certain conditions (i.e., low concentration in vitroand the presence of metal ions), vitamin C can exert a pro-oxidant effect, increasing oxidative damage to lipids, DNA and protein, besides being a potential direct or indirect modulator of gene expression [9]. In fact, our understanding of the physiological processes of vitamin C at the molecular level and its relationship with oxidative stress, as well as its role in the protection and modulation of DNA damage is still incomplete. As a consequence, the evidence indicating the potential of vitamin C in counteracting oxidative stress, a key component in various pathological conditions including cardiovascular disease, neurological disorders, diabetes, and cancer [3, 10, 11], has not been translated, at least conclusively, in many randomized controlled trials.

Advertisement

2. Heavy metals and oxidative stress: the case of vanadium and chromium

It is well established that redox-active metals participate closely in the generation of different free radicals [6]. Exposure to transition metal ions(n+) such as chromium (Cr) and vanadium (V) hence represent a realistic in vivoproduction of ROS and free radicals due to intra-cellular reduction. The majority of the hydroxyl radicals (OH) generated in vivocome from the metal-catalyzed breakdown of hydrogen peroxide (H2O2) through the Fenton and Haber-Weiss reactions [4, 12]:

Transition metal ion(n+)+H2O2Transition metal ion(n+1)+O·H+OHE1

The OH is the most reactive of all the ROS (half-life <1 ns) and interacts with all components of the DNA molecule. The initial stage of mutagenesis, carcinogenesis, and aging involves the permanent modification of genetic material. In fact, it has been well documented that in various cancer tissues, free radical-mediated DNA damage has occurred. ROS-induced DNA damage involves single- or double-stranded DNA breaks, purine, pyrimidine, or deoxyribose modifications, and DNA cross-links [5, 13, 14].

As mentioned above, the main genotoxic mechanism of V(V) and Cr(VI) compounds has been linked to reduction and generation of OH [15, 16]. Reduction of V(V) to V(IV) takes place outside the cell (Figure 2). In plasma, V(V) is rapidly reduced to V(IV) by nicotinamide adenine dinucleotide phosphate (NADPH) and ascorbic acid. Once reduced, it is bonded with plasma proteins that carry it into the cell, where peroxovanadyl radicals [V(IV)–OO] and vanadyl hydroperoxide [V(IV)–HO] are formed. The generated superoxide is further converted into H2O2 by the dismutation reaction with superoxide dismutase (SOD). V(IV) can react through the Fenton reaction with H2O2 forming a OH (Figure 2, RI) [5, 17, 18]. Nevertheless, Cr(VI) can actively enter the cells through channels for the transfer of isoelectric and isostructural anions, such as those for SO42− and HPO42− [19]. Once inside the cell, Cr(VI) quickly forms a complex with glutathione, reducing to Cr(V) (Figure 3, RII). Additionally, NAD(P)H can also reduce Cr(VI) to Cr(V), mediated by ascorbate (Figure 3, RI). Cr(V) can react through the Fenton reaction with H2O2 forming OH [15].

Figure 2.

Routes of V(V) involved in the induction, protection and modulation of DNA oxidative damage (outside and inside cell).

Figure 3.

Routes of Cr(VI) involved in the induction, protection and modulation of DNA oxidative damage (all occurring inside the cell).

The genetic damage by the production of C8-OH-adduct radical of deoxyguanosine is generated by the interaction between OH and 2-deoxyguanosine. Therefore, there are two ways in which the protection and modulation of DNA oxidative damage could be caused. First, AscH could react with OH, quenching and converting it into a poorly reactive semi-hydroascorbate radical, which do not cause DNA damage (Figures 2 and 3, RIII). Second, AscH can activate the repair mechanisms to eliminate C8-OH-adduct radical of deoxyguanosine. During catalysis of OH in the reaction with 2-deoxyguanosine with molecular oxygen, C8-OH-adduct radical of deoxyguanosine is formed (Figures 2 and 3, RIIand RIVrespectively), which is a form of oxidative DNA damage because it induces DNA strand breaks [20, 21]. Thus, AscH could activate repair mechanisms and eliminate this radical through 8-hydroxydeoxyguanosine (8-OH-dG, 7,8-dihy-dro-8-oxodeoxyguanosine), which is a marker repairer of oxidative stress in biological systems that can be measured in fluids such as blood, urine, and saliva (Figures 2 and 3, RIVand RV, respectively).

Although the direct relationship between DNA damage and OH is not completely clear, Patlolla et al. [22] have suggested a role for ROS in Cr(VI)-induced genotoxicity and cytotoxicity. They showed that Cr(VI) induced genomic DNA damage through the formation of 8-OH-dG. Nevertheless, Rudolf and Cérvinka [23] observed that Cr(VI) induced time- and concentration-dependent cytotoxicity, resulting in oxidative stress, but through suppression of antioxidant systems and by activation of p53-dependent apoptosis. Other studies have questioned the genotoxic/mutagenic effect of OH in the context of Cr exposure, suggesting that reduction of Cr(VI) by physiological concentrations of vitamin C generates ascorbate-Cr(III)-DNA crosslinks and binary Cr(III)-DNA adducts. Therefore, Cr-DNA adducts are responsible for both the mutagenicity and genotoxicity of Cr(VI) [24].

Advertisement

3. Protective effects of vitamin C against genotoxic damage from vanadium(V) and chromium(VI)

For humans, vitamin C is an essential micronutrient that plays multiple biological roles. It must be obtained from the ingestion of particular foods, mainly fresh fruits and vegetables, since our body is incapable of synthesizing it. The consequences of the intake of very high doses of vitamin C (>2 g/day) remain a subject of intense debate. However, it has been observed that supplementation of vitamin C reduces the incidence of stomach, lung and colorectal cancer; likewise, low serum levels of vitamin C in high-risk populations may contribute to increased risk of gastric metaplasia or chronic gastritis, which are both precancerous lesions [5, 25]. Nevertheless, analyses of the effects of vitamin C are rather complicated because diet and vitamin supplementation determine the levels of vitamin C in plasma.

Cameron and Pauling highlighted the beneficial properties of vitamin C in the 1970s. They suggested that high doses of vitamin C (>10 g/day) cure and prevent cancer by promoting collagen synthesis [26]. However, researchers now suggest that vitamin C prevents cancer by neutralizing ROS before they can damage DNA and initiate tumor growth. Furthermore, it has been proposed that vitamin C may also act as a pro-oxidant, helping the body’s own ROS destroy early-stage tumors [27, 28]. Currently, the recommended dietary allowance (RDA) in many countries ranges from 40–90 mg/day, although the results of various studies suggesting that the protective vitamin C concentrated in plasma for the minimum risk of free radical diseases corresponds to an intake of 124.2 mg/day (in the range of 92–181 mg) [10, 29].

Vitamin C possesses double bonds with an associated electron deficiency, making it highly reactive to free radicals from molecular oxygen. It donates two electrons from C-2 and C-3 double-bonded carbons, resulting in the formation of tricarbonyl ascorbate radical (AscH), which is present in the nonprotonated form, a semidehydroascorbate radical (Asc•−). The resulting ascorbate free radicals reduce to a neutral ascorbate molecule (Figures 2 and 3, RIII). Thus, the oxidation of ascorbate by many ROS is Asc•−, a poorly reactive radical that is considered terminal [3032], and the level of Asc•− radical function is an effective measurement of the degree of oxidative stress in biological systems [33].

In a previous study, we observed that the frequency of micronuclei in polychromatic erythrocytes (MN-PCE) increased with the administration of 40 mg/kg of V2O5 through ip [8], consistent with other studies testing soluble vanadium compounds (Na3VO4, SVO5, and NH4VO3) [3436]. However, the in vivoadministration of vitamin C prior to the V2O5 injection decreased MN-PCE formation compared to administering V2O5 alone, reducing basal MN-PCE, and presenting the strongest protection against genotoxic damage induced by V2O5. This was probably because the vitamin C acted as a potent antioxidant (reducing agent) that scavenged free radicals of reactive oxygen and nitrogen species and prevented them from damaging nucleic acids [27, 37]. Interestingly, the MN-PCE decrease we observed with vitamin C was more effective than with the administration of beverages with high levels of antioxidants such as green tea [38], red wine [39] and their antioxidant components such as polyphenols [4042].

Despite the important studies on the cytotoxic and anticarcinogenic effects of antioxidants in tumor model systems, it is clear that the molecular mechanisms underlying the benefits of antioxidants in cancer prevention are not yet well understood. Some ascorbyl forms of stearate inhibited cell proliferation by interfering with the cell cycle, reversing the phenotype and inducing apoptosis in human brain tumor glioblastoma (T98G) cells. Therefore, it has been proposed that the chemopreventive properties of antioxidants are related to their ability to target specific cellular signaling pathways that regulate cellular proliferation and apoptosis [43]. This proposal is consistent with our results since the frequencies of apoptotic cells (particularly, late apoptotic cells) indeed increased significantly with the administration of vitamin C, and their administration prior to treatment of V2O5 increased them even further [8]. Additionally, other studies have reported that the apoptosis-inducing activity of antioxidants might be synergistically enhanced by a combined treatment with chemopreventive [44] or genotoxic agents [40]. Therefore, it is plausible that enhanced induction of apoptosis following a combined treatment may positively contribute to the elimination of the cells with V2O5-induced DNA damage (MN-PCE).

On the other hand, some compounds including vanadium-oxide(V) have been proposed for clinical use as therapeutic drugs for cancer because the intracellular cascade mechanisms may be involved in causing apoptotic cell death. For many decades, vanadium was considered a low-toxicity essential trace element with anticarcinogenic properties [45]. However, important events have taken place since then. In 2006, the International Association for Research on Cancer (IARC) classified vanadium pentoxide (V2O5) as a Group 2B substance (possibly carcinogenic to humans) based on results in experimental animals [46]. In 2009, the American Council of Government and Industrial Hygienists (ACGIH) placed V2O5 in category A3 (confirmed animal carcinogen with unknown relevance to humans) [47].

The low levels of ROS promoting mRNA formation and encoding proteins known to be regulated by vanadium can induce the activation of transcription factors. In contrast, high levels of ROS are cytotoxic to the cells and trigger apoptotic mechanisms. Therefore, it has been proposed that the cytotoxic effects of vanadium compounds should be used to generate ROS and reactive nitrogen species to combat cancer cell lines [48, 49]. Of all the proposed mechanisms of V(V) toxicity, the induction of oxidative stress is of particular importance for biological systems [50, 51]. As explained above, antioxidants can deactivate highly reactive molecules such as ROS that are generated during various biochemical processes in the cells [3]. As a consequence, substances with antioxidant properties emerge as putative preventatives and co-adjuvants in the treatment of chronic degenerative diseases related to oxidative stress and DNA damage [41]. Additionally, the promising low costs of vanadium-based drugs make it particularly attractive, and the ability to overcome the adverse effects of vanadium compounds during therapeutic action is an urgent and crucial issue for its future use in medicine [49]. Our findings strongly suggest that vitamin C can be used effectively in therapy either alone (antioxidant) or in combination with other agents such as V2O5 to reduce their genotoxicity [8].

With regard to Cr(VI) compounds, they have been of particular interest and broadly studied because of their importance in different industrial applications including chrome plating, metallurgy, pigment manufacturing, leather tanning, and wood preservation and, most relevant to this chapter, because they are associated with the induction of cancer [5253]. Cr usually exists in various oxidation states, primarily Cr(III) and Cr(VI). The former is an essential micronutrient that plays a key role in protein, sugar, and fat metabolism. The latter is particularly effective in inducing genotoxicity by producing several types of DNA lesions and gene mutations. Some of the major factors that may play a significant role in determining cellular genotoxicity are Cr(VI)-induced DNA-DNA interstrand crosslinks, oxidative DNA damage, and mutations in the tumor suppressor gene p53 [19, 54]. It has been observed that Cr(VI) induces DNA damage through changes in the 8-OH-dG levels in DNA in rats. Furthermore, both endogenic (enzyme system) and exogenic (antioxidant consumption) antioxidant systems might counteract ROS and free radicals. In a recent study, we observed that administration of Cr(VI) increased MN-PCE (genotoxic damage), nonviable cells (cytotoxic damage), and glutathione (GSH) levels (a molecule that intervenes in its reduction to Cr(V), (Figure 3, RII) and decreased the total levels of antioxidants. Treatments with vitamin C prior to administration of CrO3 decreased MN frequencies (protection or modulation of genotoxic damage) and nonviable cells (decreased cytotoxic damage). A decrease in the levels of 8-OHdG in CrO3 group was observed, which could be related to the inhibition of repair mechanisms. However, when the organism was treated with vitamin C, a significant increase in the levels of 8-OHdG was observed, suggesting that it increases DNA repair. Our findings showed a protective effect of vitamin C on genotoxic damage induced by Cr(VI), possibly related to its ROS-suppression properties before the oxidative stress generated by the reduction of Cr(VI) to Cr(III) [5557]. Figure 4 summarizes the proposal of the interaction between vitamin C and heavy metals, that is, (1) the free radicals generated by heavy metals can be scavenged by vitamin C inhibiting their genotoxic effects; (2) the repair mechanisms inactivated by heavy metals can be reactivated by vitamin C; and (3) heavy metals induce apoptosis by damaging DNA and vitamin C contributes to this process.

Figure 4.

Summary of the interactions between vitamin C and heavy metals.

Advertisement

4. Conclusions

Vitamin C is a potent antioxidant found mainly in fresh fruits and vegetables. It can be readily absorbed and concentrated in tissues and biofluids at a physiologically relevant level, presenting effects in both the aqueous and membrane domains. Furthermore, it plays an essential role in the organism since it scavenges free radicals, chelates redox metals, and regenerates other antioxidants within the “antioxidant network.” All these characteristics make the study of the effects of the in vivoadministration of vitamin C on the genotoxic effects induced by agents associated with oxidative stress particularly important. In this sense, heavy metals such as V(V) and Cr(VI) are of particular relevance since they generate a realistic in vivoproduction of ROS and free radicals due to intra-cellular reduction. ROS-induced DNA damage involves single- or double-stranded DNA breaks, purine, pyrimidine or deoxyribose modifications, and DNA cross-links. Several studies, including our own results, have solidly concluded that vitamin C does play a significant role in the protection against the genotoxicity caused by metal compounds such as V(V) and Cr(VI). Although the main described mechanism of antioxidants is the scavenging of free radicals, our studies suggest that DNA repair and apoptosis are possible pathways involved in the protection and modulation of DNA. However, it has to be taken into account that under certain conditions (i.e., low concentration in vitroof vitamin C and the presence of metal ions), vitamin C can exert a pro-oxidant effect, increasing oxidative damage to DNA. More studies are necessary to fully understand the mechanisms involved in the modulation of and protection against metal-induced genotoxic damage and the adequate doses of vitamin C to stimulate these properties. In addition, it is possible that the impact of vitamin C on DNA damage depends also on both background values of vitamin C within the organism and the level of exposure to xenobiotics or oxidative stress.

Advertisement

Acknowledgments

The authors wish to thank Estefani Y. Hernández-Cruz for his excellent technical assistance. Financial support was obtained from DGAPA-UNAM PAPIIT-IN219216.

Advertisement

Abbreviations

AscH2, AscH−, Asc2−Forms of ascorbic acid (vitamin C)
AscH•Tricarbonyl ascorbate radical
Asc•−Semidehydroascorbate radical
CrChromium
Cr(VI)Chromium hexavalent
CrO3Chromium trioxide
GSHGlutathione
H2O2Hydrogen peroxide
ipIntraperitoneal
MNMicronucleus
MN-PCEMicronucleated polychromatic erythrocytes
NADPHNicotinamide adenine dinucleotide phosphate
NAD(P)+Oxidated form of nicotinamide adenine dinucleotide phosphate
Na3VO4Sodium orthovanadate
NH4VO3Ammonium metavanadate
•OHHydroxyl radical
PCEPolychromatic erythrocytes
ROSReactive oxygen species
SODSuperoxide dismutase
SVO5Vanadyl sulfate
VVanadium
V(IV)–OO•Peroxovanadyl radicals
V(IV)–HO•Vanadyl hydroperoxide
V(V)Vanadium pentavalent
V2O5Vanadium pentoxide
8-OH-dG8-hydroxydeoxyguanosine

References

  1. 1. Seifried HE, Pilch SM. Antioxidants in health and disease. In: Nutrition in the Prevention and Treatment of Disease. 3rd ed. London: Academic Press. 2013. p. 319-339. Available from:http://doi.org/10.1016/B978-0-12-391884-0.00062-7
  2. 2. Combs GF. Vitamin C. In: The Vitamines. 4th ed. London: Elsevier Press. 2012. p. 233-259. Available from:http://doi.org/10.1016/B978-0-12-381980-2.00009-8
  3. 3. Daud ZAM, Ismail A, Sarmadi B. Ascorbic acid: Physiology and health effects. In: Encyclopedia of Food and Health. 1st ed. Oxford: Elsevier Ltd. 2016. p. 266-274. Available from:http://doi.org/10.1016/B978-0-12-384947-2.00045-3
  4. 4. Leonard SS, Harris GK, Shi X. Metal-induced oxidative stress and signal transduction. Free Radical Biology and Medicine. 2004;37(12):1921-1942.
  5. 5. Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chemico-Biological Interactions. 2006;160(1):1-40. Available from:http://linkinghub.elsevier.com/retrieve/pii/S0009279705004333
  6. 6. Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease. Toxicology. 2011;283(2-3):65-87. Available from:http://dx.doi.org/10.1016/j.tox.2011.03.001
  7. 7. Harabawy ASA, Mosleh YYI. The role of vitamins A, C, E and selenium as antioxidants against genotoxicity and cytotoxicity of cadmium, copper, lead and zinc on erythrocytes of Nile tilapia,Oreochromis niloticus. Ecotoxicology and Environmental Safety. 2014;104(1):28-35. Available from:http://dx.doi.org/10.1016/j.ecoenv.2014.02.015
  8. 8. García-Rodríguez MC, Hernández-Cortés LM, Altamirano-Lozano MA. In vivo effects of vanadium pentoxide and antioxidants (ascorbic acid and alpha-tocopherol) on apoptotic, cytotoxic, and genotoxic damage in peripheral blood of mice. Oxidative Medicine and Cellular Longevity. 2016;2016:1-11. Available from:http://www.hindawi.com/journals/omcl/2016/6797851/
  9. 9. Griffiths HR, Lunec J. Ascorbic acid in the 21st century: More than a simple antioxidant. Environmental Toxicology and Pharmacology. 2001;10(4):173-182
  10. 10. Sram RJ, Binkova B, Rossner P. Vitamin C for DNA damage prevention. Mutation Research-Fundamental and Molecular Mechanisms Of Mutagenesis. 2012;733(1):39-49
  11. 11. Pisoschi AM, Pop A. The role of antioxidants in the chemistry of oxidative stress: A review. European Journal of Medicinal Chemistry. 2015;97:55-74. Available from:http://dx.doi.org/10.1016/j.ejmech.2015.04.040
  12. 12. Fenton HJH. LXXIII—Oxidation of tartaric acid in presence of iron. Journal of the Chemical Society, Transactions. 1894;65:899-910. Available from:http://xlink.rsc.org/?DOI=CT8946500899
  13. 13. Marnett LJ. Oxyradicals and DNA damage. Carcinogenesis. 2000;21(3):361-370
  14. 14. Cooke MS, Evans MD, Dizdaroglu M, Lunec J. Oxidative DNA damage: Mechanisms, mutation, and disease. FASEB Journal. 2003;17(10):1195-1214
  15. 15. Liu KJ, Shi X. In vivo reduction of chromium (VI) and its related free radical generation. Molecular and Cellular Biochemistry. 2001;222(1-2):41-47
  16. 16. Shi X, Dalal NS. Hydroxyl radical generation in the Nadh/Microsomal reduction of vanadate. Free Radical Research Communications. 1992;17(6):369-376. Available from:http://www.tandfonline.com/doi/full/10.3109/10715769209083141
  17. 17. Liochev SI, Fridovich I. Vanadate-stimulated oxidation of NAD(P)H in the presence of biological membranes and other sources of O2. Archives of Biochemistry and Biophysics. 1990;279(1):1-7
  18. 18. Stankiewicz PJ, Stern A, Davison AJ. Oxidation of NADH by vanadium: Kinetics, effects of ligands and role of H2O2 or O2. Archives of Biochemistry and Biophysics. 1991;287(1):8-17
  19. 19. Singh J, Carlisle DL, Pritchard DE, Patierno SR. Chromium-induced genotoxicity and apoptosis: Relationship to chromium carcinogenesis (review). Oncology Reports. 1998;5(6):1307-1318. Available from:http://www.spandidos-publications.com/10.3892/or.5.6.1307
  20. 20. Maeng S-HH, Chung H-WW, Yu I-JJ, Kim H-YY, Lim C-HH, Kim K-JJ, et al. Changes of 8-OH-dG levels in DNA and its base excision repair activity in rat lungs after inhalation exposure to hexavalent chromium. Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 2003;539(1-2):109-116. Available from:http://linkinghub.elsevier.com/retrieve/pii/S1383571803001542
  21. 21. Setyaningsih Y, Husodo AH, Astuti I. Detection of Urinary 8-hydroxydeoxyguanosine (8-OHdG) levels as a biomarker of oxidative DNA damage among home industry workers exposed to chromium. Procedia Environmental Sciences. 2015;23:290-296. Available from:http://dx.doi.org/10.1016/j.proenv.2015.01.043
  22. 22. Patlolla AK, Barnes C, Hackett D, Tchounwou PB. Potassium dichromate induced cytotoxicity, genotoxicity and oxidative stress in human liver carcinoma (HepG2) cells. International Journal of Environmental Research and Public Health. 2009;6(2):643-653
  23. 23. Rudolf E, Cervinka M. The role of intracellular zinc in chromium(VI)-induced oxidative stress, DNA damage and apoptosis. Chemico-Biological Interactions. 2006;162(3):212-227. Available from:http://www.ncbi.nlm.nih.gov/pubmed/16887109
  24. 24. Zhitkovich A. Importance of chromium-DNA adducts in mutagenicity and toxicity of chromium(VI). Chemical Research in Toxicology. 2005;18(1):3-11. Available from:http://www.ncbi.nlm.nih.gov/pubmed/15651842
  25. 25. Aditi A, Graham DY. Vitamin c, gastritis, and gastric disease: A historical review and update. Digestive Diseases and Sciences. 2012;57(10):2504-2515
  26. 26. Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proceedings of the National Academy of Sciences of the United States of America. 1976;73(10):3685-3689
  27. 27. Du J, Cullen JJ, Buettner GR. Ascorbic acid: Chemistry, biology and the treatment of cancer. Biochimica et Biophysica Acta - Reviews on Cancer. 2012;1826(2):443-457. Available from:http://dx.doi.org/10.1016/j.bbcan.2012.06.003
  28. 28. Unlu A, Kirca O, Ozdogan M, Nayır E. High-dose vitamin C and cancer. Journal of Oncological Science. 2016;1:10-12
  29. 29. Krajcovicova-Kudlackova M, Dušinská M, Valachovičová M, Blažíček P, Pauková V. Products of DNA, protein and lipid oxidative damage in relation to vitamin C plasma concentration. Physiological Research. 2006;55(2):227-231
  30. 30. Atkinson CJ, Nestby R, Ford YY, Dodds PAA. Enhancing beneficial antioxidants in fruits: A plant physiological perspective. BioFactors. 2005;23(4):229-234
  31. 31. Williams DJ, Edwards D, Pun S, Chaliha M, Sultanbawa Y. Profiling ellagic acid content: The importance of form and ascorbic acid levels. Food Research International. 2014;66:100-106. Available from:http://dx.doi.org/10.1016/j.foodres.2014.09.003
  32. 32. Srdić-Rajić T, Konić Ristić A. Antioxidants: Role on health and prevention. In: Encyclopedia of Food and Health. 1st ed. Oxford: Elsevier Ltd. 2016. p. 227-233. Available from:http://doi.org/10.1016/B978-0-12-384947-2.00038-6
  33. 33. Kašparová S, Brezová V, Valko M, Horecký J, Mlynárik V, Liptaj T, et al. Study of the oxidative stress in a rat model of chronic brain hypoperfusion. Neurochemistry International. 2005;46(8):601-611
  34. 34. Ciranni R, Antonetti M, Migliore L. Vanadium salts induce cytogenetic effects in in vivo treated mice. Mutatation Research Toxicology. 1995;343(1):53-60
  35. 35. Leopardi P, Villani P, Cordelli E, Siniscalchi E, Veschetti E, Crebelli R. Assessment of the in vivo genotoxicity of vanadate: Analysis of micronuclei and DNA damage induced in mice by oral exposure. Toxicology Letters. 2005;158(1):39-49
  36. 36. Rojas-Lemus M, Altamirano-Lozano M, Fortoul TI. Sex differences in blood genotoxic and cytotoxic effects as a consequence of vanadium inhalation: Micronucleus assay evaluation. Journal of Applied Toxicology. 2014;34(3):258-264
  37. 37. Crott JW, Fenech M. Effect of vitamin C supplementation on chromosome damage, apoptosis and necrosis ex vivo. Carcinogenesis. 1999;20(6):1035-1041. Available from:http://www.ncbi.nlm.nih.gov/pubmed/10357785
  38. 38. García-Rodríguez MC, Vilches-Larrea RE, Nicolás-Mendez T, Altamirano-Lozano MA. El té verde en la quimioprevención in vivo del daño genotóxico inducido por metales cancerígenos (cromo [VI]). Nutricion Hospitalaria. 2012;27(4):1204-1212
  39. 39. García-Rodríguez MC, Mateos-Nava RA, Altamirano-Lozano M. Efecto in vivo del vino tinto sin diluir, diluido (75%) y sin alcohol sobre el daño genotóxico inducido por metales pesados con potencial cancerígeno: Cromo [VI]. Nutricion Hospitalaria. 2015;32(4):1645-1652
  40. 40. García-Rodríguez MC, Montaño-Rodríguez AR, Altamirano-Lozano MA. Modulation of hexavalent chromium-induced genotoxic damage in peripheral blood of mice by epigallocatechin-3-gallate (EGCG) and its relationship to the apoptotic activity. Journal of Toxicology and Environmental Health Part A. 2016;79(1):28-38. Available from:http://www.tandfonline.com/doi/full/10.1080/15287394.2015.1104525
  41. 41. García-Rodríguez MC, Carvente-Juárez MM, Altamirano-Lozano MA. Antigenotoxic and apoptotic activity of green tea polyphenol extracts on hexavalent chromium-induced DNA damage in peripheral blood of CD-1 mice: Analysis with differential acridine orange/ethidium bromide staining. Oxidative Medicine and Cellular Longevity. 2013;2013:486419. Available from:http://www.hindawi.com/journals/omcl/2013/486419/
  42. 42. García-Rodríguez MC, Nicolás-Méndez T, Montaño-Rodríguez AR, Altamirano-Lozano MA. Antigenotoxic effects of (−)-epigallocatechin-3-gallate (EGCG), quercetin, and rutin on chromium trioxide-induced micronuclei in the polychromatic erythrocytes of mouse peripheral blood. Journal of Toxicology and Environmental Health A. 2014;77(6):324-336. Available from:http://www.ncbi.nlm.nih.gov/pubmed/24593145
  43. 43. Kerr JF, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Journal of Internal Medicine. 1972;258(6):479-517
  44. 44. Gao Y, Li W, Jia L, Li B, Chen YC, Tu Y. Enhancement of (−)-epigallocatechin-3-gallate and theaflavin-3-3’-digallate induced apoptosis by ascorbic acid in human lung adenocarcinoma SPC-A-1 cells and esophageal carcinoma Eca-109 cells via MAPK pathways. Biochemical and Biophysical Research Communications. 2013;438(2):370-374
  45. 45. Evangelou AM. Vanadium in cancer treatment. Critical Reviews in Oncology/Hematology. 2002;42(3):249-265
  46. 46. Altamirano-Lozano M, Beyersmann D, Carter DE, Fowler BA, Fubini B, Kielhorn J, et al. Cobalt in hard metals and cobalt sulfate, gallium arsenide, indium phosphide and vanadium pentoxide. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 2006;86:1-294.
  47. 47. American Conference of Governmental Industrial Hygienists (ACGIH), “Vanadium pentoxide: Chemical substances 7th edition documentation, 9,” in Appendix B: Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs). 2012.http://www.nsc.org/facultyportal/Documents/fih-6e-appendixb.pdf
  48. 48. Kioseoglou E, Petanidis S, Gabriel C, Salifoglou A. The chemistry and biology of vanadium compounds in cancer therapeutics. Coordination Chemistry Reviews. 2015;301-302:87-105. Available from:http://dx.doi.org/10.1016/j.ccr.2015.03.010
  49. 49. Pessoa JC, Etcheverry S, Gambino D. Vanadium compounds in medicine. Coordination Chemistry Reviews. 2015;301-302:24-48. Available from:http://dx.doi.org/10.1016/j.ccr.2014.12.002
  50. 50. Assem FL, Oskarsson A. Vanadium. Handbook on the Toxicology of Metals. 2015;1347-1367. Available from:http://linkinghub.elsevier.com/retrieve/pii/B9780444594532000603
  51. 51. Soriano-Agueda LA, Ortega-Moo C, Garza J, Guevara-García JA, Vargas R. Formation of reactive oxygen species by vanadium complexes. Computational and Theoretical Chemistry. 2016;1077:99-105. Available from:http://dx.doi.org/10.1016/j.comptc.2015.11.002
  52. 52. Shi X. Reduction of chromium (VI) and its relationship to carcinogenesis. Journal of Toxicology and Environmental Health, Part B. 1999;2(1):87-104. Available from:http://www.tandfonline.com/doi/abs/10.1080/109374099281241
  53. 53. Rowbotham AL, Levy LS, Shuker LK. Critical reviews chromium in the environment: An evaluation of exposure of the UK general population and possible adverse health effects. Journal of Toxicology and Environmental Health, Part B. 2000;3(3):145-178
  54. 54. O’Brien TJ, Ceryak S, Patierno SR. Complexities of chromium carcinogenesis: Role of cellular response, repair and recovery mechanisms. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 2003;533(1-2):3-36
  55. 55. García-Rodríguez MC, Serrano-Reyes G, Altamirano-Lozano M. Comparative study in vivo of the genotoxic damage induced by CrO3 and the effects of the antioxidants: Ascorbic acid, alfa-tocopherol and beta-carotene. Free Radical Biology and Medicine. 2012;53:S216. Available from:http://linkinghub.elsevier.com/retrieve/pii/S0891584912009422
  56. 56. García-Rodríguez MC, Serrano-Reyes G, Retana-Ugalde R, Altamirano-Lozano M. Effect of Ascorbic Acid and (-)-Epigallocatechin-3-Gallate on Oxidative Damage Induced by Chromium (VI) in Hsd-ICR Mice. Free Radic Biol Med. 2015;87(1):S95. Available from:http://www.sciencedirect.com/science/article/pii/S089158491500862X
  57. 57. Nicolás-Méndez T, Serrano-Reyes G, Pacheco-Martinez M, Altamirano-Lozano M, García-Rodríguez MC. Evaluation of Apoptotic Activity, Micronucleus Induction, and Levels of 8-Hydroxydeoxyguanine and Glutathione in Peripheral Blood of Hsd:ICR Mice Exposed to Hexavalent Chromium Compounds. In: The Toxicologist: Supplement to Toxicological Sciences, 2017;156(1):222. Abstract no. 1942

Notes

  • The authors declare that they do not have any competing interests.

Written By

María del Carmen García-Rodríguez, Alejandro Gordillo-García and Mario Altamirano-Lozano

Submitted: November 23rd, 2016 Reviewed: March 21st, 2017 Published: August 2nd, 2017