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Oxidative Stress in Phenylketonuria: What is the Evidence?

  • Graziela S. Ribas
  • Angela Sitta
  • Moacir Wajner
  • Carmen R. Vargas
Review Paper

Abstract

Phenylketonuria (PKU) is an inborn error of amino acid metabolism caused by severe deficiency of phenylalanine hydroxylase activity, leading to the accumulation of phenylalanine and its metabolites in blood and tissues of affected patients. Phenylketonuric patients present as the major clinical feature mental retardation, whose pathomechanisms are poorly understood. In recent years, mounting evidence has emerged indicating that oxidative stress is possibly involved in the pathology of PKU. This article addresses some of the recent developments obtained from animal studies and from phenylketonuric patients indicating that oxidative stress may represent an important element in the pathophysiology of PKU. Several studies have shown that enzymatic and non-enzymatic antioxidant defenses are decreased in plasma and erythrocytes of PKU patients, which may be due to an increased free radical generation or secondary to the deprivation of micronutrients which are essential for these defenses. Indeed, markers of lipid, protein, and DNA oxidative damage have been reported in PKU patients, implying that reactive species production is increased in this disorder. A considerable set of data from in vitro and in vivo animal studies have shown that phenylalanine and/or its metabolites elicit reactive species in brain rodent. These findings point to a disruption of pro-oxidant/antioxidant balance in PKU. Considering that the brain is particularly vulnerable to oxidative attack, it is presumed that the administration of appropriate antioxidants as adjuvant agents, in addition to the usual treatment based on restricted diets or supplementation of tetrahydrobiopterin, may represent another step in the prevention of the neurological damage in PKU.

Keywords

Phenylketonuria Oxidative stress Antioxidants Free radicals 

Notes

Acknowledgments

This study was supported by CAPES, CNPq, and FIPE/HCPA-Brazil.

References

  1. Acosta PB, Yannicelli S, Marriage B, Steiner R, Gaffield B, Arnold G, Lewis V, Cho S, Berstein L, Parton P, Leslie N, Korson M (1999) Protein status of infants with phenylketonuria undergoing nutrition management. J Am Coll Nutr 18:102–107PubMedGoogle Scholar
  2. Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence? Nat Med 10(Suppl):S18–S25PubMedCrossRefGoogle Scholar
  3. Araujo GC, Christ SE, Steiner RD, Grange DK, Nardos B, McKinstry RC, White DA (2009) Response monitoring in children with phenylketonuria. Neuropsychology 23:130–134PubMedCrossRefGoogle Scholar
  4. Artuch R, Vilaseca MA, Moreno J, Lambruschini N, Cambra FJ, Campistol J (1999) Decreased serum ubiquinone-10 concentrations in phenylketonuria. Am J Clin Nutr 70:892–895PubMedGoogle Scholar
  5. Artuch R, Colomé 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 24:359–366PubMedCrossRefGoogle Scholar
  6. Artuch R, Colomé 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 37:198–203PubMedCrossRefGoogle Scholar
  7. Barschak AG, Sitta A, Deon M, de Oliveira MH, Haeser A, Dutra-Filho CS, Wajner M, Vargas CR (2006) Evidence that oxidative stress is increased in plasma from patients with maple syrup urine disease. Metab Brain Dis 21:279–286PubMedCrossRefGoogle Scholar
  8. Barschak AG, Sitta A, Deon M, Barden AT, Schmitt GO, Dutra-Filho CS, Wajner M, Vargas CR (2007) Erythrocyte glutathione peroxidase activity and plasma selenium concentration are reduced in maple syrup urine disease patients during treatment. Int J Dev Neurosci 25:335–338PubMedCrossRefGoogle Scholar
  9. Barschak AG, Sitta A, Deon M, Barden AT, Dutra-Filho CS, Wajner M, Vargas CR (2008) Oxidative stress in plasma from maple syrup urine disease patients during treatment. Metab Brain Dis 23:71–80PubMedCrossRefGoogle Scholar
  10. Bauman ML, Kemper TL (1982) Morphologic and histoanatomic observations of the brain in untreated human phenylketonuria. Acta Neuropathol 58:55–63PubMedCrossRefGoogle Scholar
  11. Bertelli A, Conte A, Ronca G (1994) L-propionyl carnitine protects erythrocytes and low density lipoproteins against peroxidation. Drugs Exp Clin Res 20:191–197PubMedGoogle Scholar
  12. Bindoli A, Rigobello MP, Deeble DJ (1992) Biochemical and toxicological properties of the oxidation products of catecholamines. Free Radic Biol Med 13:391–405PubMedCrossRefGoogle Scholar
  13. Bird S, Miller NJ, Collins JE, Rice-Evans CA (1995) Plasma antioxidant capacity in two cases of tyrosinaemia type 1: one case treated with NTBC. J Inherit Metab Dis 18:123–126PubMedCrossRefGoogle Scholar
  14. Boje KM, Arora PK (1992) Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Res 587:250–256PubMedCrossRefGoogle Scholar
  15. Bridi R, Braun CA, Zorzi GK, Wannmacher CM, Wajner M, Lissi EG, Dutra-Filho CS (2005) Alpha-keto acids accumulating in maple syrup urine disease stimulate lipid peroxidation and reduce antioxidant defences in cerebral cortex from young rats. Metab Brain Dis 20:155–167PubMedCrossRefGoogle Scholar
  16. Brigelius-Flohé R (1999) Tissue-specific functions of individual glutathione peroxidases. Free Radic Biol Med 27:951–965PubMedCrossRefGoogle Scholar
  17. Burri R, Steffen C, Stieger S, Brodbeck U, Colombo JP, Herschkowitz N (1990) Reduced myelinogenesis and recovery in hyperphenylalaninemic rats. Correlation between brain phenylalanine levels, characteristic brain enzymes for myelination, and brain development. Mol Chem Neuropathol 13:57–69PubMedCrossRefGoogle Scholar
  18. Cadenas E (1997) Basic mechanisms of antioxidant activity. Biofactors 6:391–397PubMedCrossRefGoogle Scholar
  19. Cadenas E, Sies H (1998) The lag phase. Free Radic Res 28:601–609PubMedCrossRefGoogle Scholar
  20. Castaño A, Ayala A, Rodríguez-Gómez JA, Herrera AJ, Cano J, Machado A (1997) Low selenium diet increases the dopamine turnover in prefrontal cortex of the rat. Neurochem Int 30:549–555PubMedCrossRefGoogle Scholar
  21. Castillo M, Zafra MF, Garcia-Peregrin E (1988) Inhibition of brain and liver 3-hydroxy-3-methylglutaryl-CoA reductase and mevalonate-5-pyrophosphate decarboxylase in experimental hyperphenylalaninemia. Neurochem Res 13:551–555PubMedCrossRefGoogle Scholar
  22. Chinopoulos C, Adam-Vizi V (2001) Mitochondria deficient in complex I activity are depolarized by hydrogen peroxide in nerve terminals: relevance to Parkinson’s disease. J Neurochem 76:302–306PubMedCrossRefGoogle Scholar
  23. Colomé C, Sierra C, Antònia Vilaseca M (2000) Congenital errors of metabolism: cause of oxidative stress? Med Clin (Barc) 115:111–117Google Scholar
  24. Colomé 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
  25. Colton C, Wilt S, Gilbert D, Chernyshev O, Snell J, Dubois-Dalcq M (1996) Species differences in the generation of reactive oxygen species by microglia. Mol Chem Neuropathol 28:15–20PubMedCrossRefGoogle Scholar
  26. Costabeber E, Kessler A, Severo Dutra-Filho C, de Souza Wyse AT, Wajner M, Wannmacher CM (2003) Hyperphenylalaninemia reduces creatine kinase activity in the cerebral cortex of rats. Int J Dev Neurosci 21:111–116PubMedCrossRefGoogle Scholar
  27. Curtius HC, Niederwieser A, Viscontini M, Leimbacher W, Wegmann H, Blehova B, Rey F, Schaub J, Schmidt H (1981) Serotonin and dopamine synthesis in phenylketonuria. Adv Exp Med Biol 133:277–291PubMedGoogle Scholar
  28. Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R (2003) Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta 329:23–38PubMedCrossRefGoogle Scholar
  29. Dalle-Donne I, Rossi R, Colombo R, Giustarini D, Milzani A (2006) Biomarkers of oxidative damage in human disease. Clin Chem 52:601–623PubMedCrossRefGoogle Scholar
  30. Darling G, Mathias P, O’Regan M, Naughten E (1992) Serum selenium levels in individuals on PKU diets. J Inherit Metab Dis 15:769–773PubMedCrossRefGoogle Scholar
  31. de Freitas MS, de Mattos AG, Camargo MM, Wannmacher CM, Pessoa-Pureur R (1995) Effect of phenylalanine and alpha-methylphenylalanine on in vitro incorporation of 32P into cytoskeletal cerebral proteins. Neurochem Int 26:381–385PubMedCrossRefGoogle Scholar
  32. de Oliveira Marques F, Hagen ME, Pederzolli CD, Sgaravatti AM, Durigon K, Testa CG, Wannmacher CM, de Souza Wyse AT, Wajner M, Dutra-Filho CS (2003) Glutaric acid induces oxidative stress in brain of young rats. Brain Res 964:153–158PubMedCrossRefGoogle Scholar
  33. Di Lisa F, Bernardi P (1998) Mitochondrial function as a determinant of recovery or death in cell response to injury. Mol Cell Biochem 184:379–391PubMedCrossRefGoogle Scholar
  34. Dizdaroglu M, Jaruga P, Birincioglu M, Rodriguez H (2002) Free radical-induced damage to DNA: mechanisms and measurement. Free Radic Biol Med 32:1102–1115PubMedCrossRefGoogle Scholar
  35. Draper HH, Hadley M (1990) A review of recent studies on the metabolism of exogenous and endogenous malondialdehyde. Xenobiotica 20:901–907PubMedCrossRefGoogle Scholar
  36. Duez P, Helson M, Some TI, Dubois J, Hanocq M (2000) Chromatographic determination of 8-oxo-7, 8-dihydro-20-deoxyguanosine in cellular DNA: a validation study. Free Radic Res 33:243–260PubMedCrossRefGoogle Scholar
  37. El Kossi MM, Zakhary MM (2000) Oxidative stress in the context of acute cerebrovascular stroke. Stroke 31:1889–1892PubMedGoogle Scholar
  38. Ellis EM (2007) Reactive carbonyls and oxidative stress: potential for therapeutic intervention. Pharmacol Ther 115:13–24PubMedCrossRefGoogle Scholar
  39. Ercal N, Aykin-Burns N, Gurer-Orhan H, McDonald JD (2002) Oxidative stress in a phenylketonuria animal model. Free Radic Biol Med 32:906–911PubMedCrossRefGoogle Scholar
  40. Esterbauer H, Schaur RJ, Zollner H (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11:81–128PubMedCrossRefGoogle Scholar
  41. Evans P, Halliwell B (2001) Micronutrients: oxidant/antioxidant status. Br J Nutr 85(suppl 2):S67PubMedCrossRefGoogle Scholar
  42. Fairbairn DW, Olive PL, O’Neill KL (1995) The comet assay: a comprehensive review. Mutat Res 339:35–59Google Scholar
  43. Fang YZ, Yang S, Wu G (2002) Free radicals, antioxidants, and nutrition. Nutrition 18:872–879PubMedCrossRefGoogle Scholar
  44. Feksa LR, Cornelio AR, Rech VC, Dutra-Filho CS, Wyse AT, Wajner M, Wannmacher CM (2002) Alanine prevents the reduction of pyruvate kinase activity in brain cortex of rats subjected to chemically induced hyperphenylalaninemia. Neurochem Res 27:947–952PubMedCrossRefGoogle Scholar
  45. Fernandes CG, Leipnitz G, Seminotti B, Amaral AU, Zanatta A, Vargas CR, Dutra Filho CS, Wajner M (2010) Experimental evidence that phenylalanine provokes oxidative stress in hippocampus and cerebral cortex of developing rats. Cell Mol Neurobiol 30:317–326PubMedCrossRefGoogle Scholar
  46. Ferrari R, Ciampalini G, Agnoletti G, Cargnoni A, Ceconi C, Visioli O (1988) Effect of L-carnitine derivatives on heart mitochondrial damage induced by lipid peroxidation. Pharmacol Res Commun 20:125–132PubMedCrossRefGoogle Scholar
  47. Fontella FU, Pulrolnik V, Gassen E, Wannmacher CM, Klein AB, Wajner M, Dutra-Filho CS (2000) Propionic and L-methylmalonic acids induce oxidative stress in brain of young rats. Neuroreport 11:541–544PubMedCrossRefGoogle Scholar
  48. Fridovich I (1995) Superoxide radical and superoxide dismutases. Annu Rev Biochem 64:97–112PubMedCrossRefGoogle Scholar
  49. Fridovich I (1999) Fundamental aspects of reactive oxygen species, or what’s the matter with oxygen? Ann N Y Acad Sci 893:13–18PubMedCrossRefGoogle Scholar
  50. Gassió R, Artuch R, Vilaseca MA, Fusté E, Colome R, Campistol J (2008) Cognitive functions and the antioxidant system in phenylketonuric patients. Neuropsychology 22:426–431PubMedCrossRefGoogle Scholar
  51. Giovannini M, Verduci E, Salvatici E, Fiori L, Riva E (2007) Phenylketonuria: dietary and therapeutic challenges. J Inherit Metab Dis 30:145–152PubMedCrossRefGoogle Scholar
  52. Gülçin I (2006) Antioxidant and antiradical activities of L-carnitine. Life Sci 78:803–811PubMedCrossRefGoogle Scholar
  53. Halliwell B (2001) Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs Aging 18:685–716PubMedCrossRefGoogle Scholar
  54. Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97:1634–1658PubMedCrossRefGoogle Scholar
  55. Halliwell B, Gutteridge JMC (1999) 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
  56. Halliwell B, Gutteridge JMC (2007) Free radicals in biology and medicine. Clarendon Press, OxfordGoogle Scholar
  57. Hanley WB, Lee AW, Hanley AJ, Lehotay DC, Austin VJ, Schoonheyt WE, Platt BA, Clarke JT (2000) “Hypotyrosinemia” in phenylketonuria. Mol Genet Metab 69:286–294PubMedCrossRefGoogle Scholar
  58. Hasselbalch S, Knudsen GM, Toft PB, Hogh P, Tedeschi E, Holm S, Videbaek C, Henriksen O, Lou HC, Paulson OB (1996) Cerebral glucose metabolism is decreased in white matter changes in patients with phenylketonuria. Pediatr Res 40:21–24PubMedCrossRefGoogle Scholar
  59. Hawkins CL, Morgan PE, Davies MJ (2009) Quantification of protein modification by oxidants. Free Radic Biol Med 46:965–988PubMedCrossRefGoogle Scholar
  60. Heales SJ, Bolaños JP, Brand MP, Clark JB, Land JM (1996) Mitochondrial damage: an important feature in a number of inborn errors of metabolism? J Inherit Metab Dis 19:140–142PubMedCrossRefGoogle Scholar
  61. Himwich HE (1951) Thought processes as related to brain metabolism in certain abnormal conditions. J Nerv Ment Dis 114:450–458PubMedGoogle Scholar
  62. Ischiropoulos H (2003) Biological selectivity and functional aspects of protein tyrosine nitration. Biochem Biophys Res Commun 305:776–783PubMedCrossRefGoogle Scholar
  63. Jenner P, Olanow CW (1996) Oxidative stress and the pathogenesis of Parkinson’s disease. Neurology 47:S161–S170PubMedGoogle Scholar
  64. Kaneko T, Tahara S, Matsuo M (1996) Non-linear accumulation of 8-hydroxy-2′-deoxyguanosine, a marker of oxidized DNA damage, during aging. Mutat Res 316:277–285PubMedGoogle Scholar
  65. Kienzle Hagen ME, Pederzolli CD, Sgaravatti AM, Bridi R, Wajner M, Wannmacher CM, Wyse AT, Dutra-Filho CS (2002) Experimental hyperphenylalaninemia provokes oxidative stress in rat brain. Biochim Biophys Acta 1586:344–352PubMedGoogle Scholar
  66. Kovacic P, Pozos RS, Somanathan R, Shangari N, O’Brien PJ (2005) Mechanism of mitochondrial uncouplers, inhibitors, and toxins: focus on electron transfer, free radicals, and structure-activity relationships. Curr Med Chem 12:2601–2623PubMedCrossRefGoogle Scholar
  67. Krause W, Halminski M, McDonald L, Dembure P, Salvo R, Freides D, Elsas L (1985) Biochemical and neuropsychological effects of elevated plasma phenylalanine in patients with treated phenylketonuria. A model for the study of phenylalanine and brain function in man. J Clin Invest 75:40–48PubMedCrossRefGoogle Scholar
  68. Lambruschini N, Pérez-Dueñas B, Vilaseca MA, Mas A, Artuch R, Gassió R, Gómez L, Gutiérrez A, Campistol J (2005) Clinical and nutritional evaluation of phenylketonuric patients on tetrahydrobiopterin monotherapy. Mol Genet Metab 86(Suppl 1):S54–S60PubMedCrossRefGoogle Scholar
  69. Latini A, Borba Rosa R, Scussiato K, Llesuy S, Bello-Klein A, Wajner M (2002) 3-Hydroxyglutaric acid induces oxidative stress and decreases the antioxidant defences in cerebral cortex of young rats. Brain Res 956:367–373PubMedCrossRefGoogle Scholar
  70. Leipnitz G, Seminotti B, Amaral AU, de Bortoli G, Solano A, Schuck PF, Wyse AT, Wannmacher CM, Latini A, Wajner M (2008) Induction of oxidative stress by the metabolites accumulating in 3-methylglutaconic aciduria in cerebral cortex of young rats. Life Sci 82:652–662PubMedCrossRefGoogle Scholar
  71. Levine RL (2001) Carbonyl modified proteins in cellular regulation, aging, and disease. Free Radic Biol Med 32:790–796CrossRefGoogle Scholar
  72. Lissi E, Salim-Hanna M, Pascual C, del Castillo MD (1995) Evaluation of total antioxidant potential (TRAP) and total antioxidant reactivity from luminol-enhanced chemiluminescence measurements. Free Radic Biol Med 18:153–158PubMedCrossRefGoogle Scholar
  73. Liu D, Wen J, Liu J, Li L (1999) The roles of free radicals in amyotrophic lateral sclerosis: reactive oxygen species and elevated oxidation of protein, DNA, and membrane phospholipids. FASEB J 13:2318–2328PubMedGoogle Scholar
  74. Lütz Mda G, Feksa LR, Wyse AT, Dutra-Filho CS, Wajner M, Wannmacher CM (2003) Alanine prevents the in vitro inhibition of glycolysis caused by phenylalanine in brain cortex of rats. Metab Brain Dis 18:87–94PubMedCrossRefGoogle Scholar
  75. Martinez-Cruz F, Pozo D, Osuna C, Espinar A, Marchante C, Guerrero JM (2002) Oxidative stress induced by phenylketonuria in the rat: prevention by melatonin, vitamin E, and vitamin C. J Neurosci Res 69:550–558PubMedCrossRefGoogle Scholar
  76. Martínez-Cruz F, Osuna C, Guerrero JM (2006) Mitochondrial damage induced by fetal hyperphenylalaninemia in the rat brain and liver: its prevention by melatonin, Vitamin E, and Vitamin C. Neurosci Lett 392:1–4PubMedCrossRefGoogle Scholar
  77. Masella R, Di Benedetto R, Varì R, Filesi C, Giovannini C (2005) Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes. J Nutr Biochem 16:577–586PubMedCrossRefGoogle Scholar
  78. McCord JM (2000) The evolution of free radicals and oxidative stress. Am J Med 108:652–659PubMedCrossRefGoogle Scholar
  79. Miller DM, Buettner GR, Aust SD (1990) Transition metals as catalysts of “autoxidation” reactions. Free Radic Biol Med 8:95–108PubMedCrossRefGoogle Scholar
  80. Moncada S, Higgs A (1993) The l-arginine-nitric oxide pathway. N Engl J Med 329:2002–2012PubMedCrossRefGoogle Scholar
  81. Moraes TB, Zanin F, da Rosa A, de Oliveira A, Coelho J, Petrillo F, Wajner M, Dutra-Filho CS (2010) Lipoic acid prevents oxidative stress in vitro and in vivo by an acute hyperphenylalaninemia chemically-induced in rat brain. J Neurol Sci 292:89–95PubMedCrossRefGoogle Scholar
  82. Moyano D, Vilaseca MA, Pineda M, Campistol J, Vernet A, Póo P, Artuch R, Sierra C (1997) Tocopherol in inborn errors of intermediary metabolism. Clin Chim Acta 263:147–155PubMedCrossRefGoogle Scholar
  83. Nigam MP, Labar DR (1979) The effect of hyperphenylalaninemia on size and density of synapses in rat neocortex. Brain Res 179:195–198PubMedCrossRefGoogle Scholar
  84. Niki E (2009) Lipid peroxidation: physiological levels and dual biological effects. Free Radic Biol Med 47:469–484PubMedCrossRefGoogle Scholar
  85. Perry G, Taddeo MA, Petersen RB, Castellani RJ, Harris PL, Siedlak SL, Cash AD, Liu Q, Nunomura A, Atwood CS, Smith MA (2003) Adventiously-bound redox active iron and copper are at the center of oxidative damage in Alzheimer disease. Biometals 16:77–81PubMedCrossRefGoogle Scholar
  86. Pietz J (1998) Neurological aspects of adult phenylketonuria. Curr Opin Neurol 11:679–688PubMedCrossRefGoogle Scholar
  87. Poustie VJ, Wildgoose J (2010) Dietary interventions for phenylketonuria. Cochrane Database Syst Rev 20:CD001304Google Scholar
  88. Przyrembel H, Bremer HJ (2000) Nutrition, physical growth, and bone density in treated phenylketonuria. Eur J Pediatr 159(Suppl 2):S129–S135PubMedCrossRefGoogle Scholar
  89. Rech VC, Feksa LR, Dutra-Filho CS, Wyse AT, Wajner M, Wannmacher CM (2002) Inhibition of the mitochondrial respiratory chain by phenylalanine in rat cerebral cortex. Neurochem Res 27:353–357PubMedCrossRefGoogle Scholar
  90. Reilly C, Barrett JE, Patterson CM, Tinggi U, Latham SL, Marrinan A (1990) Trace element nutrition status and dietary intake of children with phenylketonuria. Am J Clin Nutr 52:159–165PubMedGoogle Scholar
  91. Reynolds A, Laurie C, Mosley RL, Gendelman HE (2007) Oxidative stress and the pathogenesis of neurodegenerative disorders. Int Rev Neurobiol 82:297–325PubMedCrossRefGoogle Scholar
  92. Reznick AZ, Packer L (1993) Free radicals and antioxidants in muscular neurological diseases and disorders. In: Poli G, Albano E, Dianzani MU (eds) Free radicals: from basic science to medicine. Birkhäuser Verlag, Basel, pp 425–437Google Scholar
  93. 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 28:127–132PubMedCrossRefGoogle Scholar
  94. Richard E, Alvarez-Barrientos A, Pérez B, Desviat LR, Ugarte M (2007) Methylmalonic acidaemia leads to increased production of reactive oxygen species and induction of apoptosis through the mitochondrial/caspase pathway. J Pathol 213:453–461PubMedCrossRefGoogle Scholar
  95. Richter C (1987) Biophysical consequences of lipid peroxidation in membranes. Chem Phys Lipids 44:175–189PubMedCrossRefGoogle Scholar
  96. Rodrigues NR, Wannmacher CM, Dutra-Filho CS, Pires RF, Fagan PR, Wajner M (1990) Effect of phenylalanine, p-chlorophenylalanine and alpha-methylphenylalanine on glucose uptake in vitro by the brain of young rats. Biochem Soc Trans 18:419PubMedGoogle Scholar
  97. Rottoli A, Lista G, Zecchini G, Butté C, Longhi R (1985) Plasma selenium levels in treated phenylketonuric patients. J Inherit Metab Dis Suppl 2:127–128CrossRefGoogle Scholar
  98. 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 79:930–934PubMedCrossRefGoogle Scholar
  99. Schulpis KH, Tsakiris S, Karikas GA, Moukas M, Behrakis P (2003) Effect of diet on plasma total antioxidant status in phenylketonuric patients. Eur J Clin Nutr 57:383–387PubMedCrossRefGoogle Scholar
  100. 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 38:239–242PubMedCrossRefGoogle Scholar
  101. Scriver CR, Kaufmann S (2001) The hyperphenylalaninemias. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited disease. McGraw-Hill, New York, pp 1667–1724Google Scholar
  102. Shah SN, Peterson NA, McKean CM (1972) Lipid composition of human cerebral white matter and myelin in phenylketonuria. J Neurochem 19:2369–2376PubMedCrossRefGoogle Scholar
  103. 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 276:1–9PubMedCrossRefGoogle Scholar
  104. Sies H (1985) Oxidative stress: introductory remarks. In: Sies H (ed) Oxidative stress. Academic Press, London, pp 1–7Google Scholar
  105. 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
  106. 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 21:287–296PubMedCrossRefGoogle Scholar
  107. Sitta A, Manfredini V, Biasi L, Treméa R, Schwartz IV, Wajner M, Vargas CR (2009a) Evidence that DNA damage is associated to phenylalanine blood levels in leukocytes from phenylketonuric patients. Mutat Res 679:13–16PubMedGoogle Scholar
  108. Sitta A, Barschak AG, Deon M, de Mari JF, Barden AT, Vanzin CS, Biancini GB, Schwartz IV, Wajner M, Vargas CR (2009b) L-carnitine blood levels and oxidative stress in treated phenylketonuric patients. Cell Mol Neurobiol 29:211–218PubMedCrossRefGoogle Scholar
  109. Sitta A, Barschak AG, Deon M, Barden AT, Biancini GB, Vargas PR, de Souza CF, Netto C, Wajner M, Vargas CR (2009c) Effect of short- and long-term exposition to high phenylalanine blood levels on oxidative damage in phenylketonuric patients. Int J Dev Neurosci 27:243–247PubMedCrossRefGoogle Scholar
  110. Smith I, Knowles J (2000) Behaviour in early treated phenylketonuria: a systematic review. Eur J Pediatr 159(Suppl 2):S89–S93PubMedCrossRefGoogle Scholar
  111. Solano AF, Leipnitz G, De Bortoli GM, Seminotti B, Amaral AU, Fernandes CG, Latini AS, Dutra-Filho CS, Wajner M (2008) Induction of oxidative stress by the metabolites accumulating in isovaleric acidemia in brain cortex of young rats. Free Radic Res 42:707–715PubMedCrossRefGoogle Scholar
  112. Steiner G, Menzel H, Lombeck I, Ohnesorge FK, Bremer HJ (1982) Plasma glutathione peroxidase after selenium supplementation in patients with reduced selenium state. Eur J Pediatr 138:138–140PubMedCrossRefGoogle Scholar
  113. Streck EL, Zugno AI, Tagliari B, Franzon R, Wannmacher CM, Wajner M, Wyse AT (2001) Inhibition of rat brain Na+, K+-ATPase activity induced by homocysteine is probably mediated by oxidative stress. Neurochem Res 26:1195–1200PubMedCrossRefGoogle Scholar
  114. Streck EL, Vieira PS, Wannmacher CM, Dutra-Filho CS, Wajner M, Wyse AT (2003) In vitro effect of homocysteine on some parameters of oxidative stress in rat hippocampus. Metab Brain Dis 18:147–154PubMedCrossRefGoogle Scholar
  115. Teunissen CE, de Vente J, Steinbusch HW, De Bruijn C (2002) Biochemical markers related to Alzheimer’s dementia in serum and cerebrospinal fluid. Neurobiol Aging 23:485–508PubMedCrossRefGoogle Scholar
  116. Uchida K (2003) 4-Hydroxy-2-nonenal: a product and mediator of oxidative stress. Prog Lipid Res 42:318–343PubMedCrossRefGoogle Scholar
  117. Ushakova GA, Gubkina HA, Kachur VA, Lepekhin EA (1997) Effect of experimental hyperphenylalaninemia on the postnatal rat brain. Int J Dev Neurosci 15:29–36PubMedCrossRefGoogle Scholar
  118. Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J (2004) Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem 266:37–56PubMedCrossRefGoogle Scholar
  119. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84PubMedCrossRefGoogle Scholar
  120. van Bakel MM, Printzen G, Wermuth B, Wiesmann UN (2000) Antioxidant and thyroid hormone status in selenium-deficient phenylketonuric and hyperphenylalaninemic patients. Am J Clin Nutr 72:976–981PubMedGoogle Scholar
  121. Wajner M, Latini A, Wyse AT, Dutra-Filho CS (2004) The role of oxidative damage in the neuropathology of organic acidurias: insights from animal studies. J Inherit Metab Dis 27:427–448PubMedCrossRefGoogle Scholar
  122. Weber C, Bysted A, Holmer G (1997) Coenzyme Q10 in the diet-daily intake and relative bioavailability. Mol Aspects Med 18(Suppl):S251–S254PubMedCrossRefGoogle Scholar
  123. Weglage J, Pietsch M, Fünders B, Koch HG, Ullrich K (1995) Neurological findings in early treated phenylketonuria. Acta Paediatr 84:411–415PubMedCrossRefGoogle Scholar
  124. 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 207:137–142PubMedCrossRefGoogle Scholar
  125. Wyse AT, Wajner M, Brusque A, Wannmacher CM (1995) Alanine reverses the inhibitory effect of phenylalanine and its metabolites on Na+, K(+)-ATPase in synaptic plasma membranes from cerebral cortex of rats. Biochem Soc Trans 23:227SPubMedGoogle Scholar
  126. Wyse AT, Noriler ME, Borges LF, Floriano PJ, Silva CG, Wajner M, Wannmacher CM (1999) Alanine prevents the decrease of Na+, K+-ATPase activity in experimental phenylketonuria. Metab Brain Dis 14:95–101PubMedCrossRefGoogle Scholar
  127. Wyse AT, Zugno AI, Streck EL, Matté C, Calcagnotto T, Wannmacher CM, Wajner M (2002) Inhibition of Na(+), K(+)-ATPase activity in hippocampus of rats subjected to acute administration of homocysteine is prevented by vitamins E and C treatment. Neurochem Res 27:1685–1689PubMedCrossRefGoogle Scholar
  128. Zheng M, Storz G (2000) Redox sensing by prokaryotic transcription factors. Biochem Pharmacol 59:1–6PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Graziela S. Ribas
    • 1
    • 2
  • Angela Sitta
    • 2
    • 3
  • Moacir Wajner
    • 2
    • 3
  • Carmen R. Vargas
    • 1
    • 2
    • 3
  1. 1.Programa de Pós-Graduação em Ciências FarmacêuticasUFRGSPorto AlegreBrazil
  2. 2.Serviço de Genética MédicaHCPAPorto AlegreBrazil
  3. 3.Programa de Pós-Graduação em Ciências Biológicas: BioquímicaUFRGSPorto AlegreBrazil

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