Peroxisome proliferator-activated receptor delta is a specific sensor for teratogenic valproic acid derivatives

Eur J Pharmacol. 2001 Nov 9;431(1):25-33. doi: 10.1016/s0014-2999(01)01423-6.


The antiepileptic drug valproic acid (2-propylpentanoic acid) is a potent teratogen in both humans and mice. Valproic acid can induce differentiation of F9 teratocarcinoma cells and stimulate peroxisome proliferator-activated receptor (PPAR) activity. In this study, the structure-activity relationship between valproic acid, its teratogenic and non-teratogenic analogues (branched small- and medium chain fatty acids) and the three PPAR subtypes alpha, gamma or delta was investigated. PPAR-alpha and PPAR-gamma were activated by some valproic acid-derivatives; however, no correlation between teratogenicity and receptor activation could be observed. In contrast, only valproic acid and exclusively its teratogenic analogues were able to activate PPAR-delta in different cellular systems. However, valproic acid appears not to be a direct ligand of PPAR-delta, since in contrast to carbaprostacyclin (cPGI), valproic acid showed not to be able to induce complex formation of PPAR-delta-retinoid X receptor (RXR) heterodimers on DNA. In conclusion, in contrast to PPAR-alpha and PPAR-gamma, PPAR-delta shows to be a specific sensor for teratogenic valproic acid-derivatives.

Publication types

  • Comparative Study

MeSH terms

  • Alkaline Phosphatase / analysis
  • Animals
  • Anticonvulsants / pharmacology*
  • CHO Cells
  • Cricetinae
  • Ligands
  • Luciferases / genetics
  • Mice
  • Molecular Structure
  • Protein Binding
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / drug effects*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Retinoic Acid / metabolism
  • Retinoid X Receptors
  • Structure-Activity Relationship
  • Teratogens / pharmacology
  • Transcription Factors / chemistry
  • Transcription Factors / drug effects*
  • Transcription Factors / metabolism
  • Transfection
  • Valproic Acid / analogs & derivatives
  • Valproic Acid / pharmacology*
  • Valproic Acid / toxicity


  • Anticonvulsants
  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Teratogens
  • Transcription Factors
  • Valproic Acid
  • Luciferases
  • Alkaline Phosphatase