Differential effect of valproate and its Delta2- and Delta4-unsaturated metabolites, on the beta-oxidation rate of long-chain and medium-chain fatty acids.
Overall fatty acid oxidation rates were investigated in rat hepatocytes using [9,10-3H]-palmitic, [9,10-3H]-oleic, [9,10-3H]-myristic and [2,3-3H]-phenylpropionic acids. The effect of both valproate (VPA) (0-10 mM) and two of its unsaturated metabolites, Delta2(E)-VPA and Delta4-VPA (0-10 mM), on the overall 3H2O production rate was studied. The results give evidence of a general inhibitory effect of VPA on the beta-oxidation rate of all the tested substrates. Similar effects were observed with both VPA metabolites but these effects appeared to be dependent on the chain length of the substrate. When the effect on the oxidation of the medium-chain fatty acid 3-phenylpropionate (PPA) was studied, Delta2(E)-VPA at 0.5 mM caused a 94% inhibition of the overall beta-oxidation rate. However, with long-chain substrates, 0.5 mM Delta(4)-VPA was a more potent inhibitor (20-30% of control activity) than 0.5 mM Delta(2E)-VPA (60-80% of control activity). Our results suggest that VPA and/or its metabolites inhibit fatty acyl-CoA metabolism within the mitochondrion by two different mechanisms. The first mechanism involves CoASH sequestration, which affects the oxidation rate of all fatty acids with different chain length. The second mechanism is more specific in nature and involves selective inhibition of particular enzymes implicated in fatty acid beta-oxidation.
Silva
M F
MF
Department of Clinical Chemistry and Paediatrics, University of Amsterdam, Academic Medical Centre, 1105 AZ, Amsterdam, Netherlands.
Ruiter
J P
JP
IJlst
L
L
Jakobs
C
C
Duran
M
M
de Almeida
I T
IT
Wanders
R J
RJ
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism* / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D019814:Myristic Acid / Q000378:metabolism; D019301:Oleic Acid / Q000378:metabolism; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism; D010666:Phenylpropionates / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014316:Tritium; D014635:Valproic Acid / Q000494:pharmacology*
D000927:Anticonvulsants; D005229:Fatty Acids, Monounsaturated; D010666:Phenylpropionates; D019814:Myristic Acid; D014316:Tritium; C045022:2-propyl-4-pentenoic acid; D019301:Oleic Acid; D019308:Palmitic Acid; C035253:3-phenylpropionic acid; C014168:2-propyl-2-pentenoic acid; D014635:Valproic Acid