Glutathione metabolism enzymes in brain and liver of hyperphenylalaninemic rats and the effect of lipoic acid treatment

Abstract

Phenylketonuria (PKU) is a disorder caused by a deficiency in phenylalanine hydroxylase activity, which converts phenylalanine (Phe) to tyrosine, leading to hyperphenylalaninemia (HPA) with accumulation of Phe in tissues of patients. The neuropathophysiology mechanism of disease remains unknown. However, recently the involvement of oxidative stress with decreased glutathione levels in PKU has been reported. Intracellular glutathione (GSH) levels may be maintained by the antioxidant action of lipoic acid (LA). The aim of this study was to evaluate the activity of the enzymes involved in the metabolism and function of GSH, such as glutathione peroxidase (GSH-Px), glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase (GR), glutamate-cysteine ligase (GCL), glutathione-S-transferase (GST) and GSH content in brain and liver of young rats subjected to a chemically induced model of HPA and the effect of LA for a week. In brain, the administration of Phe reduced the activity of the GSH-Px, GR and G6PD and LA prevented these effects totally or partially. GCL activity was increased by HPA and was not affect by LA antioxidant treatment. GST activity did not differ between groups. GSH content was increased by LA and decreased by HPA treatment in brain samples. Considering the liver, all parameters analyzed were increased in studied HPA animals and LA was able to hinder some effects except for the GCL, GST enzymes and GSH content. These results suggested that HPA model alter the metabolism of GSH in rat brain and liver, which may have an important role in the maintenance of GSH function in PKU although liver is not a directly affected organ in this disease. So, an antioxidant therapy with LA may be useful in the treatment of oxidative stress in HPA.

The effect of lipoic acid on acrylamide-induced neuropathy in rats with reference to biochemical, hematological, and behavioral alterations

“…Furthermore, Moraes et al (2014) reported that LA could prevent the reduction in GPx, GR activities, and the reduced GSH level without any changes in the GST activity in hyerphenylalaninemic rats.…”

White matter disturbances in phenylketonuria: Possible underlying mechanisms

“…OLs and its precursors are sensitive to alterations in redox homeostasis (Brill, Scheuer, Bührer, Endesfelder, & Schmitz, 2017;Takase et al, 2018). Several reports indicate that oxidative stress is implicated in the pathophysiology of PKU, as demonstrated in animal HPA models (Fernandes et al, 2010;Lu et al, 2011;Mazzola et al, 2011;Moraes et al, 2014;Simon et al, 2013) and in samples from PKU patients (Huemer et al, 2012;Item et al, 2017;Okano & Nagasaka, 2013;Sitta et al, 2009Sitta et al, , 2011. The interplay between oxidative stress and bioenergetics dyshomeostasis has been associated with myelin defects.…”

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

“…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). Imbalance in redox homeostasis in PKU is now admitted, but its link with metabolic disturbances observed in the disease remains unclear.…”