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: Daiane Grigolo Bardemaker Rodrigues, Daniella de Moura Coelho, Ângela Sitta, Carlos Eduardo Diaz Jacques, Tatiane Hauschild, Vanusa Manfredini, Abdellatif Bakkali, Eduard A Struys, Cornelis Jakobs, Moacir Wajner, Carmen Regla Vargas
• Journal: Toxicology in vitro : an international journal published in association with BIBRA (Toxicol In Vitro) Vol. 42 Pg. 47-53 (Aug 2017) ISSN: 1879-3177 [Electronic] England
• PMID: 28396261 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Glutarates
• Protective Agents
• Reactive Nitrogen Species
• 8-epi-prostaglandin F2alpha
• alpha-hydroxyglutarate
• Tyrosine
• Guanine
• Dinoprost
• dityrosine
• Carnitine

Topics

• Adolescent
• Adult
• Brain Diseases, Metabolic, Inborn (genetics, urine)
• Carnitine (pharmacology)
• Child
• Child, Preschool
• Comet Assay
• DNA Damage (drug effects)
• Dinoprost (analogs & derivatives, urine)
• Glutarates (toxicity)
• Guanine (analogs & derivatives, urine)
• Humans
• Leukocytes (drug effects, metabolism)
• Oxidative Stress (drug effects)
• Protective Agents (pharmacology)
• Reactive Nitrogen Species (urine)
• Tyrosine (analogs & derivatives, urine)
• Young Adult