title: Experimental evidence of oxidative stress in patients with l-2-hydroxyglutaric aciduria and that l-carnitine attenuates in vitro DNA damage caused by d-2-hydroxyglutaric and l-2-hydroxyglutaric acids.
abstract: d-2-hydroxyglutaric (D-2-HGA) and l-2-hydroxyglutaric (L-2-HGA) acidurias are rare neurometabolic disorders biochemically characterized by increased levels of d-2-hydroxyglutaric acid (D-2-HG) and l-2-hydroxyglutaric acid (L-2-HG) respectively, in biological fluids and tissues. These diseases are caused by mutations in the specific enzymes involved in the metabolic pathways of these organic acids. In the present work, we first investigated whether D-2-HG and L-2-HGA could provoke DNA oxidative damage in blood leukocytes and whether l-carnitine (LC) could prevent the in vitro DNA damage induced by these organic acids. It was verified that 50μM of D-2-HG and 30μM of L-2-HG significantly induced DNA damage that was prevented by 30 and 150μM of LC. We also evaluated oxidative stress parameters in urine of L-2-HGA patients and observed a significant increase of oxidized guanine species and di-tyrosine, biomarkers of oxidative DNA and protein damage, respectively. In contrast, no significant changes of urinary isoprostanes and reactive nitrogen species levels were observed in these patients. Taken together, our data indicate the involvement of oxidative damage, especially on DNA, in patients affected by these diseases and the protective effect of LC.
authors.affiliation: Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, UFRGS, Av. Ipiranga, 2752, CEP 90610-000 Porto Alegre, RS, Brazil; Serviço de Genética Médica, HCPA, R. Ramiro Barcelos, 2350, CEP 90035-003 Porto Alegre, RS, Brazil. Electronic address: daianegbr@hotmail.com.
authors.forename: Daiane Grigolo Bardemaker
authors.initials: DGB
authors.lastname: Rodrigues
authors.affiliation: Serviço de Genética Médica, HCPA, R. Ramiro Barcelos, 2350, CEP 90035-003 Porto Alegre, RS, Brazil.
authors.forename: Daniella
authors.initials: D
authors.lastname: de Moura Coelho
authors.affiliation: Serviço de Genética Médica, HCPA, R. Ramiro Barcelos, 2350, CEP 90035-003 Porto Alegre, RS, Brazil.
authors.forename: Ângela
authors.initials: Â
authors.lastname: Sitta
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, R. Ramiro Barcelos, 2600, CEP 90035-003 Porto Alegre, RS, Brazil; Serviço de Genética Médica, HCPA, R. Ramiro Barcelos, 2350, CEP 90035-003 Porto Alegre, RS, Brazil.
authors.forename: Carlos Eduardo Diaz
authors.initials: CED
authors.lastname: Jacques
authors.affiliation: Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, UFRGS, Av. Ipiranga, 2752, CEP 90610-000 Porto Alegre, RS, Brazil; Serviço de Genética Médica, HCPA, R. Ramiro Barcelos, 2350, CEP 90035-003 Porto Alegre, RS, Brazil.
authors.forename: Tatiane
authors.initials: T
authors.lastname: Hauschild
authors.affiliation: Programa de Pós-Graduação em Bioquímica, BR 472, Km 585, 118, Universidade Federal do Pampa, CEP 97500-970 Uruguaiana, RS, Brazil.
authors.forename: Vanusa
authors.initials: V
authors.lastname: Manfredini
authors.affiliation: Metabolic Unit, Clinical Chemistry, VUmc Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Abdellatif
authors.initials: A
authors.lastname: Bakkali
authors.affiliation: Metabolic Unit, Clinical Chemistry, VUmc Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Eduard A
authors.initials: EA
authors.lastname: Struys
authors.affiliation: Metabolic Unit, Clinical Chemistry, VUmc Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, R. Ramiro Barcelos, 2600, CEP 90035-003 Porto Alegre, RS, Brazil; Serviço de Genética Médica, HCPA, R. Ramiro Barcelos, 2350, CEP 90035-003 Porto Alegre, RS, Brazil.
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
authors.affiliation: Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, UFRGS, Av. Ipiranga, 2752, CEP 90610-000 Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, R. Ramiro Barcelos, 2600, CEP 90035-003 Porto Alegre, RS, Brazil; Serviço de Genética Médica, HCPA, R. Ramiro Barcelos, 2350, CEP 90035-003 Porto Alegre, RS, Brazil. Electronic address: crvargas@hcpa.edu.br.
authors.forename: Carmen Regla
authors.initials: CR
authors.lastname: Vargas
mesh_terms: D000293:Adolescent; D000328:Adult; D020739:Brain Diseases, Metabolic, Inborn / Q000235:genetics* / Q000652:urine; D002331:Carnitine / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D005977:Glutarates / Q000633:toxicity*; D006147:Guanine / Q000031:analogs & derivatives / Q000652:urine; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D026361:Reactive Nitrogen Species / Q000652:urine; D014443:Tyrosine / Q000031:analogs & derivatives / Q000652:urine; D055815:Young Adult
chemical_list: D005977:Glutarates; D020011:Protective Agents; D026361:Reactive Nitrogen Species; C075750:8-epi-prostaglandin F2alpha; C019417:alpha-hydroxyglutarate; D014443:Tyrosine; D006147:Guanine; D015237:Dinoprost; C007543:dityrosine; D002331:Carnitine
keywords: DNA damage; Oxidative stress; d-2-hydroxyglutaric aciduria; l-2-hydroxyglutaric aciduria; l-carnitine