Toxicity of octanoate and decanoate in rat peripheral tissues: evidence of bioenergetic dysfunction and oxidative damage induction in liver and skeletal muscle.
The accumulation of octanoic (OA) and decanoic (DA) acids in tissue is the common finding in medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD), the most frequent defect of fatty acid oxidation. Affected patients present hypoketotic hypoglycemia, rhabdomyolysis, hepatomegaly, seizures and lethargy, which may progress to coma and death. At present, the pathophysiological mechanisms underlying hepatic and skeletal muscle alterations in affected patients are poorly known. Therefore, in the present work, we investigated the in vitro effects of OA and DA, the accumulating metabolites in MCADD, on various bioenergetics and oxidative stress parameters. It was verified that OA and DA decreased complexes I-III, II-III and IV activities in liver and also inhibit complex IV activity in skeletal muscle. In addition, DA decreased complexes II-III activity in skeletal muscle. We also verified that OA and DA increased TBA-RS levels and carbonyl content in both tissues. Finally, DA, but not OA, significantly decreased GSH levels in rat skeletal muscle. Our present data show that the medium-chain fatty acids that accumulate in MCADD impair electron transfer through respiratory chain and elicit oxidative damage in rat liver and skeletal muscle. It may be therefore presumed that these mechanisms are involved in the pathophysiology of the hepatopathy and rhabdomyolysis presented by MCADD-affected patients.
Programa de Pós-graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil.
Giselli
G
Scaini
Kellen R
KR
Simon
Anelise M
AM
Tonin
Estela N B
EN
Busanello
Alana P
AP
Moura
Gustavo C
GC
Ferreira
Moacir
M
Wajner
Emilio L
EL
Streck
Patrícia F
PF
Schuck
D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D002210:Caprylates / Q000378:metabolism* / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism; D003651:Decanoates / Q000378:metabolism* / Q000494:pharmacology; D004579:Electron Transport; D003576:Electron Transport Complex IV / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D050050:Protein Carbonylation; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D002210:Caprylates; D003651:Decanoates; D017392:Thiobarbituric Acid Reactive Substances; D042964:Acyl-CoA Dehydrogenase; D003576:Electron Transport Complex IV; D003402:Creatine Kinase; D005978:Glutathione; C031492:octanoic acid