title: Acute lysine overload provokes protein oxidative damage and reduction of antioxidant defenses in the brain of infant glutaryl-CoA dehydrogenase deficient mice: a role for oxidative stress in GA I neuropathology.
abstract: We evaluated the antioxidant defense system and protein oxidative damage in the brain and liver of 15-day-old GCDH deficient knockout (Gcdh(-/-)) mice following an acute intraperitoneal administration of Lys (8 μmol/g). We determined reduced glutathione (GSH) concentrations, sulfhydryl content, carbonyl formation and the activities of the antioxidant enzymes glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GR) in the brain and liver of these animals. 2',7'-dihydrodichlorofluorescein (DCFH) oxidation was also measured as an index of free radical formation. The only parameters altered in Gcdh(-/-) compared to wild type (Gcdh(+/+)) mice were a reduction of liver GSH concentrations and of brain sulfhydryl content. Acute Lys injection provoked a decrease of GSH concentration in the brain and sulfhydryl content in the liver, and an increase in carbonyl formation in the brain and liver of Gcdh(-/-) mice. Lys administration also induced a decrease of all antioxidant enzyme activities in the brain, as well as an increase of the activities of SOD and CAT in the liver of Gcdh(-/-) mice. Finally, Lys elicited a marked increase of DCFH oxidation in the brain and liver. It is concluded that Lys overload compromises the brain antioxidant defenses and induces protein oxidation probably secondary to reactive species generation in infant Gcdh(+/+) mice.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Bianca
authors.initials: B
authors.lastname: Seminotti
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Rafael Teixeira
authors.initials: RT
authors.lastname: Ribeiro
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Alexandre Umpierrez
authors.initials: AU
authors.lastname: Amaral
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Mateus Struecker
authors.initials: MS
authors.lastname: da Rosa
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Carolina Coffi
authors.initials: CC
authors.lastname: Pereira
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Guilhian
authors.initials: G
authors.lastname: Leipnitz
authors.affiliation: Department of Pediatrics, Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Koeller
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Goodman
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Woontner
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil. Electronic address: mwajner@ufrgs.br.
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000150:complications / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism*; D001928:Brain Diseases, Metabolic / Q000150:complications / Q000473:pathology*; D001930:Brain Injuries / Q000209:etiology / Q000517:prevention & control; D002374:Catalase; D004195:Disease Models, Animal; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency* / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase; D008239:Lysine / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D013482:Superoxide Dismutase
chemical_list: D018696:Neuroprotective Agents; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D050770:Glutaryl-CoA Dehydrogenase; D005978:Glutathione; D008239:Lysine
keywords: 3-Hydroxyglutaric acid; Antioxidant defenses; Brain damage; Glutaric acid; Glutaric acidemia type I; Infant Gcdh(−/−) mice