Hepatic and renal contributions to valproic acid-induced hyperammonemia

Valproic acid (VPA) consistently and reproducibly elevates arterial ammonia in rats injected with an amino acid load. The extent of the hyperammonemia is dependent on the dose of VPA injected or VPA plasma concentration and the amino acid dose. Bilaterally nephrectomized rats injected with VPA and an amino acid load also develop hyperammonemia, which overall approximates 75% of that achieved in non-nephrectomized animals. In non-nephrectomized animals injected with an amino acid load, valproic acid produces a marked reduction in baseline and activated hepatic mitochondrial carbamyl phosphate synthetase I activity. Our results suggest that VPA-induced hyperammonemia after an amino acid load results from inhibition of hepatic intramitochondrial citrullinogenesis with only a limited contribution from the kidneys.