The effect of valproic acid on hepatic and plasma levels of 15-F2t-isoprostane in rats

Free Radic Biol Med. 2003 Jun 1;34(11):1435-46. doi: 10.1016/s0891-5849(03)00151-5.


The mechanism by which valproic acid (VPA) induces liver injury remains unknown, but it is hypothesized to involve the generation of toxic metabolites and/or reactive oxygen species. This study's objectives were to determine the effect of VPA on plasma and hepatic levels of the F(2)-isoprostane, 15-F(2t)-IsoP, a marker for oxidative stress, and to investigate the influence of cytochrome P450- (P450-) mediated VPA biotransformation on 15-F(2t)-IsoP levels in rats. In rats treated with VPA (500 mg/kg), plasma 15-F(2t)-IsoP was increased 2.5-fold at t(max) = 0.5 h. Phenobarbital pretreatment (80 mg/kg/d for 4 d) in VPA-treated rats increased plasma and liver levels of free 15-F(2t)-IsoP by 5-fold and 3-fold, respectively, when compared to control groups. This was accompanied by an elevation in plasma and liver levels of P450-mediated VPA metabolites. Pretreatment with SKF-525A (80 mg/kg) or 1-aminobenzotriazole (100 mg/kg), which inhibited P450-mediated VPA metabolism, did not attenuate the increased levels of plasma 15-F(2t)-IsoP in VPA-treated groups. Plasma and hepatic levels of 15-F(2t)-IsoP were further elevated after 14 d of VPA treatment compared to single-dose treatment. Our data indicate that VPA increases plasma and hepatic levels of 15-F(2t)-IsoP and this effect can be enhanced by phenobarbital by a mechanism not involving P450-catalyzed VPA biotransformation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / toxicity*
  • Biotransformation
  • Cytochrome P-450 Enzyme System / physiology
  • Dinoprost* / analogs & derivatives*
  • Enzyme Inhibitors / pharmacology
  • F2-Isoprostanes / blood
  • F2-Isoprostanes / metabolism*
  • Gas Chromatography-Mass Spectrometry
  • Lipid Peroxides
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Oxidative Stress
  • Phenobarbital / pharmacology
  • Proadifen / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Thiobarbituric Acid Reactive Substances
  • Triazoles / pharmacology
  • Valproic Acid / toxicity*


  • Anticonvulsants
  • Enzyme Inhibitors
  • F2-Isoprostanes
  • Lipid Peroxides
  • Thiobarbituric Acid Reactive Substances
  • Triazoles
  • 1-aminobenzotriazole
  • 8-epi-prostaglandin F2alpha
  • Valproic Acid
  • Cytochrome P-450 Enzyme System
  • Proadifen
  • Dinoprost
  • Phenobarbital