Differential effect of valproate and its Delta(2)- and Delta(4)-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 usi ng [9,10-H-3]palmitic, [9,10-H-3]-oleic, [9.10-H-3]-myristic and [2,3-H-3]- phenylpropionic acids. The effect of both valproate (VPA) (0-10 mM) and two of its unsaturated metabolites, Delta (2(E))-VPA and Delta (4)-VPA (0-10 m M), on the overall (H2O)-H-3 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 m etabolites but these effects appeared to be dependent on the chain length o f the substrate. When the effect on the oxidation of the medium-chain fatty acid 3-phenylpropionate (PPA) was studied, Delta (2(E))-VPA at 0.5 mM caus ed 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 (2(E))-VPA (60-80% of control activ ity). Our results suggest that VPA and/or its metabolites inhibit fatty acy l-CoA metabolism within the mitochondrion by two different mechanisms. The first mechanism involves CoASH sequestration, which affects the oxidation r ate of all fatty acids with different chain length. The second mechanism is more specific in nature and involves selective inhibition of particular en zymes implicated in fatty acid beta -oxidation. (C) 2001 Elsevier Science I reland Ltd. All rights reserved.