title: Long-chain 3-hydroxy fatty acids accumulating in LCHAD and MTP deficiencies induce oxidative stress in rat brain.
abstract: Accumulation of long-chain 3-hydroxy fatty acids is the biochemical hallmark of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiencies. These disorders are clinically characterized by neurological symptoms, such as convulsions and lethargy, as well as by cardiomyopathy and muscle weakness. In the present work we investigated the in vitro effect of 3-hydroxydodecanoic (3HDA), 3-hydroxytetradecanoic (3HTA) and 3-hydroxypalmitic (3HPA) acids, which accumulate in these disorders, on important oxidative stress parameters in cerebral cortex of young rats in the hope to clarify the mechanisms leading to the brain damage found in patients affected by these disorders. It was first verified that these compounds significantly induced lipid peroxidation, as determined by increased thiobarbituric acid-reactive substances levels. In addition, carbonyl formation was significantly increased and sulfhydryl content decreased by 3HTA and 3HPA, which indicates that these fatty acids elicit protein oxidative damage. 3HTA and 3HPA also diminished the reduced glutathione (GSH) levels, without affecting nitrate and nitrite production. Finally, we observed that the addition of the antioxidants and free radical scavengers trolox and deferoxamine (DFO) was able to partially prevent lipid oxidative damage, whereas DFO fully prevented the reduction on GSH levels induced by 3HTA. Our present data showing that 3HDA, 3HTA and 3HPA elicit oxidative stress in rat brain indicate that oxidative damage may represent an important pathomechanism involved in the neurologic symptoms manifested by patients affected by LCHAD and MTP deficiencies.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Anelise M
authors.initials: AM
authors.lastname: Tonin
authors.forename: Mateus
authors.initials: M
authors.lastname: Grings
authors.forename: Estela N B
authors.initials: EN
authors.lastname: Busanello
authors.forename: Alana P
authors.initials: AP
authors.lastname: Moura
authors.forename: Gustavo C
authors.initials: GC
authors.lastname: Ferreira
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Viegas
authors.forename: Carolina G
authors.initials: CG
authors.lastname: Fernandes
authors.forename: Patrícia F
authors.initials: PF
authors.lastname: Schuck
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000172:deficiency*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001928:Brain Diseases, Metabolic / Q000139:chemically induced / Q000378:metabolism*; D003652:Decanoic Acids / Q000378:metabolism / Q000633:toxicity; D005227:Fatty Acids / Q000378:metabolism / Q000633:toxicity; D052439:Lipid Metabolism Disorders / Q000139:chemically induced / Q000378:metabolism*; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase; D008297:Male; D063991:Mitochondrial Trifunctional Protein; D009097:Multienzyme Complexes / Q000172:deficiency*; D009227:Myristic Acids / Q000378:metabolism / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010169:Palmitic Acids / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003652:Decanoic Acids; D005227:Fatty Acids; D009097:Multienzyme Complexes; D009227:Myristic Acids; D010169:Palmitic Acids; C009893:beta-hydroxymyristic acid; C108229:3-hydroxypalmitic acid; D015094:3-Hydroxyacyl CoA Dehydrogenases; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase; D063991:Mitochondrial Trifunctional Protein; C017552:myrmicacin