8-epi-prostaglandin-f2alpha and Phenylketonurias

Oxidative stress has been proposed as an important pathophysiologic feature of various inborn errors of metabolism, including phenylketonuria (PKU). Considering that there are few studies relating oxidative stress and inflammation directly in PKU disease, the aim of this study was to evaluate and correlate oxidative damage to biomolecules, antioxidant defenses, pro-inflammatory cytokines, phenylalanine (Phe) and its metabolites (phenyllactic acid--PLA and phenylacetic acid--PAA) levels in urine and plasma from patients with PKU under dietary treatment. We observed a marked increase of isoprostanes, which is a lipid peroxidation biomarker, in urine from these treated patients. Next, we demonstrated that protein oxidative damage, measured by di-tyrosine formation, was significantly increased in urine from PKU treated patients and that decreased urinary antioxidant capacity was also observed. Our findings concerning to the inflammatory cytokines interleukin-6 and interleukin-1β, both significantly increased in these patients, provide evidence that the pro-inflammatory state occurs. Besides, interleukin-1β was positively correlated with isoprostanes. We observed a negative correlation between interleukin-6 and interleukin-10, an anti-inflammatory cytokine. Di-tyrosine was positively correlated with Phe, which indicates oxidative damage to proteins, as well as with PAA. These findings may suggest that the protein damage may be induced by Phe and its metabolite PAA in PKU. Our results indicate that pro-oxidant and pro-inflammatory states occur and are, in part, correlated and protein oxidation seems to be induced by Phe and PPA in PKU patients.

Topics: Adolescent; Biomarkers; Child; Creatine Kinase; Cytokines; Dinoprost; Female; Humans; Lipid Peroxidation; Male; Oxidative Stress; Phenylalanine; Phenylketonurias; Reactive Oxygen Species; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Tyrosine; Young Adult

Phenylketonuria (PKU) is the most frequent inherited disorder of amino acid metabolism. In our previous work, we investigated the role of NADPH oxidase (NOX) in a Pahenu2-BTBR PKU mouse model, and an in vitro cell culture model of PKU. In the current study, we evaluated various oxidative stress parameters, namely total antioxidant capacity (T-AOC), glutathione (GSH) and maleic dialdehyde (MDA) in the plasma of 40 PKU children, for further investigating the oxidative molecular regulation mechanism of NOX in PKU. It was observed that T-AOC and GSH markedly decreased in PKU as compared with the control group (P<0.01), and seemed to correlate negatively with Phe level. However, there was no statistical difference in MDA level among the three groups. And 8-isoprostane in the blood samples of PKU2 groups was slightly higher than control group (P<0.05). Additionally, mRNA levels of subunits of NOX included p47(phox) and p67(phox) significantly increased in PKU group (P<0.01). These results reflected that NOX is the important source of reactive oxygen species and is involved in the oxidative molecular regulation mechanism in PKU, which shows a new perspective toward understanding the biological underpinnings of PKU.

Topics: Aldehydes; Analysis of Variance; Apoptosis; Child; Child, Preschool; Dinoprost; Female; Flow Cytometry; Glutathione; Humans; Infant; Infant, Newborn; Leukocytes, Mononuclear; Male; NADPH Oxidases; Phenylketonurias; RNA, Messenger