New insights on the mechanisms of valproate-induced hyperammonemia: inhibition of hepatic N-acetylglutamate synthase activity by valproyl-CoA

J Hepatol. 2011 Aug;55(2):426-34. doi: 10.1016/j.jhep.2010.11.031. Epub 2010 Dec 13.


Background & aims: Hyperammonemia is a frequent side-effect of valproic acid (VPA) therapy, which points to an imbalance between ammoniagenesis and ammonia disposal via the urea cycle. The impairment of this liver-specific metabolic pathway induced either by primary genetic defects or by secondary causes, namely associated with drugs administration, may result in accumulation of ammonia. To elucidate the mechanisms which underlie VPA-induced hyperammonemia, the aim of this study was to evaluate the effect of both VPA and its reactive intermediate, valproyl-CoA (VP-CoA), on the synthesis of N-acetylglutamate (NAG), a prime metabolite activator of the urea cycle.

Methods: The amount of NAG in livers of rats treated with VPA was quantified by HPLC-MS/MS. The NAG synthase (NAGS) activity was evaluated in vitro in rat liver mitochondria, and the effect of both VPA and VP-CoA was characterized.

Results: The present results clearly show that VP-CoA is a stronger inhibitor of NAGS activity in vitro than the parent drug VPA. The hepatic levels of NAG were significantly reduced in VPA-treated rats as compared with control tissues.

Conclusions: These data strongly suggest that the hyperammonemia observed in patients under VPA treatment may result from a direct inhibition of the NAGS activity by VP-CoA. The subsequent reduced availability of NAG will impair the flux through the urea cycle and compromise the major role of this pathway in ammonia detoxification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl Coenzyme A / metabolism*
  • Acyl Coenzyme A / toxicity
  • Amino-Acid N-Acetyltransferase / antagonists & inhibitors*
  • Ammonia / blood
  • Animals
  • Anticonvulsants / toxicity
  • Citrulline / biosynthesis
  • Disease Models, Animal
  • Glutamates / metabolism
  • Glutamine / blood
  • Humans
  • Hyperammonemia / chemically induced*
  • Hyperammonemia / metabolism*
  • In Vitro Techniques
  • Liver / drug effects*
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Rats
  • Rats, Wistar
  • Urea / blood
  • Urea / metabolism
  • Valproic Acid / toxicity*


  • Acyl Coenzyme A
  • Anticonvulsants
  • Glutamates
  • valproyl-coenzyme A
  • Glutamine
  • Citrulline
  • Valproic Acid
  • Ammonia
  • Urea
  • Amino-Acid N-Acetyltransferase
  • N-acetylglutamic acid