title: Oxidative stress induced by phenylketonuria in the rat: Prevention by melatonin, vitamin E, and vitamin C.
abstract: Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of the phenylalanine hydroxylation system and is characterized by a block in the conversion of phenylalanine (PHE) to tyrosine. We examined the effects of maternal hyperphenylalaninemia on the morphological and biochemical development of pup rat brain and cerebellum. In our model of PKU we evaluated a number of markers of oxidative stress such as Ehrlich adducts formation, lipid peroxidation, as well as the levels of reduced and oxidized glutathione, and the activities of the enzymes glutathione peroxidase and glutathione reductase. We also studied the expression of heme-oxigenase-1 and mitogen-activated protein kinase 1/2 (MAPK 1/2) as additional markers of oxidative stress. We demonstrate that PKU strongly increased most of the oxidative stress markers studied and induced significant morphological damage. We also showed that daily administration of melatonin (20 mg/kg BW), vitamin E (30 mg/kg BW), and vitamin C (30 mg/kg BW) until delivery prevented the oxidative biomolecular damage in the rat brain and cerebellum. Although no significant differences were observed among the antioxidants studied, it should be noted that the doses of melatonin were less than those for vitamins E and C. We conclude that PKU induces a clear state of oxidative stress that is somehow involved in the brain and body damage occurring in this inborn error. Moreover, melatonin and other antioxidants are capable of preventing completely the damage induced by PKU.
authors.affiliation: Department of Medical Biochemistry and Molecular Biology, University of Seville School of Medicine and Virgen Macarena Hospital, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Martinez-Cruz
authors.forename: David
authors.initials: D
authors.lastname: Pozo
authors.forename: Carmen
authors.initials: C
authors.lastname: Osuna
authors.forename: Auxiliadora
authors.initials: A
authors.lastname: Espinar
authors.forename: Concepcion
authors.initials: C
authors.lastname: Marchante
authors.forename: Juan M
authors.initials: JM
authors.lastname: Guerrero
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000002:abnormalities / Q000187:drug effects* / Q000378:metabolism; D002531:Cerebellum / Q000002:abnormalities / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008550:Melatonin / Q000378:metabolism / Q000494:pharmacology; D009421:Nervous System Malformations / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010649:Phenylalanine / Q000378:metabolism / Q000494:pharmacology; D010661:Phenylketonurias / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D014810:Vitamin E / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D014810:Vitamin E; D010649:Phenylalanine; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005978:Glutathione; D008550:Melatonin; D001205:Ascorbic Acid