Oxidative stress in patients with phenylketonuria

Abstract

Phenylketonuria (PKU) is an autossomal recessive disease caused by phenylalanine-4-hydroxylase deficiency, which is a liver-specific enzyme that catalyzes the hydroxylation of l-phenylalanine (Phe) to l-tyrosine (Tyr). The deficiency of this enzyme leads to the accumulation of Phe in the tissues and plasma of patients. The clinical characterization of this disease is mental retardation and other neurological features. The mechanisms of brain damage are poorly understood. Oxidative stress is observed in some inborn errors of intermediary metabolism owing to the accumulation of toxic metabolites leading to excessive free radical production and may be a result of restricted diets on the antioxidant status. In the present study we evaluated various oxidative stress parameters, namely thiobarbituric acid-reactive species (TBA-RS) and total antioxidant reactivity (TAR) in the plasma of PKU patients. The activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were also measured in erythrocytes from these patients. It was observed that phenylketonuric patients present a significant increase of plasma TBA-RS measurement, indicating a stimulation of lipoperoxidation, as well as a decrease of plasma TAR, reflecting a deficient capacity to rapidly handle an increase of reactive species. The results also showed a decrease of erythrocyte GSH-Px activity. Therefore, it is presumed that oxidative stress is involved in the pathophysiology of the tissue damage found in PKU.

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

“…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.…”

“…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. Martinez-Cruz et al (2002) determined that in an experimentally induced rat model of maternal PKU, oxidative stress parameters were increased and adversely influenced morphologic and biochemical development in rat pup brain and cerebellum.…”

Diagnostic and Therapeutic Significance of the Oxidative Stress Parameters in Children

“…Diabetes mellitus (19-23), glutathione synthetase deficiency (24), hyperthyroidism (25), iodinedeficient goiter (26), mitochondrial disorder (27,28), multimetabolic syndrome (29), phenylketonuria (30) and X-linked adrenoleukodystrophy (31) are endocrinologic/metabolic diseases in children where the link with oxidative stress has also been shown.…”

Biochemical Characterisation and Whole Genome Expression Profiling of Cultured Skin Fibroblasts from Two South African Adults with Urinary 3-Hydroxyisovaleric Acid and 3-Methylcrotonylglycine

“…Similar to the transcriptome of symptomatic, clinically severe MCC deficiency and neurological studies on the cerebral cortex of young rats [55][56][57][60][61][62][63][64][65], this marginal MCC deficiency skin fibroblast transcriptome also had a genetic footprint suggestive of partial mitochondrial dysfunction, oxidative stress and disruption of energy homeostasis. Transcripts of mitochondrial respiratory chain complexes I, II and IV were significantly differentially expressed (Table 4) affecting the OXPHOS system (NDUFS2, SDHD, MT-CO1/COX1, COX6 and COX17).…”