Antioxidant status in hyperphenylalaninemia

Sierra, Cristina; Vilaseca, M. A.; Moyano, Dolores; Brandi, Nuria; Campistol, Jaume; Lambruschini, Nilo; Cambra, Fco.José; Deulofeu, R.; Mira, Áurea

doi:10.1016/s0009-8981(98)00091-6

Cited by 59 publications

(52 citation statements)

References 22 publications

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“…Figure 3 illustrates the results of our study compared with results of several studies on PKU patients, in vitro and in vivo models. 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.…”

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: 59%

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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: 76%

Section: Discussionsupporting

confidence: 59%

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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“…Numerous studies have provided experimental evidence demonstrating oxidative stress in human PKU patients and animal models (Artuch et al, 2001(Artuch et al, ,2004Colome et al, 2003;Ercal et al, 2002;Martinez-Cruz et al, 2002;Sierra et al, 1998;Sirtori et al, 2005). Our laboratory previously demonstrated increased inducible nitric oxide synthase production by infiltrative cd11b macrophage cells in the mesencephalon and hypothalamus of PKU mice (Embury et al, 2005), providing further evidence of oxidative processes occurring in these regions.…”

Section: Discussionmentioning

confidence: 76%

“…Ercal et al (2002) provided experimental evidence of oxidative damage in Pah enu2 mice that included increased concentration of the lipid peroxidation by-product malon-dialdehyde in brain tissue, decreased glutathione/glutathione disulfide also in brain and increased catalase and glucose-6-phosphate dehydrogenase in erythrocytes of these animals. Other studies indicating the role of oxidative stress in PKU include human studies by Artuch et al (2001Artuch et al ( , 2004; Colome et al (2003);and Sierra et al (1998). Sirtori et al (2005) demonstrated the involvement of oxidative stress in human PKU patients through increased levels of thiobarbituric acid reactive species (indicative of lipid peroxidation) and decreased total antioxidant reactivity, suggestive of deficient capacity to handle increases in reactive species.…”

Section: Discussionmentioning

confidence: 99%

PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pahenu2 mice

et al. 2007

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Phenylketonuria (PKU) is a common genetic disorder in humans that arises from deficient activity of phenylalanine hydroxylase (PAH), which catalyzes the conversion of phenylalanine to tyrosine. There is a resultant hyperphenylalanemia with subsequent impairment in cognitive abilities, executive functions and motor coordination. The neuropathogenesis of the disease has not been completely elucidated, however, oxidative stress is considered to be a key feature of the disease process. Hyperphenylalanemia also adversely affects monoaminergic metabolism in the brain. For this reason we chose to evaluate the nigrostriatum of Pah enu2 mice, to determine if alterations of monoamine metabolism resulted in morphologic nigrostriatal pathology. Furthermore, we believe that recent developments in adeno-associated virus (AAV)-based vectors have greatly increased the potential for long-term gene therapy and may be a viable alternative to dietary treatment for this metabolic disorder. In this study we identified neurodegenerative changes with regenerative responses in the nigrostriatum of Pah enu2 mice that are consistent with oxidative injury and occurred as early as 4 weeks of age. These neuropathologic changes were reversed following portal vein delivery of a recombinant adeno-associated virus-mouse phenylalanine hydroxylase-woodchuck hepatitis virus post-transcriptional response element (rAAV-mPAH-WPRE) vector to Pah enu2 mice and corresponded to rapid reduction of serum Phe levels.

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“…These deficiencies might cause some metabolic disturbances, such as dysfunction in several antioxidant defences thereby causing an increased oxidative stress (Darling et al, 1992;Sierra et al, 1998). Thiol status, a wellrecognized factor associated either with increased oxidative damage (high plasma and tissue tHcy values) or antioxidant properties (glutathione), has not been reported in PKU, to our knowledge.…”

Section: Discussionmentioning

confidence: 87%

Plasma thiols and their determinants in phenylketonuria

et al. 2003

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Objective: Treatment of phenylketonuria (PKU) patients consists of a phenylalanine-restricted diet supplemented with a tyrosine-, vitamin-and oligoelement-enriched amino-acid mixture. Vitamins and oligoelements may be deficient when compliance with the supplemented special formula is poor. Plasma thiol concentrations (especially homocysteine) depend mainly on B-vitamin intake. Our aim was to evaluate the plasma thiol concentrations (homocysteine, cysteine and glutathione) and their determinants (methionine, cobalamin and folate) in PKU patients under dietary treatment compared with agematched controls. Design and setting: Cross-sectional study performed in a tertiary care Hospital. Subjects: PKU (42) patients under dietary treatment compared with 42 age-matched controls. Interventions: Plasma total homocysteine, cysteine and glutathione were analyzed by HPLC with fluorescence detection. Plasma phenylalanine and methionine were analyzed by ion exchange chromatography. Serum folate and cobalamin were analyzed by radioimmunoassay procedures. Results: Total homocysteine concentrations were significantly lower in the PKU patients compared with the control group (Students t-test; Po0.0001). Serum folate and cobalamin were significantly higher in the PKU group (t-Student; Po0.0001) compared with controls. A significantly negative correlation was observed between total homocysteine and folate (r ¼ À0.378; P ¼ 0.016), and between cobalamin and phenylalanine concentrations (r ¼ À0.367; P ¼ 0.022) in the PKU group. Conclusions: Plasma total homocysteine values are lower in the PKU group than in the controls, probably because of high folate values. High phenylalanine values, an indicator of poor dietary compliance, are negatively associated with cobalamin, which might be deficient in some cases.

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Antioxidant status in hyperphenylalaninemia

Cited by 59 publications

References 22 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

PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pahenu2 mice

Plasma thiols and their determinants in phenylketonuria

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