Advertisement

Cellular and Molecular Neurobiology

, Volume 31, Issue 3, pp 429–436 | Cite as

Evidence that l-Carnitine and Selenium Supplementation Reduces Oxidative Stress in Phenylketonuric Patients

  • A. Sitta
  • C. S. Vanzin
  • G. B. Biancini
  • V. Manfredini
  • A. B. de Oliveira
  • C. A. Y. Wayhs
  • G. O. S. Ribas
  • L. Giugliani
  • I. V. D. Schwartz
  • D. Bohrer
  • S. C. Garcia
  • M. Wajner
  • C. R. Vargas
Original Research

Abstract

It is well established that the involvement of reactive species in the pathophysiology of several neurological diseases, including phenylketonuria (PKU), a metabolic genetic disorder biochemically characterized by elevated levels of phenylalanine (Phe). In previous studies, we verified that PKU patients (treated with a protein-restricted diet supplemented with a special formula not containing l-carnitine and selenium) presented high lipid and protein oxidative damage as well as a reduction of antioxidants when compared to the healthy individuals. Our goal in the present study was to evaluate the effect of Phe-restricted diet supplemented with l-carnitine and selenium, two well-known antioxidant compounds, on oxidative damage in PKU patients. We investigated various oxidative stress parameters in blood of 18 treated PKU patients before and after 6 months of supplementation with a special formula containing l-carnitine and selenium. It was verified that treatment with l-carnitine and selenium was capable of reverting the lipid peroxidation, measured by thiobarbituric acid-reactive species, and the protein oxidative damage, measured by sulfhydryl oxidation, to the levels of controls. Additionally, the reduced activity of glutathione peroxidase was normalized by the antioxidant supplementation. It was also verified a significant inverse correlation between lipid peroxidation and l-carnitine blood levels as well as a significant positive correlation between glutathione peroxidase activity and blood selenium concentration. In conclusion, our results suggest that supplementation of l-carnitine and selenium is important for PKU patients since it could help to correct the oxidative stress process which possibly contributes, at least in part, to the neurological symptoms found in phenylketonuric patients.

Keywords

Phenylketonuria Oxidative stress l-Carnitine Selenium 

Notes

Acknowledgments

This work was supported in part by grants from FAPERGS, CNPq, and FIPE/HCPA-Brazil.

References

  1. Acosta PB (1996) Nutrition studies in treated infants and children with phenylketonuria: vitamins, minerals, trace elements. Eur J Pediatr 155:136–139CrossRefGoogle Scholar
  2. Adibhatla RM, Hatcher JF (2010) Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 12:125–169CrossRefPubMedGoogle Scholar
  3. Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126CrossRefPubMedGoogle Scholar
  4. Aksenov MY, Markesbery WR (2001) Changes in thiol content and expression of glutathione redox system genes in the hippocampus and cerebellum in Alzheimer’s disease. Neurosci Lett 302:141–145CrossRefPubMedGoogle Scholar
  5. Artuch R, Vilaseca MA, Moreno J, Lambruschini N, Cambra FJ, Campistol J (1999) Decreased serum ubiquinone-10 concentration in phenylketonuria. Am J Clin Nutr 70:892–895PubMedGoogle Scholar
  6. Artuch R, Colome C, Vilaseca MA, Sierra C, Cambra FJ, Lambruschini N, Campistol J (2001) Plasma phenylalanine is associated with decreased serum ubiquinone-10 concentrations in phenylketonuria. J Inherit Metab Dis 24:359–366CrossRefPubMedGoogle Scholar
  7. Artuch R, Colome C, Sierra C, Brandi N, Lambruschini N, Campistol J, Ugarte D, Vilaseca MA (2004) A longitudinal study of antioxidant status in phenylketonuric patients. Clin Biochem 37:198–203CrossRefPubMedGoogle Scholar
  8. Barschak AG, Sitta A, Deon M, Busanello EN, Coelho DM, Cipriani F, Dutra-Filho CS, Giugliani R, Wanjer M, Vargas CR (2009) Amino acids levels and lipid peroxidation in maple syrup urine disease patients. Clin Biochem 42:462–466CrossRefPubMedGoogle Scholar
  9. Bickel H, Gerrard J, Hickmans EM (1953) Influence of phenylalanine intake on phenylketonuria. Lancet 265:812–813CrossRefPubMedGoogle Scholar
  10. Carmagnol F, Sinet PM, Jerome H (1983) Selenium-dependent and nonselenium-dependent glutathione peroxidases in human tissue extracts. Biochim Biophys Acta 759:49–57PubMedGoogle Scholar
  11. Chace DH, Hillman SL, Van Hove JLK, Naylor EW (1997) Rapid diagnosis of MCAD deficiency: quantitative analysis of octanoylcarnitine and other acylcarnitines in newborn blood spots by tandem mass spectrometry. Clin Chem 43:2106–2113PubMedGoogle Scholar
  12. Chaudière J (1994) Some chemical and biochemical constraints of oxidative stress in living cells. In: Riee-Evans CA, Burdon RH (eds) Free radical damage and its control. Elsevier, Amsterdam, pp 25–66CrossRefGoogle Scholar
  13. Colome C, Artuch R, Vilaseca MA, Sierra C, Brandi N, Lambruschini N, Cambra FJ, Campistol J (2003) Lipophilic antioxidants in patients with phenylketonuria. Am J Clin Nutr 77:185–188PubMedGoogle Scholar
  14. Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R (2003) Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta 329:23–38CrossRefPubMedGoogle Scholar
  15. Dalle-Donne I, Scaloni A, Giustarini D, Cavarra E, Tell G, Lungarella G, Colombo R, Rossi R, Milzani A (2005) Proteins as biomarkers of oxidative/nitrosative stress in diseases: the contribution of redox proteomics. Mass Spectr Rev 24:55–99CrossRefGoogle Scholar
  16. Dalle-Donne I, Aldini G, Carini M, Colombo R, Rossi R, Milzani A (2006) Protein carbonylation, cellular dysfunction, and disease progression. J Cell Mol Med 10:389–406CrossRefPubMedGoogle Scholar
  17. Davies MJ, Fu S, Wang H, Dean RT (1999) Stable markers of oxidant damage to proteins and their application in study of human disease. Free Radic Biol Med 27:1151–1161CrossRefPubMedGoogle Scholar
  18. Deon M, Sitta A, Barschak AG, Coelho DM, Pigatto M, Schmitt GO, Jardim LB, Giugliani R, Wajner M, Vargas CR (2007) Induction of lipid peroxidation and decrease of antioxidant defenses in symptomatic and asymptomatic patients with X-linked adrenoleukodystrophy. Int J Dev Neurosci 25:441–447CrossRefPubMedGoogle Scholar
  19. Derin N, Izgut-Uysal VN, Agac A, Aliciguzel Y, Demir N (2004) l-carnitine protects gastric mucosa by decreasing ischemia reperfusion induced lipid peroxidation. J Physiol Pharmacol 55:595–606PubMedGoogle Scholar
  20. Ercal N, Aykin-Burns N, Gurer-Orhan H, Mcdonald JD (2002) Oxidative stress in a phenylketonuria animal model. Free Radic Biol Med 32:906–911CrossRefPubMedGoogle Scholar
  21. Esterbauer H, Cheeseman KH (1990) Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Methods Enzymol 186:407–421CrossRefPubMedGoogle Scholar
  22. German B (1999) Free radical and antioxidant protocols. Humana Press, TotowaGoogle Scholar
  23. Greenberg ME, Li XM, Gugiu BG, Gu X, Qin J, Salomon RG, Hazen SL (2008) The lipid Whisker model of the structure of oxidized cell membranes. J Biol Chem 283:2385–2396CrossRefPubMedGoogle Scholar
  24. Hagen MEK, Pederzolli CD, Sgaravatti AM, Bridi R, Wajner M, Wanmacher CMD, Wyse ATS, Dutra-Filho CS (2002) Experimental hyperphenylalaninemia provokes oxidative stress in rat brain. Biochim Biophys Acta 1586:344–352Google Scholar
  25. Halliwell B, Gutteridge JMC (2007) Oxidative stress: adaptation, damage, repair and death. In: Halliwell B, Gutteridge JMC (eds) Free radicals in biology and medicine. Oxford University Press, Oxford, pp 246–350Google Scholar
  26. Huttenlocher PR (2000) The neuropathology of phenylketonuria: human and animal studies. Eur J Pediatr 159:102–106CrossRefGoogle Scholar
  27. Lombeck I, Jochum F, Terwolbeck K (1996) Selenium status in infants and children with phenylketonuria and in maternal phenylketonuria. Eur J Pediatr 155:140–144CrossRefGoogle Scholar
  28. Lowry OH, Rosebrough NJ, Lewis-Farr A, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  29. Markesbery WR, Lovell MA (2007) Damage to lipids, proteins, DNA, and RNA in mild cognitive impairment. Arch Neurol 64:954–956CrossRefPubMedGoogle Scholar
  30. Martinez-Cruz F, Pozo D, Osuna C, Espinar A, Marchante C, Guerrero JM (2002) Oxidative stress induced by phenylketonuria in the rat: prevent by melatonin, vitamin E and vitamin C. J Neurosci Res 69:550–558CrossRefPubMedGoogle Scholar
  31. Mc Guire PJ, Parikh A, Diaz GA (2009) Profiling of oxidative stress in patients with inborn errors of metabolism. Mol Genet Metab 98:173–180CrossRefPubMedGoogle Scholar
  32. Paglia DE, Valentine WN (1967) Glutathione peroxidase. J Lab Clin Med 70:158PubMedGoogle Scholar
  33. Pietta PG (2000) Flavonoids as antioxidants. J Nat Prod 63:1035–1042CrossRefPubMedGoogle Scholar
  34. Rajasekar P, Kaviarasan S, Anuradha CV (2005) l-carnitine administration prevents oxidative stress in high fructose-fed insulin resistant rats. Diab Croat 34:21–28Google Scholar
  35. Reznick AZ, Packer L (1994) Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Methods Enzymol 233:357–363CrossRefPubMedGoogle Scholar
  36. Ribas GS, Manfredini V, de Mari JF, Wayhs CY, Vanzin CS, Biancini GB, Sitta A, Deon M, Wajner M, Vargas CR (2010) Reduction of lipid and protein damage in patients with disorders of propionate metabolism under treatment: a possible protective role of l-carnitine supplementation. Int J Dev Neurosci 28:127–132CrossRefPubMedGoogle Scholar
  37. Schulpis KH, Nounopoulos C, Scarpalezou A, Bouloukos A, Missiou-Tsagarakis S (1990) Serum carnitine level in phenylketonuric children under dietary control in Greece. Acta Paediatr Scand 79:930–934CrossRefPubMedGoogle Scholar
  38. Schulpis KH, Tsakiris S, Traeger-Synodinos J, Papassotiriou I (2005) Low total antioxidant status is implicated with high 8-hydroxy-2-deoxyguanosine serum concentrations in phenylketonuria. Clin Biochem 38:239–242CrossRefPubMedGoogle Scholar
  39. Scriver CR, Kaufman S (2001) Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 1667–1724Google Scholar
  40. Sierra C, Vilaseca MA, Moyano D, Brandi N, Campistol J, Lambruschini N, Cambra FJ, Deulofeu R, Mira A (1998) Antioxidant status in hyperphenylalaninemia. Clin Chim Acta 276:1–9CrossRefPubMedGoogle Scholar
  41. Sirtori LR, Dutra-Filho CS, Fitarelli D, Sitta A, Haeser A, Barschak AG, Wajner M, Coelho DM, Llesuy S, Belló-Klein A, Giugliani R, Deon M, Vargas CR (2005) Oxidative stress in patients with phenylketonuria. Biochim Biophys Acta 1740:68–73PubMedGoogle Scholar
  42. Sitta A, Barschak AG, Deon M, Terroso T, Pires R, Giugliani R, Dutra-Filho CS, Wajner M, Vargas CR (2006) Investigation of oxidative stress parameters in treated phenylketonuric patients. Metab Brain Dis 21:287–296CrossRefPubMedGoogle Scholar
  43. Sitta A, Barschak AG, Deon M, Barden AT, Biancini GB, Vargas PR, de Souza CF, Netto C, Wajner M, Vargas CR (2009a) Effect of short- and long-term exposition to high phenylalanine blood levels on oxidative damage in phenylketonuric patients. Int J Dev Neurosci 27:243–247CrossRefPubMedGoogle Scholar
  44. Sitta A, Barschak AG, Deon M, De Mari JF, Barden AB, Vanzin C, Biancini GB, Schwartz IVD, Wajner M, Vargas CR (2009b) l-Carnitine blood levels and oxidative stress in treated phenylketonuric patients. Cell Mol Nurobiol 29:211–218CrossRefGoogle Scholar
  45. Smith DG, Cappai R, Barnham KJ (2007) The redox chemistry of the Alzheimer’s disease amyloid-b peptide. Biochim Biophys Acta 1768:1976–1990CrossRefPubMedGoogle Scholar
  46. Start K (1998) Treating phenylketonuria by a phenylalanine-free diet. Prof Care Mother Child 8:109–110PubMedGoogle Scholar
  47. van Backel MME, Printzen G, Wermuth B, Wiesmann UN (2000) Antioxidant and thyroid hormone status in selenium-deficient phenylketonuric and hyperphenylalaninemic patients. Am J Clin Nutr 72:976–981Google Scholar
  48. Van Spronsen FJ, Smit PG, Koch R (2001) Phenylketonuria: tyrosine beyond the phenylalanine-restricted diet. J Inherit Metab Dis 24:1–4CrossRefPubMedGoogle Scholar
  49. Wilke BC, Vidailhet M, Favier A, Guillemin C, Ducros V, Arnaud J, Richard MJ (1992) Selenium, glutathione peroxidase (GSH-Px) and lipid peroxidation products before and after selenium supplementation. Clin Chim Acta 207:137–142CrossRefPubMedGoogle Scholar
  50. Woo HA, Chae HZ, Hwang SC, Yang KS, Kang SW, Kim K, Rhee SG (2003) Reversing the inactivation of peroxiredoxin caused by cysteine sulfinic acid formation. Science 300:53–656CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • A. Sitta
    • 1
    • 2
  • C. S. Vanzin
    • 1
    • 2
  • G. B. Biancini
    • 1
    • 2
  • V. Manfredini
    • 3
    • 4
  • A. B. de Oliveira
    • 1
  • C. A. Y. Wayhs
    • 1
    • 4
  • G. O. S. Ribas
    • 1
    • 4
  • L. Giugliani
    • 1
  • I. V. D. Schwartz
    • 1
  • D. Bohrer
    • 5
  • S. C. Garcia
    • 4
  • M. Wajner
    • 1
    • 2
  • C. R. Vargas
    • 1
    • 2
    • 4
  1. 1.Serviço de Genética MédicaHCPA, UFRGSPorto AlegreBrazil
  2. 2.Programa de Pós-Graduação em CB:BioquímicaUFRGSPorto AlegreBrazil
  3. 3.Universidade Regional Integrada do Alto Uruguai e das MissõesErechimBrazil
  4. 4.Programa de Pós-Graduação em Ciências FarmacêuticasUFRGSPorto AlegreBrazil
  5. 5.Departamento de QuímicaUFSMSanta MariaBrazil

Personalised recommendations