Skip to main content

Advertisement

Log in

The sulfite molecule enhances homocysteine toxicity in SH-SY5Y cells

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Homocysteine (hcy) is an amino acid that contains sulfur species. In healthy individuals, plasma hcy levels are low. The aim of this study was to investigate the potential neurotoxic effects of hcy and sulfite (sft) molecules alone and in their combination, and also to identify the relationship of these substances on oxidative stress. SH-SY5Y cells were used as an invitro neurodegenerative disease model. The SH-SY5Y cells were treated with various concentrations of hcy alone, sft alone (final concentrations in the well were 10–250 µM and 0.1–5 mM, respectively) and a combination of both (hcy + sft). Their cytotoxicity and genotoxic effects were investigated using the XTT test and Comet assay and, their impact on oxidative stress was examined using total antioxidant–oxidant status (TAS-TOS) kits. The highest toxic doses of hcy and sft were found to be 250 μM and 5 mM, respectively, but the maximum toxic effect was observed for hcy + sft (p < 0.001). In addition, an increase in DNA damage was evident in all groups, but maximal damage was inflicted using in hcy + sft (p < 0.001). The oxidative stress index was significantly increased in hcy + sft (p < 0.05). Determining the increase in sft and hcy levels may contribute to delaying the occurrence of diseases before symptoms of neurodegenerative disease appear.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. du Vigneaud V (1952) A trail of research in sulfur chemistry and metabolism and related fields, vol xii. Cornell University Press, Ithaca, p 191

    Google Scholar 

  2. Finkelstein JD (2000) Pathways and regulation of homocysteine metabolism in mammals. Semin Thromb Hemost 26(3):219–225. https://doi.org/10.1055/s-2000-8466

    Article  CAS  PubMed  Google Scholar 

  3. Moore P, El-sherbeny A, Roon P, Schoenlein PV, Ganapathy V, Smith SB (2001) Apoptotic cell death in the mouse retinal ganglion cell layer is induced in vivo by the excitatory amino acid homocysteine. Exp Eye Res 73(1):45–57

    Article  CAS  Google Scholar 

  4. Ho PI, Ashline D, Dhitavat S, Ortiz D, Collins SC, Shea TB, Rogers E (2003) Folate deprivation induces neurodegeneration: roles of oxidative stress and increased homocysteine. Neurobiol Dis 14(1):32–42

    Article  CAS  Google Scholar 

  5. Kruman II, Culmsee C, Chan SL, Kruman Y, Guo ZH, Penix L, Mattson MP (2000) Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 20(18):6920–6926

    Article  CAS  Google Scholar 

  6. Kruman II, Kumaravel TS, Lohani A, Pedersen WA, Cutler RG, Kruman Y, Haughey N, Lee J, Evans M, Mattson MP (2002) Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer’s disease. J Neurosci 22(5):1752–1762

    Article  CAS  Google Scholar 

  7. Brosnan JT, Brosnan ME (2006) The sulfur-containing amino acids: an overview. J Nutr 136(6 Suppl):1636S–1640S. https://doi.org/10.1093/jn/136.6.1636s

    Article  CAS  PubMed  Google Scholar 

  8. Ostrakhovitch EA, Tabibzadeh S (2015) Homocysteine in chronic kidney disease. Adv Clin Chem 72:77–106. https://doi.org/10.1016/bs.acc.2015.07.002

    Article  CAS  PubMed  Google Scholar 

  9. Castro R, Rivera I, Blom HJ, Jakobs C, Tavares de Almeida I (2006) Homocysteine metabolism, hyperhomocysteinaemia and vascular disease: an overview. J Inherit Metab Dis 29(1):3–20. https://doi.org/10.1007/s10545-006-0106-5

    Article  CAS  PubMed  Google Scholar 

  10. Perna M, Roman MJ, Alpert DR, Crow MK, Lockshin MD, Sammaritano L, Devereux RB, Cooke JP, Salmon JE (2010) Relationship of asymmetric dimethylarginine and homocysteine to vascular aging in systemic lupus erythematosus patients. Arthritis Rheumatol 62(6):1718–1722. https://doi.org/10.1002/art.27392

    Article  Google Scholar 

  11. Keshteli AH, Baracos VE, Madsen KL (2015) Hyperhomocysteinemia as a potential contributor of colorectal cancer development in inflammatory bowel diseases: a review. World J Gastroenterol 21(4):1081–1090. https://doi.org/10.3748/wjg.v21.i4.1081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Obeid R, Herrmann W (2006) Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett 580(13):2994–3005. https://doi.org/10.1016/j.febslet.2006.04.088

    Article  CAS  PubMed  Google Scholar 

  13. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, Wilson PW, Wolf PA (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 346(7):476–483. https://doi.org/10.1056/nejmoa011613

    Article  CAS  PubMed  Google Scholar 

  14. Van Dam F, Van Gool WA (2009) Hyperhomocysteinemia and Alzheimer’s disease: a systematic review. Arch Gerontol Geriatr 48(3):425–430. https://doi.org/10.1016/j.archger.2008.03.009

    Article  CAS  PubMed  Google Scholar 

  15. Ganguly P, Alam SF (2015) Role of homocysteine in the development of cardiovascular disease. Nutr J 14:6. https://doi.org/10.1186/1475-2891-14-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nabi H, Bochud M, Glaus J, Lasserre AM, Waeber G, Vollenweider P, Preisig M (2013) Association of serum homocysteine with major depressive disorder: results from a large population-based study. Psychoneuroendocrinology 38(10):2309–2318. https://doi.org/10.1016/j.psyneuen.2013.04.018

    Article  CAS  PubMed  Google Scholar 

  17. Permoda-Osip A, Dorszewska J, Skibinska M, Chlopocka-Wozniak M, Rybakowski JK (2013) Hyperhomocysteinemia in bipolar depression: clinical and biochemical correlates. Neuropsychobiology 68(4):193–196. https://doi.org/10.1159/000355292

    Article  CAS  PubMed  Google Scholar 

  18. Ho PI, Collins SC, Dhitavat S, Ortiz D, Ashline D, Rogers E, Shea TB (2001) Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress. J Neurochem 78(2):249–253

    Article  CAS  Google Scholar 

  19. Hubmacher D, Tiedemann K, Bartels R, Brinckmann J, Vollbrandt T, Batge B, Notbohm H, Reinhardt DP (2005) Modification of the structure and function of fibrillin-1 by homocysteine suggests a potential pathogenetic mechanism in homocystinuria. J Biol Chem 280(41):34946–34955. https://doi.org/10.1074/jbc.m504748200

    Article  CAS  PubMed  Google Scholar 

  20. Heafield MT, Fearn S, Steventon GB, Waring RH, Williams AC, Sturman SG (1990) Plasma cysteine and sulfate levels in patients with motor-neuron, Parkinsons and Alzheimers-disease. Neurosci Lett 110(1–2):216–220. https://doi.org/10.1016/0304-3940(90)90814-p

    Article  CAS  PubMed  Google Scholar 

  21. McCaddon A, Hudson P, Hill D, Barber J, Lloyd A, Davies G, Regland B (2003) Alzheimer’s disease and total plasma aminothiols. Biol Psychiatry 53(3):254–260

    Article  CAS  Google Scholar 

  22. Kocamaz E, Adiguzel E, Er B, Gundogdu G, Kucukatay V (2012) Sulfite leads to neuron loss in the hippocampus of both normal and SOX-deficient rats. Neurochem Int 61(3):341–346. https://doi.org/10.1016/j.neuint.2012.06.010

    Article  CAS  PubMed  Google Scholar 

  23. Kucukatay V, Bor-Kucukatay M, Atsak P, Agar A (2007) Effect of ingested sulfite on hippocampus antioxidant enzyme activities in sulfite oxidase competent and deficient rats. Int J Neurosci 117(7):971–983. https://doi.org/10.1080/00207450600934085

    Article  CAS  PubMed  Google Scholar 

  24. Sai X, Kawamura Y, Kokame K, Yamaguchi H, Shiraishi H, Suzuki R, Suzuki T, Kawaichi M, Miyata T, Kitamura T, De Strooper B, Yanagisawa K, Komano H (2002) Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid beta-protein. J Biol Chem 277(15):12915–12920. https://doi.org/10.1074/jbc.m112372200

    Article  CAS  PubMed  Google Scholar 

  25. Fontecave M, Atta M, Mulliez E (2004) S-adenosylmethionine: nothing goes to waste. Trends Biochem Sci 29(5):243–249. https://doi.org/10.1016/j.tibs.2004.03.007

    Article  CAS  PubMed  Google Scholar 

  26. Reynolds EH (2014) The neurology of folic acid deficiency. Handb Clin Neurol 120:927–943. https://doi.org/10.1016/b978-0-7020-4087-0.00061-9

    Article  CAS  PubMed  Google Scholar 

  27. Gonsette RE (2008) Neurodegeneration in multiple sclerosis: the role of oxidative stress and excitotoxicity. J Neurol Sci 274(1–2):48–53. https://doi.org/10.1016/j.jns.2008.06.029

    Article  CAS  PubMed  Google Scholar 

  28. Erel O (2005) A new automated colorimetric method for measuring total oxidant status. Clin Biochem 38(12):1103–1111. https://doi.org/10.1016/j.clinbiochem.2005.08.008

    Article  CAS  PubMed  Google Scholar 

  29. Erel O (2004) A novel automated method to measure total antioxidant response against potent free radical reactions. Clin Biochem 37(2):112–119

    Article  CAS  Google Scholar 

  30. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275

    CAS  PubMed  Google Scholar 

  31. Grieco AJ (1977) Homocystinuria: pathogenetic mechanisms. Am J Med Sci 273(2):120–132

    Article  CAS  Google Scholar 

  32. Uttara B, Singh AV, Zamboni P, Mahajan RT (2009) Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 7(1):65–74. https://doi.org/10.2174/157015909787602823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Scola G, Kim HK, Young LT, Andreazza AC (2013) A fresh look at complex I in microarray data: clues to understanding disease-specific mitochondrial alterations in bipolar disorder. Biol Psychiatry 73(2):E4–E5. https://doi.org/10.1016/j.biopsych.2012.06.028

    Article  PubMed  Google Scholar 

  34. Yao JK, Keshavan MS (2011) Antioxidants, redox signaling, and pathophysiology in schizophrenia: an integrative view. Antioxid Redox Signal 15(7):2011–2035. https://doi.org/10.1089/ars.2010.3603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ventura P, Panini R, Verlato C, Scarpetta G, Salvioli G (2000) Peroxidation indices and total antioxidant capacity in plasma during hyperhomocysteinemia induced by methionine oral loading. Metab, Clin Exp 49(2):225–228. https://doi.org/10.1016/s0026-0495(00)91403-3

    Article  CAS  Google Scholar 

  36. McCully KS (1969) Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 56(1):111–128

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Finkelstein JD (1998) The metabolism of homocysteine: pathways and regulation. Eur J Pediatr 157:S40–S44. https://doi.org/10.1007/pl00014300

    Article  CAS  PubMed  Google Scholar 

  38. Mosharov E, Cranford MR, Banerjee R (2000) The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes. Biochemistry 39(42):13005–13011

    Article  CAS  Google Scholar 

  39. Hoffer LJ (2002) Methods for measuring sulfur amino acid metabolism. Curr Opin Clin Nutr Metab Care 5(5):511–517

    Article  CAS  Google Scholar 

  40. Hoffer LJ (2004) Homocysteine remethylation and trans-sulfuration. Metabolism 53(11):1480–1483

    Article  CAS  Google Scholar 

  41. Lowicka E, Beltowski J (2007) Hydrogen sulfide (H2S)—the third gas of interest for pharmacologists. Pharmacol Rep 59(1):4–24

    CAS  PubMed  Google Scholar 

  42. Reist M, Jenner P, Halliwell B (1998) Sulphite enhances peroxynitrite-dependent alpha1-antiproteinase inactivation. A mechanism of lung injury by sulphur dioxide? FEBS Lett 423(2):231–234

    Article  CAS  Google Scholar 

  43. White AR, Huang X, Jobling MF, Barrow CJ, Beyreuther K, Masters CL, Bush AI, Cappai R (2001) Homocysteine potentiates copper- and amyloid beta peptide-mediated toxicity in primary neuronal cultures: possible risk factors in the Alzheimer’s-type neurodegenerative pathways. J Neurochem 76(5):1509–1520

    Article  CAS  Google Scholar 

  44. Surtees R, Leung DY, Bowron A, Leonard J (1997) Cerebrospinal fluid and plasma total homocysteine and related metabolites in children with cystathionine β-synthase deficiency: the effect of treatment. Pediatr Res 42(5):577

    Article  CAS  Google Scholar 

  45. Huang RF, Hsu YC, Lin HL, Yang FL (2001) Folate depletion and elevated plasma homocysteine promote oxidative stress in rat livers. J Nutr 131(1):33–38. https://doi.org/10.1093/jn/131.1.33

    Article  CAS  PubMed  Google Scholar 

  46. Corrales FJ, Perez-Mato I, Sanchez Del Pino MM, Ruiz F, Castro C, Garcia-Trevijano ER, Latasa U, Martinez-Chantar ML, Martinez-Cruz A, Avila MA, Mato JM (2002) Regulation of mammalian liver methionine adenosyltransferase. J Nutr 132(8 Suppl):2377S–2381S. https://doi.org/10.1093/jn/132.8.2377s

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by Pamukkale University Scientific Research Projects Coordination Unit with Project Numbers 2011TPF024. We thanks to Dr. Ertugrul Kilic for kindly providing SH-SY5Y cells to us.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gulsah Gundogdu.

Ethics declarations

Conflict of interest

None.

Ethical approval

This paper contains only in vitro cell culture studies. Therefore, Ethics Committee approval and information on informed consent were not required.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gundogdu, G., Dodurga, Y. & Kucukatay, V. The sulfite molecule enhances homocysteine toxicity in SH-SY5Y cells. Mol Biol Rep 46, 4017–4025 (2019). https://doi.org/10.1007/s11033-019-04850-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-019-04850-3

Keywords

Navigation