Role of N-acetylglutamate and acetyl-CoA in the inhibition of ureagenesis by isovaleric acid in isolated rat hepatocytes.

1 and 10 mmol/l isovalerate strongly inhibited urea synthesis in isolated rat hepatocytes incubated with 10 mmol/l alanine and 3 mmol/l ornithine. Isovalerate also markedly decreased N-acetylglutamate levels, and the decrease correlated with the inhibition of urea synthesis by isovalerate. This compound also lowered cellular levels of acetyl-CoA, a substrate of N-acetylglutamate synthase (EC 2.3.1.1). Isovalerate did not significantly affect the cellular levels of ATP and had no direct effect on N-acetylglutamate synthase activity. These results suggest that the inhibition of urea synthesis by isovalerate is due to decrease in N-acetylglutamate levels.