Evidence that 2-methylacetoacetate induces oxidative stress in rat brain.
In the present study we investigated the effects of 2-methylacetoacetate (MAA) and 2-methyl-3-hydroxybutyrate (MHB), the major metabolites accumulating in mitochondrial 2-methylacetoacetyl-CoA thiolase (KT) and 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiencies, on important parameters of oxidative stress in cerebral cortex from young rats. We verified that MAA induced lipid peroxidation (increase of thiobarbituric acid-reactive substances (TBA-RS) and chemiluminescence values), whereas MHB did not alter these parameters. MAA-induced increase of TBA-RS levels was fully prevented by free radical scavengers, indicating that free radicals were involved in this effect. Furthermore, MAA, but not MHB, significantly induced sulfhydryl oxidation, implying that this organic acid provokes protein oxidative damage. It was also observed that MAA reduced GSH, a naturally-occurring brain antioxidant, whereas MHB did not change this parameter. Furthermore, the decrease of GSH levels caused by MAA was not due to a direct oxidative action, since this organic acid did not alter the sulfhydryl content of a commercial solution of GSH in a cell free medium. Finally, MAA and MHB did not raise nitric oxide production. The data indicate that MAA induces oxidative stress in vitro in cerebral cortex. It is presumed that this pathomechanism may be involved in the brain damage found in patients affected by KT deficiency.
Leipnitz
Guilhian
G
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal de Rio Grande do Sul, Rua Ramiro Barcelos, Anexo, Porto Alegre, RS, Brazil.
Seminotti
Bianca
B
Amaral
Alexandre U
AU
Fernandes
Carolina G
CG
Dutra-Filho
Carlos S
CS
Wajner
Moacir
M
D000090:Acetoacetates / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001928:Brain Diseases, Metabolic / Q000139:chemically induced* / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006885:Hydroxybutyrates / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D000090:Acetoacetates; D006885:Hydroxybutyrates; C037765:2-methylacetoacetic acid; C016579:2-methyl-3-hydroxybutyric acid