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Prooxidative effects of aspartame on antioxidant defense status in erythrocytes of rats

Abstract

Since aspartame (l-aspartyl-l-phenylalanine methyl ester, ASP) is one of the most widely used artificial sweeteners, the aim of the present study was to investigate its effects on serum glucose and lipid levels as well as its effects on oxidative/antioxidative status in erythrocytes of rats. The experiment included two groups of animals: the control group was administered with water only, while the experimental group was orally administered with ASP (40 mg/kg b.w.) daily, for a period of six weeks. When compared with the control group, the group administrated with ASP indicated higher values of serum glucose, cholesterol and triglycerides. Significantly increased concentrations of superoxide anion (O2 •−), hydrogen peroxide (H2O2), peroxynitrite (ОNОО) and lipid peroxides (LPO) were recorded in the erythrocytes of ASP treated group in comparison to the control group. In the course of chronic ASP administration, the following was observed: the concentration of reduced glutathione (GSH) and the activity of catalase (CAT) increased. Thus, these findings suggest that long-term consumption of ASP leads to hyperglycemia and hyperlipidemia, as well as to oxidative stress in erythrocytes.

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References

  • Abhilash M, Sauganth Paul MV, Varghese MV and Nair RH 2011 Effect of long term intake of aspartame on antioxidant defense status in liver. Food Chem. Toxicol. 49 1203–1207

    CAS  PubMed  Article  Google Scholar 

  • Abhilash M, Sauganth Paul MV, Varghese MV and Nair RH 2013 Long-term consumption of aspartame and brain antioxidant defense status. Drug Chem. Toxicol. 36 135–140

    CAS  PubMed  Article  Google Scholar 

  • Alipour A, van Oostrom AJ, Izraeljan A, Verseyden C, Collins JM, Frayn KN, Plokker TW, Elte JW, et al. 2008 Leukocyte activation by triglyceride-rich lipoproteins. Arterioscler. Thromb. Vasc. Biol. 28 792–797

    CAS  PubMed  Article  Google Scholar 

  • Alvarez B, Demicheli V, Duran R, Trujillo M, Cervenansky C, Freeman BA and Radi R 2004 Inactivation of human CuZn superoxide dismutase by peroxynitrite and formation of histidinyl radical. Free Rad. Biol. Med. 37 813–822

    CAS  PubMed  Article  Google Scholar 

  • Auclair C and Voisin E 1985 Nitroblue tetrazolium reduction; in CRC Handbook of methods for oxygen radical research (ed) RA Greenwald (Florida: CRC Press, Boca Raton) pp 123–132

    Google Scholar 

  • Beutler E 1975 Reduced Glutathione (GSH); in Red cell metabolism, a manual of biochemical methods (ed) E Beutler (New York: Grune and Straton) pp 112–114

    Google Scholar 

  • Beutler E 1982 Catalase; in Red cell metabolism, a manual of biochemical methods (ed) E Beutler (New York: Grune and Stratton) pp 105–116

    Google Scholar 

  • Butchko HH, Stargel WW, Comer CP, Mayhew DA, Benninger C, Blackburn GL, de Sonneville LM, Geha RS, et al. 2002 Aspartame: review of safety. Regul. Toxicol. Pharmacol. 35 1–93

    Article  Google Scholar 

  • Camfield PR, Camfield CS, Dooley JM, Gordon K, Jollymore S and Weaver DF 1992 Aspartame exacerbates EEG spike-wave discharge in children with generalized absence epilepsy: a double blind controlled study. Neurology 42 1000–1003

    CAS  PubMed  Article  Google Scholar 

  • Castro GD, Costantini MH, de layno Delgado AM and Castro A 2002 Rat liver microsomal and nuclear activation of methanol to hydroxyl methyl free radicals. Toxicol. Lett. 129 227–236

    CAS  PubMed  Article  Google Scholar 

  • Chaitanya KV, Pathan AAK, Mazumdar SS, Chakravarthi GP, Parine N and Bobbarala V 2010 Role of oxidative stress in human health: an overview. J. Parm. Res. 3 1330–1333

    CAS  Google Scholar 

  • Choudhary AK and Devi RS 2014 Imbalance of the oxidant - antioxidant status by aspartame in the organs of immune system of Wistar albino rats. Afr. J. Pharm. Pharmacol. 8 220–230

    CAS  Article  Google Scholar 

  • Dargel R 1991 Lipid peroxidation–a common pathogenic mechanism? Exp. Toxicol. Pathol. 44 169–181

    Article  Google Scholar 

  • Davoli E, Cappellini L, Airoldi L and Fanelli R 1986 Serum methanol concentration in rats and in men after a single dose of aspartame. Food Chem. Toxicol. 24 187–189

    CAS  PubMed  Article  Google Scholar 

  • Dejam A, Hunter CJ, Pelletier MM, Hsu LL, Machado RF, Shiva S, Power GG, Kelm M, et al. 2005 Erythrocytes are the major intravascular storage sites of nitrite in human blood. Blood 106 734–739

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Djordjević NZ, Babić GM, Marković SD, Ognjanović BI, Stajn AS, Zikić RV and Saičić ZS 2008 Oxidative stress and changes in antioxidative defense system in erythrocytes of preeclampsia in women. Reprod. Toxicol. 25 213–218

    Article  Google Scholar 

  • Ells JT, Henry MM, Lewandowski MF, Seme MT and Murray T 2000 Development and characterization of a rodent model of methanol-induced retinal and optic nerve toxicity. Neurotoxicol. Rev. 21 321–330

    Google Scholar 

  • Fernstrom JD, Fernstrom MH and Gillis MA 1983 Acute effects of aspartame on large neutral amino acid and monoamines in rat brain. Life Sci. 32 1651–1658

    CAS  PubMed  Article  Google Scholar 

  • Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS and Tannenbaum SR 1982 Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal. Biochem. 126 131–138

    CAS  PubMed  Article  Google Scholar 

  • Goerss AL, Wagner GC and Hill WL 2000 Acute effects of aspartame on aggression and neurochemistry in rats. Life Sci. 67 1325–1329

    CAS  PubMed  Article  Google Scholar 

  • Halliwell B and Gutteridge JMC 2007 Free radicals in biology and medicine 4th ed. (New York: Oxford University Press) pp 30–110

    Google Scholar 

  • Hawkins RA, Mans AM and Biebuyck JF 1988 Regional transport and other neutral amino acids across the blood-brain barrier; in Dietary phenylalanine and brain function (eds) RJ Wurtman and E Ritter-Walker (Basel: Birkhauser) pp 63–67

    Chapter  Google Scholar 

  • Hayes JD and McLellan LI 1999 Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defence against oxidative stress. Free Radic. Res. 31 273–300

    CAS  PubMed  Article  Google Scholar 

  • Herce-Pagliai C, Kotecha S and Shuker D 1998 Analytical methods for 3-nitrotyrosine as a marker of exposure to reactive nitrogen species. A review. Nitric Oxide 2 324–336

    CAS  PubMed  Article  Google Scholar 

  • Humphries P, Pretorius E and Naude H 2008 Direct and indirect cellular effects of aspartame on the brain. Eur. J. Clin. Nutr. 62 451–462

    CAS  PubMed  Article  Google Scholar 

  • Iyyaswamy A and Rathinasamy S 2012 Effect of chronic exposure to aspartame on oxidative stress in the brain of albino rats. J. Biosci. 37 679–688

    CAS  PubMed  Article  Google Scholar 

  • Jang W, Jeoung NH and Cho KH 2011 Modified apolipoprotein (apo) A-I by artificial sweetener causes severe premature cellular senescence and atherosclerosis with impairment of functional and structural properties of apoA-I in lipid-free and lipid-bound state. Mol. Cell. 31 461–470

    CAS  Article  Google Scholar 

  • Kummer U, Zobeley J, Brasen JC, Fahmy R, Kindzelskii AL, Petty AR, Clark AJ and Petty HR 2007 Elevated glucose concentrations promote receptor-independent activation of adherent human neutrophils: an experimental and computational approach. Biophys. J. 92 2597–2607

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Lynch RE and Fridovich I 1978 Permeation of the erythrocyte stroma by superoxide radical. J. Biol. Chem. 253 4697–4699

    CAS  PubMed  Google Scholar 

  • Magnuson BA, Burdock GA, Doull J, Kroes RM, Marsh GM, Pariza MW, Spencer PS, Waddell WJ, et al. 2007 Aspartame: a safety elevation based on current use levels, regulations, and toxicological and epidemiological studies. Crit. Rev. Toxicol. 37 629–727

    CAS  PubMed  Article  Google Scholar 

  • Maher TJ and Wurtman RJ 1987 Possible neurologic effects of aspartame, a widely used food additive. Environ. Health Perspect. 75 3–57

    Article  Google Scholar 

  • Makhro A, Wang J, Vogel J, Boldyrev AA, Gassmann M, Kaestner L and Bogdanova A 2010 Functional NMDA receptors in rat erythrocytes. Am. J. Physiol. Cell Physiol. 298 1315–1325

    Article  Google Scholar 

  • Marklund SL and Marklund G 1974 Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur. J. Biochem. 47 469–474

    CAS  PubMed  Article  Google Scholar 

  • Matés JM 2000 Effects of antioxidant enzymes in the molecular control of reactive oxygen species toxicology. Toxicology 153 83–104

    PubMed  Article  Google Scholar 

  • McMartin KE, Ambre JJ and Tephly TR 1980 Methanol poisoning in human subjects. Role or formic acid accumulation in the metabolic acidosis. Am. J. Med. 68 414–418

    CAS  PubMed  Article  Google Scholar 

  • McCord JM and Fridovich I 1969 Superoxide dismutase: an enzymic function for erythrocuprein (hemocuprein). J. Biol. Chem. 244 6049–6055

    CAS  PubMed  Google Scholar 

  • Moser RH 1994 Aspartame and memory loss. JAMA 272 1543

    CAS  PubMed  Article  Google Scholar 

  • Mourad IM 2011 Effect of aspartame on some oxidative stress parameters in liver and kidney of rats. Afr. J. Pharm. Pharmacol. 5 678–682

    CAS  Article  Google Scholar 

  • Mourad IM and Noor NA 2011 Aspartame (a widely used artificial sweetener) and oxidative stress in the rat cerebral cortex. Int. J. Pharm. Biomed. Sci. 2 4–10

    Google Scholar 

  • Ohkawa H, Okishi N and Yagi K 1979 Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 95 351–358

    CAS  PubMed  Article  Google Scholar 

  • Pacher P, Beckman JS and Liaudet L 2007 Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87 315–424

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Parthasarathy JN, Ramasundaram SK, Sundaramahalingam M and Pathinasamy SD 2006 Methanol induced oxidative stress in rat lymphoid organs. J. Occup. Health 48 20–27

    CAS  PubMed  Article  Google Scholar 

  • Petnehazy T, Stokes KY, Wood KC, Russell J and Granger DN 2006 Role of blood cell-associated AT1 receptors in the microvascular responses to hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 26 313–318

    CAS  PubMed  Article  Google Scholar 

  • Pick E and Keisari Y 1980 A simple colorimetric method for the measurement of hydrogen peroxide produced by cells in culture. J. Immunol. Methods 38 161–170

    CAS  PubMed  Article  Google Scholar 

  • Riordan JF and Vallee BL 1972 Nitration with tetranitromethane; in Methods in Enzymology (eds) CHW Hirs and SN Timasheff (New York: Academic Press) 25 515–521

  • Stegink LD 1987 The aspartame story: a model for the clinical testing of a food additive. Am. J. Clin. Nutr. 46 204–215

    CAS  PubMed  Google Scholar 

  • Sugano R, Matsuoka H, Haramaki N, Umei H, Murase E, Fukami K, Iida S, Ikeda H, et al. 2005 Polymorphonuclear leukocytes may impair endothelial function: results of crossover randomized study of lipid-lowering therapies. Arterioscler. Thromb. Vasc. Biol. 25 1262–1267

    CAS  PubMed  Article  Google Scholar 

  • Tephly TR 1991 The toxicity of methanol. Life Sci. 48 1031–1041

    CAS  PubMed  Article  Google Scholar 

  • Van den Eeden SK, Koepsell TD, Longstreth WT Jr, van Belle G, Daling JR and McKnight B 1994 Aspartame ingestion and headaches: a randomized crossover trial. Neurology 44 1787–1793

    PubMed  Article  Google Scholar 

  • Walton RG 1988 The possible role of aspartame in seizure induction; in Dietary phenylalanine and brain function (eds) RJ Wurthman and E Ritter-Walker (Boston: Birkhauser) pp 159–162

    Chapter  Google Scholar 

  • Wang X, Tanus-Santos JE, Reiter CD, Dejam A, Shiva S, Smith RD, Hogg N and Gladwin MT 2004 Biological activity of nitric oxide in the plasmatic compartment. Proc. Natl. Acad. Sci. U. S. A. 101 11477–11482

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Wink DA and Mitchell JB 1998 Chemical biology of nitric oxide: insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Radic. Biol. Med. 25 434–456

    CAS  PubMed  Article  Google Scholar 

  • Winterbourn CC and Stern A 1987 Human red cells scavenge extracellular hydrogen peroxide and inhibit formation of hypochlorous acid and hydroxycal radical. J. Clin. Invest. 80 1486–1491

    CAS  PubMed Central  PubMed  Article  Google Scholar 

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Acknowledgements

This study was supported by the Ministry of Education, Science and Technological Development of Republic of Serbia, grant no. 173041. The authors are grateful to Dr Radmila Paunović Štajn for proofreading this article.

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Correspondence to Branka I Ognjanović.

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[Prokić MD, Paunović MG, Matić MM, Djordjević NZ, Ognjanović BI, Štajn AŠ and Saičić ZS 2014 Prooxidative effects of aspartame on antioxidant defense status in erythrocytes of rats. J. Biosci. 39 1–8] DOI 10.1007/s12038-014-9487-z

Corresponding editor: MARÍA ELIANO LANIO

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Prokić, M.D., Paunović, M.G., Matić, M.M. et al. Prooxidative effects of aspartame on antioxidant defense status in erythrocytes of rats. J Biosci 39, 859–866 (2014). https://doi.org/10.1007/s12038-014-9487-z

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  • DOI: https://doi.org/10.1007/s12038-014-9487-z

Keywords

  • Antioxidative defense system
  • aspartame
  • erythrocytes
  • oxidative stress
  • rat