Comparative toxicity of valproic acid and its metabolites in liver slices from adult rats, weanling rats and humans

The incidence of fatal hepatic failure associated with valproic acid (VPA) treatment is low but when it occurs, 90% of the affected patients are below the age of 20 yr. At present the mechanism of VPA hepatotoxicity is unclear; however, it may be a combination of the formation and action of toxic metabolites in developing tissues. In the study reported here we investigated the action of VPA and its metabolites in liver slices prepared from adult and weanling Sprague-Dawley rats and from human livers (non-transplantable livers from organ donors, or biopsy material from patients undergoing surgical liver resection). VPA, 2-propyl-2-pentenoic acid (2-en-VPA or Δ²-VPA), 2-propyl-4-pentenoic acid (4-en-VPA or Δ⁴-VPA) were incubated for various times at concentrations of 100 or 300 μg/ml. Protein synthesis and K^| content were used to assess functional integrity or general viability. The question addressed was whether there were differences in the in vitro toxicity of VPA and its metabolites that were related to the age of the livers from which the slices were taken. Liver slices from weanling rats were significantly more sensitive to VPA and its metabolites than the slices from livers of adult rats. The rank order of toxicities (4-en-VPA > VPA > 2-en-VPA) was the same in both sets of rat slices. The human liver slices were significantly affected by VPA and its metabolites but these compounds were equal in their ability to produce this toxicity. There was also an indication of differences in sensitivity to the toxicity of VPA in slices from livers of donors of different ages.