title: DNA damage induced by phenylalanine and its analogue p-chlorophenylalanine in blood and brain of rats subjected to a model of hyperphenylalaninemia.
abstract: Phenylketonuria (PKU) is a disease caused by a deficiency of phenylalanine hydroxylase (PAH), resulting in an accumulation of phenylalanine (Phe) in the brain tissue, cerebrospinal fluid, and other tissues of PKU patients. Considering that high levels of Phe are associated with neurological dysfunction and that the mechanisms underlying the neurotoxicity in PKU remain poorly understood, the main objective of this study was to investigate the in vivo and in vitro effects of Phe on DNA damage, as determined by the alkaline comet assay. The results showed that, compared to control group, the levels of DNA migration were significantly greater after acute administration of Phe, p-chlorophenylalanine (p-Cl-Phe, an inhibitor of PAH), or a combination thereof in cerebral cortex and blood, indicating DNA damage. These treatments also provoked increase of carbonyl content. Additionally, when Phe or p-Cl-Phe was present in the incubation medium, we observed an increase in the frequency and index of DNA damage in the cerebral cortex and blood, without affecting lactate dehydrogenase (LDH) release. Our in vitro and in vivo findings indicate that DNA damage occurs in the cerebral cortex and blood of rats receiving Phe, suggesting that this mechanism could be, at least in part, responsible for the neurological dysfunction in PKU patients.
authors.affiliation: a Laboratório de Erros Inatos do Metabolismo, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Avenida Universitária, 1105, Bloco S, Sala 6, 88806-000 Criciúma, SC, Brazil.
authors.forename: Kellen R
authors.initials: KR
authors.lastname: Simon
authors.forename: Rosane M
authors.initials: RM
authors.lastname: Dos Santos
authors.forename: Giselli
authors.initials: G
authors.lastname: Scaini
authors.forename: Daniela D
authors.initials: DD
authors.lastname: Leffa
authors.forename: Adriani P
authors.initials: AP
authors.lastname: Damiani
authors.forename: Camila B
authors.initials: CB
authors.lastname: Furlanetto
authors.forename: Jéssica L
authors.initials: JL
authors.lastname: Machado
authors.forename: José H
authors.initials: JH
authors.lastname: Cararo
authors.forename: Tamires P
authors.initials: TP
authors.lastname: Macan
authors.forename: Emilio L
authors.initials: EL
authors.lastname: Streck
authors.forename: Gustavo C
authors.initials: GC
authors.lastname: Ferreira
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Andrade
authors.forename: Patrícia F
authors.initials: PF
authors.lastname: Schuck
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects*; D010134:Fenclonine / Q000097:blood / Q000378:metabolism*; D008297:Male; D010649:Phenylalanine / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000097:blood; D010651:Phenylalanine Hydroxylase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010661:Phenylketonurias / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase; D010134:Fenclonine