Mechanism of Hyperammonemia in an Experimental Model of Propionic Acidemia
We have reported (J. Clin. Invest. 66:484, 1980) that rats injected with 10–20 mmol/kg of propionate develop severe hyperammonemia following amino acid loads, while acetate has no such effect. The mechanism was shown to be an impairment in the rise in N-acetylglutamate (AGA) and secondarily in carbamyl phosphate synthetase that normally follows amino acid loads. In order to determine whether this failure of AGA synthesis was caused (1) by competitive inhibition of AGA synthetase by propionyl CoA and/or methylmalonyl CoA or (2) by depletion of acetyl CoA, one of the substrates for AGA synthesis, ethanol in doses of 0.1 to 5 mmoles/kg was given with propionate or acetate. The hyperammonemia was attenuated or prevented, and AGA levels were restored towards normal. Acetyl CoA levels were also restored towards normal, while unidentified medium chain thioesters changed little. Thus these results support mechanism (1) rather than (2) as the cause of hyperammonemia in propionic acidemia.