Experimental evidence that phenylalanine is strongly associated to oxidative stress in adolescents and adults with phenylketonuria

Sanayama, Yoshitami; Nagasaka, Hironori; Takayanagi, Masaki; Ohura, Toshihiro; Sakamoto, Osamu; Ito, Tetsuya; Ishige-Wada, Mika; Usui, Hiromi; Yoshino, Makoto; Ohtake, Akira; Yorifuji, Tohru; Tsukahara, Hirokazu; Hirayama, Satoshi; Miida, Takashi; Fukui, Manabu; Okano, Yoshiyuki

doi:10.1016/j.ymgme.2011.03.019

Cited by 64 publications

(73 citation statements)

References 29 publications

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“…We noted that 11 genes had a decreased expression significantly correlated with high plasma concentrations of Phe after multiple testing correction. These data support results of previous studies highlighting disturbance in redox system with reduction of total antioxidant status or unbalance of prooxidant-antioxidant system in blood samples of PKU patients (Sitta et al 2009;Sanayama et al 2011;Preissler et al 2016;Tavana et al 2016). Several plasma amino acids and urinary organic acids seem to be correlated with antioxidant expression profile.…”

Section: Discussionsupporting

confidence: 91%

“…As in the present study, several studies on PKU patients, adults and children with or without restrictive diet, highlighted a decrease of GPx enzyme in various (Menzel et al 1983;Reilly et al 1990;Sierra et al 1998;Sitta et al 2006;Sanayama et al 2011). The reduced expression of antioxidant systems that we observed could lead to an inefficient response to oxidative stress and by consequences to elevation of ROS levels (superoxide and hydroxyl anions especially) responsible for cellular damages previously highlighted in PKU (Ercal et al 2002;Sitta et al 2009;Sanayama et al 2011) and which may lead to brain injury observed in the disease. In the present study, ROS production in PKU patients trends to increase in monocytes but interindividual variability and lack of statistical power prevent us from concluding.…”

Section: Discussionsupporting

confidence: 76%

“…3 Schematic representation of main results of the study (black arrows) compared with results of several studies on PKU patients, in vitro and in vivo models (grey arrows). As in this study, several studies highlighted a decrease of GPx enzyme in various tissues in PKU (Menzel et al 1983;Reilly et al 1990;Sierra et al 1998;Sitta et al 2006;Sanayama et al 2011). The combination of a decrease in expression of GPX and GSR may suggest a reduced activity of the GSH antioxidant system.…”

Section: Discussionsupporting

confidence: 60%

“…It might be interesting to extend this study by performing a wide range of oxidative stress markers, especially markers of cellular damages such as 8-hydroxy-2 0 -deoxyguanosine (DNA damages), malondialdehyde (lipid peroxidation), and carbonylated proteins (Sitta et al 2009;Sanayama et al 2011), in order to validate assumptions from our data and previous studies, and to evaluate their relation with biological markers and clinical data in a longitudinal larger cohort of PKU patients. Analysis of disease phenotype, age (adults vs children), gender, metabolic status or diets, and environmental oxidative stress factors which may introduce a bias (i.e., self-medication treatments, life-style, or activities) could also bring new perspectives in PKU pathophysiology understanding.…”

Section: Discussionmentioning

confidence: 85%

“…In PKU, accumulation of Phe and/or its metabolites may lead to a disturbance of redox homeostasis (Artuch et al 2004;Mazzola et al 2013). Some studies showed an increase of lipoperoxidation markers (Sanayama et al 2011) and DNA damages (Sitta et al 2009), or a reduction of various antioxidant compounds, especially selenium, coenzyme Q10, or antioxidant system of glutathione (Menzel et al 1983;Sitta et al 2006;Sanayama et al 2011). Decrease of antioxidant compounds was also observed in animal and in vitro models of PKU (Ercal et al 2002;Fernandes et al 2010;Mazzola et al 2011;Moraes et al 2014).…”

Section: Introductionmentioning

confidence: 99%

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Hyperphenylalaninemia Correlated with Global Decrease of Antioxidant Genes Expression in White Blood Cells of Adult Patients with Phenylketonuria

et al. 2017

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Background: Several studies have highlighted disturbance of redox homeostasis in patients with phenylketonuria (PKU) which may be associated with neurological disorders observed in patients, especially during adulthood when phenylalanine restrictive diets are not maintained. The aim of this study was to assess the antioxidant profile in a cohort of PKU patients in comparison to the controls and to evaluate its relation to biochemical parameters especially phenylalaninemia. Methods:We measured RNA expression of 22 antioxidant genes and reactive oxygen species (ROS) levels in white blood cells of 10 PKU patients and 10 age-and gendermatched controls. We also assessed plasma amino acids, vitamins, oligo-elements, and urinary organic acids concentrations. Then we evaluated the relationship between redox status and biochemical parameters. Results: In addition to expected biochemical disturbances, we highlighted a significant global decrease of antioxidant genes expression in PKU patients in comparison to the controls. This global decrease of antioxidant genes expression, including various isoforms of peroxiredoxins, glutaredoxins, glutathione peroxidases, and superoxide dismutases, was significantly correlated to hyperphenylalaninemia. Conclusion: This study is the first to evaluate the expression of 22 antioxidant genes in white blood cells regarding biochemical parameters in PKU. These findings highlight the association of hyperphenylalaninemia with antioxidant genes expression. New experiments to specify the role of oxidative stress in PKU pathogenesis may be useful in suggesting new recommendations in PKU management and new therapeutic trials based on antioxidant defenses.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 76%

Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Hyperphenylalaninemia Correlated with Global Decrease of Antioxidant Genes Expression in White Blood Cells of Adult Patients with Phenylketonuria

et al. 2017

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Increased cytokine levels induced by high phenylalanine concentrations in late diagnosis PKU patients compared to early diagnosis: Anti‐inflammatory effect of L‐carnitine

Faverzani

Hammerschmidt

Mescka

et al. 2023

Cell Biochemistry & Function

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Phenylketonuria (PKU) was the first genetic disease to have an effective therapy, which consists of phenylalanine intake restriction. However, there are patients who do not adhere to treatment and/or are not submitted to neonatal screening. PKU patients present L‐carnitine (L‐car) deficiency, compound that has demonstrated an antioxidant and anti‐inflammatory role in metabolic diseases. This study evaluated the effect caused by exposure time to high Phe levels in PKU patients at early and late diagnosis, through pro‐ and anti‐inflammatory cytokines, as well as the L‐car effect in patients under treatment. It was observed that there was a decrease in phenylalanine levels in treated patients compared to patients at diagnosis, and an increase in L‐car levels in the patients under treatment. Inverse correlation between Phe versus L‐car and nitrate plus nitrite versus L‐car in PKU patients was also showed. We found increased proinflammatory cytokines levels: interleukin (IL)‐1β, interferons (IFN)‐gamma, IL‐2, tumor necrosis factor (TNF)‐alpha, IL‐8 and IL‐6 in the patients at late diagnosis compared to controls, and IL‐8 in the patients at early diagnosis and treatment compared to controls. Increased IL‐2, TNF‐alpha, IL‐6 levels in the patients at late diagnosis compared to early diagnosis were shown, and reduced IL‐6 levels in the treated patients compared to patients at late diagnosis. Moreover, it verified a negative correlation between IFN‐gamma and L‐car in treated patients. Otherwise, it was observed that there were increased IL‐4 levels in the patients at late diagnosis compared to early diagnosis, and reduction in treated patients compared to late diagnosed patients. In urine, there was an increase in 8‐isoprostane levels in the patients at diagnosis compared to controls and a decrease in oxidized guanine species in the treated patients compared to the diagnosed patients. Our results demonstrate for the first time in literature that time exposure to high Phe concentrations generates a proinflammatory status, especially in PKU patients with late diagnosis. A pro‐oxidant status was verified in not treated PKU patients. Our results demonstrate the importance of early diagnosis and prompt start of treatment, in addition to the importance of L‐car supplementation, which can improve cellular defense against inflammation and oxidative damage in PKU patients.

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Tetrahydrobiopterin treatment in phenylketonuria: A repurposing approach

Evers

Vliet

Spronsen

2019

J of Inher Metab Disea

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In phenylketonuria (PKU) patients, early diagnosis by neonatal screening and immediate institution of a phenylalanine‐restricted diet can prevent severe intellectual impairment. Nevertheless, outcome remains suboptimal in some patients asking for additional treatment strategies. Tetrahydrobiopterin (BH4) could be one of those treatment options, as it may not only increase residual phenylalanine hydroxylase activity in BH4‐responsive PKU patients, but possibly also directly improves neurocognitive functioning in both BH4‐responsive and BH4‐unresponsive PKU patients. In the present review, we aim to further define the theoretical working mechanisms by which BH4 might directly influence neurocognitive functioning in PKU having passed the blood‐brain barrier. Further research should investigate which of these mechanisms are actually involved, and should contribute to the development of an optimal BH4 treatment regimen to directly improve neurocognitive functioning in PKU. Such possible repurposing approach of BH4 treatment in PKU may improve neuropsychological outcome and mental health in both BH4‐responsive and BH4‐unresponsive PKU patients.

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Experimental evidence that phenylalanine is strongly associated to oxidative stress in adolescents and adults with phenylketonuria

Cited by 64 publications

References 29 publications

Hyperphenylalaninemia Correlated with Global Decrease of Antioxidant Genes Expression in White Blood Cells of Adult Patients with Phenylketonuria

Hyperphenylalaninemia Correlated with Global Decrease of Antioxidant Genes Expression in White Blood Cells of Adult Patients with Phenylketonuria

Increased cytokine levels induced by high phenylalanine concentrations in late diagnosis PKU patients compared to early diagnosis: Anti‐inflammatory effect of L‐carnitine

Tetrahydrobiopterin treatment in phenylketonuria: A repurposing approach

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