Oxidative stress in phenylketonuria: what is the evidence?

Abstract

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.

Fig. 1

Suggested pathomechanisms for neurological damage in PKU. Phenylalanine (Phe) may induce generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and reduce tissue antioxidant defenses producing oxidative stress. Phe can also inhibit key enzymatic activities of energy metabolism, such as Na⁺, K⁺-ATPase, mitochondrial creatine kinase isoform (mit-CK), and the mitochondrial electron transfer chain (METC) leading to energy failure. METC blockage may result in the increased production of ROS. The increased ROS and RNS cause lipid and protein oxidation and DNA damage. Phe disturbs the transport of various large neutral amino acids (LNAA) into the brain. The reduction of LNAA into the brain associated with a reduction of tyrosine (Tyr) levels reduce the availability for neurotransmitter synthesis, such as dopamine and noradrenalin