Skip to main content
SpringerLink
Log in

Effect of Blood Phenylalanine Levels on Oxidative Stress in Classical Phenylketonuric Patients

  • Original Research
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Mental retardation, which occurs in phenylketonuric patients, is associated with increased levels of phenylalanine, increased oxidative stress, and an imbalance of amino acids in the brain. Recent studies have shown that oxidative stress plays a role in the pathogenesis of phenylketonuria. In this work, we aimed to compare the influence of blood phenylalanine levels on oxidative stress parameters in phenylketonuric patients who divided patients into groups according to blood Phe levels during follow-up visits and compared these groups with healthy controls. Results showed significant differences in glutathione peroxidase (GSHPx), coenzyme Q10 (Q10), Q10/cholesterol, and l-carnitine levels in phenylketonuria patients and the control group. GSHPx, Q10, and Q10/cholesterol levels were significantly lower in poor adherence patients than in the control groups. l-carnitine levels were significantly increased in good adherence patients than poor adherence patients and decreased in poor adherence patients than healthy controls. No correlations were observed between phenylalanine and l-carnitine concentrations in poor adherence group. No significant differences were observed in paraoxonase 1 (PON1), total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) levels. As a result, in this work, poor adherence patients are prone to oxidative stress. Although the patients may have the same diagnosis, patients have different clinical characteristics and different prognosis. Antioxidants can be used as an adjuvant therapy in order to avoid neurological damage in these patients.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Artuch R et al (1999) Decreased serum ubiquinone-10 concentrations in phenylketonuria. Am J Clin Nutr 70:892–895

    Article  PubMed  CAS  Google Scholar 

  • Artuch R et al (2001) Plasma phenylalanine is associated with decreased serum ubiquinone-10 concentrations in phenylketonuria. J Inherit Metab Dis 24(3):359–366

    Article  PubMed  CAS  Google Scholar 

  • Artuch R et al (2004) A longitudinal study of antioxidant status in phenylketonuric patients. Clin Biochem 37:198–203

    Article  PubMed  CAS  Google Scholar 

  • Barschak AG et al (2008) Oxidative stress in plasma from maple syrup urine disease patients during treatment. Metab Brain Dis 23:71–80

    Article  PubMed  CAS  Google Scholar 

  • Camp KM et al (2014) Phenylketonuria scientific review conference: state of the science and future research needs. Mol Genet Metab 112(2):87–122

    Article  PubMed  CAS  Google Scholar 

  • 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(6):551–555

    Article  PubMed  CAS  Google Scholar 

  • Colome C et al (2003) Lipophilic antioxidants in patients with phenylketonuria. Am J Clin Nutr 77(1):185–188

    Article  PubMed  CAS  Google Scholar 

  • Deon M et al (2015) Urinary biomarkers of oxidative stress and plasmatic inflammatory profile in phenylketonuric treated patients. Int J Dev Neurosci 47:259–265

    Article  PubMed  CAS  Google Scholar 

  • 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(3):595–606

    PubMed  CAS  Google Scholar 

  • Erel O (2004) A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 37(4):277–285

    Article  PubMed  CAS  Google Scholar 

  • Erel O (2005) A new automated colorimetric method for measuring total oxidant status. Clin Biochem 38(12):1103–11111

    Article  PubMed  CAS  Google Scholar 

  • Fischer GM et al (2000) Metabolism of carnitine in phenylacetic acid-treated rats and in patients with phenylketonuria. Biochim et Biophys Acta Mol Basis Dis 1501:200–210

    Article  CAS  Google Scholar 

  • Hagen K, Martine E et al (2002) Experimental hyperphenylalaninemia provokes oxidative stress in rat brain. Biochim et Biophys Acta Mol Basis Dis 1586:344–352

    Article  Google Scholar 

  • Halliwell B, Gutteridge JMC (2007) Free radicals in biology and medicine. Oxford University Press, Oxford

    Google Scholar 

  • Hargreaves IP (2007) Coenzyme Q10 in phenylketonuria and mevalonic aciduria. Mitochondrion 7:175–180

    Article  CAS  Google Scholar 

  • Işık A, Selek S (2007) Total antioxidant response and oxidative stress in patients with rheumatoid arthritis. F Ü Sağ Bil Tıp Derg 21(2):67–73

    Google Scholar 

  • Lu J, Holmgren A (2009) Selenoproteins. J Biol Chem 284(2):723–727

    Article  PubMed  CAS  Google Scholar 

  • Matalon R et al (2007) Double blind placebo control trial of large neutral amino acids in treatment of PKU: effect on blood phenylalanine. J Inherit Metab Dis 30(2):153–158

    Article  PubMed  CAS  Google Scholar 

  • Moraes TB et al (2010) Lipoic acid prevents oxidative stress in vitro and in vivo by an acute hyperphenylalaninemia chemically-induced in rat brain. J Neurol Sci 292(1–2):89–95

    Article  PubMed  CAS  Google Scholar 

  • Ribas GS, Sitta A, Wajner M, Vargas CR (2011) Oxidative stress in phenylketonuria: what is the evidence? Cell Mol Neurobiol 31:653–662

    Article  PubMed  CAS  Google Scholar 

  • Rocha JC, Martel F (2009) Large neutral amino acids supplementation in phenylketonuric patients. J Inherit Metab Dis 32:472–480

    Article  PubMed  CAS  Google Scholar 

  • Rocha JC, Martins MJ (2012) Oxidative stress in phenylketonuria: future directions. J Inherit Metab Dis 35:381–398

    Article  PubMed  CAS  Google Scholar 

  • Sanayama Y et al (2011) Experimental evidence that phenylalanine is strongly associated to oxidative stress in adolescents and adults with phenylketonuria. Mol Genet Metab 103(3):220–225

    Article  PubMed  CAS  Google Scholar 

  • 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(2):383–387

    Article  PubMed  CAS  Google Scholar 

  • 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(3):239–242

    Article  PubMed  CAS  Google Scholar 

  • Schulpis KH, Bartzeliotou A, Tsakiris S, Gounaris A, Papassotiriou I (2007) Serum paraoxonase/arylesterase activities in phenylketonuric patients on diet. Eur J Clin Nutr 61:803–808

    Article  PubMed  CAS  Google Scholar 

  • Scriver CR, Kaufman S (2001) Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: The metabolic and molecular bases of inherited disease, pp 1667–1724

  • Selek S, Aslan M, Horoz M, Gur M, Erel O (2007) Oxidative status and serum PON1 activity in beta-thalassemia minor. Clin Biochem 40(5–6):287–291

    Article  PubMed  CAS  Google Scholar 

  • Sierra C et al (1998) Antioxidant status in hyperphenylalaninemia. Clin Chim Acta 276:1–9

    Article  PubMed  CAS  Google Scholar 

  • Sirtori LR et al (2005) Oxidative stress in patients with phenylketonuria. Biochem et Biophys Acta 1740:68–73

    CAS  Google Scholar 

  • Sitta A et al (2006) Investigation of oxidative stress parameters in treated phenylketonuric patients. Metab Brain Dis 21:287–296

    Article  PubMed  CAS  Google Scholar 

  • Sitta A et al (2009) l-carnitine blood levels and oxidative stress in treated phenylketonuric patients. Cell Mol Neurobiol 29:211–218

    Article  PubMed  CAS  Google Scholar 

  • Sitta A et al (2011) Evidence that l-carnitine and selenium supplementation reduces oxidative stress in phenylketonuric patients. Cell Mol Neurobiol 31:429–436

    Article  PubMed  CAS  Google Scholar 

  • Uysal S, Akyol S, Hasgül R, Armutcu F, Yiğitoğlu F (2011) Paraoxonase: a multifaceted enzyme. Yeni Tıp Dergisi 28(3):136–141

    Google Scholar 

  • Van Bakel 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(4):976–981

    Article  PubMed  Google Scholar 

  • Vockley J et al (2014) Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med 16(2):188–200

    Article  PubMed  CAS  Google Scholar 

  • Weigel C et al (2008) Carnitine status in early-treated children, adolescents and young adults with phenylketonuria on low phenylalanine diets. Ann Nutr Metab 53:91–95

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by Gaziantep University Scientific Research Projects Governing Unit.

Author information

Authors and Affiliations

  1. Division of Nutrition and Diet, Gaziantep Cengiz Gökçek Maternity and Children’s Hospital, Gaziantep, Turkey

    Burcu Kumru

  2. Division of Physiology, Gaziantep University, Gaziantep, Turkey

    Davut Sinan Kaplan

  3. Division of Pediatric Metabolism and Nutrition, Tepecik Training and Research Hospital, Izmir, Turkey

    Burcu Oztürk Hismi

  4. Division of Physiology, Harran University, Sanlıurfa, Turkey

    Hakim Celik

Authors
  1. Burcu Kumru
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Davut Sinan Kaplan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Burcu Oztürk Hismi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hakim Celik
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

BK, DSK, and BOH conceived the study design. BK, DSK, BOH, and HC performed the experiment. BK and DSK participated in the data analysis and interpretation. BOH helped to draft and revise the manuscript. All authors read and approved the final manuscripts.

Corresponding author

Correspondence to Burcu Kumru.

Ethics declarations

Conflict of interest

The authors (Burcu Kumru, Davut Sinan Kaplan, Burcu Oztürk Hismi, Hakim Celik) declare that there are no financial interests and/or no conflict of interest disclosure associated with this manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumru, B., Kaplan, D.S., Oztürk Hismi, B. et al. Effect of Blood Phenylalanine Levels on Oxidative Stress in Classical Phenylketonuric Patients. Cell Mol Neurobiol 38, 1033–1038 (2018). https://doi.org/10.1007/s10571-017-0573-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-017-0573-2

Keywords

Search

Navigation