Abstract
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 α, γ or δ was investigated. PPAR-α and PPAR-γ 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-δ in different cellular systems. However, valproic acid appears not to be a direct ligand of PPAR-δ, since in contrast to carbaprostacyclin (cPGI), valproic acid showed not to be able to induce complex formation of PPAR-δ–retinoid X receptor (RXR) heterodimers on DNA. In conclusion, in contrast to PPAR-α and PPAR-γ, PPAR-δ shows to be a specific sensor for teratogenic valproic acid-derivatives.
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