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

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.