INHIBITION OF HEPATIC PROPIONYL-COA SYNTHETASE-ACTIVITY BY ORGANIC-ACIDS - REVERSAL OF PROPIONATE INHIBITION OF PYRUVATE METABOLISM

Intracellular accumulation of propionyl-CoA is associated with impairment of important hepatic metabolic pathways. Since propionate absorbed from the intestine can be converted to propionyl-CoA in the liver, inhibition of propionyl-CoA synthesis from propionate and CoA may provide a strategy for decreasing toxicity from plasma propionate. Therefore, inhibition of propionyl-CoA formation by several organic acids was investigated. In isolated, solubilized mitochondria, octanoate, butyrate, salicylate and p-nitrobenzoate inhibited propionyl-CoA synthesis. Octanoate was the most potent inhibitor of propionyl-CoA synthetase activity and had a K(i) of 58-mu-M. In isolated hepatocytes, octanoate inhibited propionate oxidation in a concentration-dependent manner. Consistent with previous studies, propionate (1.0 mM) inhibited the rates of (CO2)-C-14 formation from [1-C-14]pyruvate (10 mM) to 55% of the control values in the hepatocyte system. Octanoate (0.8 mM) had no effect on [1-C-14]pyruvate oxidation under control conditions, but increased (CO2)-C-14 formation from pyruvate to 88% of the control values in the presence of 1.0 mM propionate. Reversal of propionate inhibition of pyruvate oxidation by octanoate was associated with a 44% decrease in hepatocyte propionyl-CoA content. In contrast, while pyruvate oxidation rates were decreased to 53% of control rates in the presence of 10 mM propionylcarnitine, octanoate stimulated pyruvate oxidation under these conditions only to 67% of control levels. In conclusion, mitochondrial propionyl-CoA synthetase activity and hepatocyte propionyl-CoA accumulation can be inhibited by octanoate with consequent decreased propionate oxidation and toxicity in intact hepatocytes. The reversal by octanoate of propionate's inhibition of cellular metabolism may be useful in reducing tissue toxicity from circulating propionate.