l-Carnitine Blood Levels and Oxidative Stress in Treated Phenylketonuric Patients

Sitta, Ângela; Barschak, Alethéa Gatto; Deon, Marion; Mari, Jurema Fatíma de; Barden, Amanda; Vanzin, Camila Simioni; Biancini, Giovana Brondani; Schwartz, Ida Vanessa Döederlein; Wajner, Moaçir; Vargas, Carmen Regla

doi:10.1007/s10571-008-9313-y

Cited by 58 publications

(40 citation statements)

References 31 publications

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“…The investigation of redox status in cell cultures exposed to the metabolites and in the liver-specific HL-deficient mice model developed by Gauthier et al (2013) would also be of great importance for this purpose. As regards to L-carnitine, it was shown that supplementation of this compound normalized various parameters of oxidative stress in patients with HL deficiency and other inborn errors (Sitta et al 2009;Mescka et al 2013;dos Santos et al 2015;Guerreiro et al 2015). This beneficial effect could be due to its capacity to remove toxic metabolites and/or its antioxidant properties, signalizing the potential use of this compound as an adjuvant therapy for these inherited metabolic conditions.…”

Section: Discussionmentioning

confidence: 99%

Disturbance of redox homeostasis as a contributing underlying pathomechanism of brain and liver alterations in 3‐hydroxy‐3‐methylglutaryl‐CoA lyase deficiency

Leipnitz

Vargas

Wajner

2015

J of Inher Metab Disea

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3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is an inherited disorder of organic acid metabolism biochemically characterized by tissue accumulation and high urinary excretion of 3-hydroxy-3-methylgutarate, 3-methylglutarate, 3-methylglutaconate and 3-hydroxyisovalerate. Affected patients predominantly present neurological symptoms that are accompanied by mild hepatopathy during episodes of catabolic crisis. The pathophysiology of this disease is poorly known, although recent animal and human in vitro and in vivo studies have suggested that oxidative stress caused by the major accumulating organic acids may represent a pathomechanism of brain and liver damage in HL deficiency. In this review we focus on the deleterious effects of these carboxylic acids on redox homeostasis in rat and human tissues that may offer new perspectives for potential novel adjuvant therapeutic strategies in this disorder.

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Section: Discussionmentioning

confidence: 99%

Disturbance of redox homeostasis as a contributing underlying pathomechanism of brain and liver alterations in 3‐hydroxy‐3‐methylglutaryl‐CoA lyase deficiency

Leipnitz

Vargas

Wajner

2015

J of Inher Metab Disea

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“…An increase of malondialdehyde, which is a marker of lipid peroxidation, was observed in plasma of PKU patients at diagnosis and during dietary treatment (Colomé et al 2003;Gassió et al 2008;Sitta et al 2006Sitta et al , 2009bSirtori et al 2005). In addition, increased lipid and protein oxidative damage was also verified in plasma from affected patients with late diagnosis as compared to early diagnosed PKU patients (Sitta et al 2009c).…”

Section: Oxidative Stress In Pku Patientsmentioning

confidence: 99%

“…When the disorder is diagnosed and treated promptly at an early age, mental retardation can be prevented, although mild neuropsychological findings, such as poor school performance and a slight reduction in the intelligence quotient may occur, especially when careful dietary compliance is not achieved (Weglage et al 1995). However, deficiency of selenium and carnitine has been found in treated PKU patients, probably secondary to a poor dietary compliance with the enriched formulas or impaired bioavailability of some micronutrients in these diets (Acosta et al 1999;van Bakel et al 2000;Gassió et al 2008;Sitta et al 2009b).…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress in Phenylketonuria: What is the Evidence?

et al. 2011

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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.

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“…In this scenario, DNA damage was reported in peripheral blood from PKU patients in vivo and in vitro in a dosedependent manner [31,32]. In addition, protein and lipid oxidative damage, measured by carbonyl formation and sulfhydryl oxidation, and thiobarbituric acid-reactive species (TBA-RS) and malondialdehyde (MDA) content, respectively, were described in plasma and erythrocytes from PKU patients [31,[33][34][35][36]. Decreased antioxidant defenses, both enzymatic and non-enzymatic, were also found in these subjects.…”

Section: Oxidative Stressmentioning

confidence: 99%

“…Decreased antioxidant defenses, both enzymatic and non-enzymatic, were also found in these subjects. Low levels of plasma total antioxidant status and reactivity, L-carnitine, betacarotene and coenzyme Q10, and altered catalase [CAT], superoxide dismutase [SOD] and glutathione peroxidase [GPx] activities in PKU patients samples indicate an impairment of antioxidant defense that could result in oxidative stress [31,33,35,36]. Some of these findings were reversed by L-carnitine and selenium supplementation [37].…”

Section: Oxidative Stressmentioning

confidence: 99%

Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations

Schuck¹,

Malgarin²,

Cararo³

et al. 2015

Aging and disease

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Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism caused by the deficiency of phenylalanine hydroxylase. This deficiency leads to the accumulation of Phe and its metabolites in tissues and body fluids of PKU patients. The main signs and symptoms are found in the brain but the pathophysiology of this disease is not well understood. In this context, metabolic alterations such as oxidative stress, mitochondrial dysfunction, and impaired protein and neurotransmitters synthesis have been described both in animal models and patients. This review aims to discuss the main metabolic disturbances reported in PKU and relate them with the pathophysiology of this disease. The elucidation of the pathophysiology of brain damage found in PKU patients will help to develop better therapeutic strategies to improve quality of life of patients affected by this condition.

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l-Carnitine Blood Levels and Oxidative Stress in Treated Phenylketonuric Patients

Abstract: Our results suggest that L-carnitine should be measured in plasma of treated PKU patients, and when a decrease of this endogenous component is detected in plasma, supplementation should be considered as an adjuvant therapy.

Cited by 58 publications

References 31 publications

Disturbance of redox homeostasis as a contributing underlying pathomechanism of brain and liver alterations in 3‐hydroxy‐3‐methylglutaryl‐CoA lyase deficiency

Disturbance of redox homeostasis as a contributing underlying pathomechanism of brain and liver alterations in 3‐hydroxy‐3‐methylglutaryl‐CoA lyase deficiency

Oxidative Stress in Phenylketonuria: What is the Evidence?

Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations

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